NHMRC Research Achievements - SUMMARY
FUNDED RESEARCH INTO INJURY RELATED RESEARCH
ENDING 2000 TO 2012
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Australian National University
Brain Research Institute
Centenary Institute of Cancer Medicine and Cell
Biology
Centre for Eye Research Australia Ltd
Curtin University of Technology
Flinders University
Garvan Institute of Medical Research
Griffith University
Howard Florey Institute
Injury Prevention and Control (Australia) Ltd
Institute of Medical and Veterinary Science
La Trobe University
Macquarie University
Mater Medical Research Institute, Brisbane
Melbourne Health
Menzies Research Institute
Menzies School of Health Research
Monash University
Murdoch Childrens Research Institute
Murdoch University
National Stroke Foundation
Prince Henry's Institute of Medical Research
Queensland University of Technology
Repatriation General Hospital, Daw Park
RMIT University
Royal Prince Alfred Hospital
Sir Charles Gairdner Hospital
University of Adelaide
University of Ballarat
University of Melbourne
University of New South Wales
University of Newcastle
University of Queensland
University of South Australia
University of Sydney
University of Tasmania
University of Technology Sydney
University of Western Australia
University of Western Sydney
University of Wollongong
Victor Chang Cardiac Research Institute
Victoria University
NHMRC Research Achievements - SUMMARY
Grant ID: 471418
CIA Name: Prof Angela Dulhunty
Main RFCD: Peripheral Nervous System
Admin Inst: Australian National University
Start Year: 2008
End Year: 2011
Total funding: $603,100
Grant Type: NHMRC Project Grants
Title of research award: Communication between calcium ion channels in skeletal muscle excitationcontraction coupling
Lay Description (from application):
Ageing, injury, drugs or genetic defects cause muscle weakness, prevent exercise, compromise life style and
contribute to poor health and osteoporosis. In order to move signals travel from our brain to muscles, where one
calcium ion channel detects the signal and tells a second calcium channel to open and release calcium ions to
initiate contraction. The project will pave the way for developing drugs to help with muscle disorders by trageting
the site of interaction between the channels.
Research achievements (from final report):
Work supported by this grant enabled us to perform the first study of the second of three SPRY domains in the
skeletal muscle ryanodine receptor (RyR1). In this comprehensive work we used NMR, CD to examine the
structure the recombinant DHPR II-III loop bound to the SPRY2 domain of RyR1 and cryoelectron microscopy to
locate the domain in the RyR protein (Cui et al., 2009; Tae et al., 2009; Tae et al., 2011; Perálvarez-Marín et al.,
2011). We quantified DHPR alpha1s II-III loop, and the variably spliced AS1 region of RyR1, binding to SPRY2.
Mutation of specific acidic residues in SPRY2 or basic residues in the II-III loop or in the ASI region, prevent the
ASI/SPRY2 binding (Tae et al., 2009). A cyclised II-III loop was expressed using novel intein technology and is a
stronger activator of RyR1 that the linear version of the loop (Tae et al. 2011b). In an elite international
collaboration we show that mutation of the critical regions in the SPRY2 domain do not influence EC coupling
(Tae et al., 2011a), indicating unexpectedly, that there is a specific influence of the DHPR complex on interactions
of the SPRY2 domain, possibly involving the intracellular β1a subunit of the DHPR. The grant further supported
preliminary paradigm shifting work with the DHPR β1a subunit, and a peptide corresponding to its C-tail, both of
which bind to and activate RyR1 with pM affinity, supporting a role for β1a in excitation-contraction coupling
(Karunasekera et al., 2009; Rebbeck et al., 2011).
Expected future outcomes:
We have identified the SPRY2 domain as a potential therapeutic target for modulating calcium release through
RyR1, and thus skeletal muscle contraction. The β1a work provided background for current studies of β1a
interactions with RyR1 and the alpha1S II-III loop and mechanisms that allow β1a to contribute to EC coupling
Name of contact: Angela Dulhunty
Email of contact: angela.dulhunty@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157307
CIA Name: A/Pr Paul McCrory
Main RFCD: Sports Medicine
Admin Inst: Brain Research Institute
Start Year: 2001
End Year: 2004
Total funding: $130,807
Grant Type: Early Career Fellowships (Australia)
Title of research award: Prospective validation of an ass. and outcome scale for mild traumatic brain injury & to
det. the influence of ApoE sus
Lay Description (from application):
Not Available
Research achievements (from final report):
Mild traumatic brain injury has the potential to cause significant morbidity due to its effects on cognitive and
psychological function. The condition also has significant social costs in terms of work absenteeism,
hospital/medical costs and possible impairment in school performance in younger people. This study developed an
assessment scale which may have widespread application in emergency departments, general medical practice,
and sports medicine as well as in rehabilitation settings. This scale has now been incorporated into international
guidelines for the management of sports concussion. In addition, the characterization of specific sequelae of head
injury such as concussive convulsions and second impact syndrome has enabled clinicians to manage these
conditions using an evidence-based approach.
Expected future outcomes:
The work will have two broad outcomes. Firstly, the adoption internationally of evidence-based management
guidelines and second, the ongoing development of computerised cognitive screening strategies which will
simplify the neurocognitive assessment of head injured patients of all ages.
Name of contact: Paul Mccrory
Email of contact: paulmccr@bigpond.net.au
NHMRC Research Achievements - SUMMARY
Grant ID: 183770
Start Year: 2002
CIA Name: Dr Nicholas Shackel
End Year: 2005
Main RFCD: Gastroenterology and Hepatology
Total funding: $233,168
Admin Inst: Centenary Institute of Cancer Medicine and Cell Biology
Grant Type: Early Career Fellowships
(Overseas)
Title of research award: Differential gene expression in hepatic wound healing.
Lay Description (from application):
Not Available
Research achievements (from final report):
The C.J. Martin was an invaluable opportunity enabling me to be trained in a number of important laboratory
techniques not commonly performed within Australia. This included the isolation of primary cells from liver
tissue, the use of therpaeutic stem cells and viral transduction. Additonal outcomes of the C.J. Martin included the
establishment of long-term collaborations within the USA and especially at Duke University and to-date the
publication of three peer-reviewed mansucripts.
Expected future outcomes:
The ongoing long-term collobartion with researchers at Duke University and a further three published manuscripts
are in preperation.
Name of contact: Dr Nicholas Shackel
Email of contact: n.shackel@centenary.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 529918
CIA Name: Prof Jonathan Crowston
Main RFCD: Surgery
Admin Inst: Centre for Eye Research Australia Ltd
Start Year: 2009
End Year: 2011
Total funding: $280,400
Grant Type: NHMRC Project Grants
Title of research award: The impact of fluid mechanics on wound healing after glaucoma surgery- an
engineering-based approach
Lay Description (from application):
Excess scarring after glaucoma surgery is the major reason why surgery fails.This study will investigate how
biomechanical forces in the eye influence wound healing and provide a new approach to regulating scar
formation. This will provide key information for developing surgical techniques that improve outcome and
prevent vision loss. The annual cost to Australia from vision loss due to glaucoma will double to $4.3 billion by
2025 unless better treatments are developed (Access Economics).
Research achievements (from final report):
Glaucoma is the second leading cause of blindness worldwide and effects 1 in 10 Australians over the age of 80.
Successful glaucoma filtration surgery is the most effective treatment for lowering intraocular pressure (IOP) and
preventing vision loss in glaucoma. The success of filtration surgery is dependent on interrupting the wound
healing response, where scar formation frequently leads to surgical failure. We wished to use experimental
measurements and computational modelling to determine the optimal physical conditions to reduce post-operative
scarring.
We created a biomechanical model of the eye after glaucoma surgery, in terms of tissue properties and fluid
drainage. This model was informed by experimental data and clinical observations, and describes what is
happening to a healing eye. We have used this model to predict the impact of hydrostatic forces at the wound site
and determine some ideal parameters for a drainage operation. This knowledge has enabled us to begin developing
and testing new glaucoma drainage devices.
Additionally we developed a new method for assessing how drainage operations function in the rabbit, which may
improve the clinical relevance of future work using animal models of glaucoma surgery. The new method
provides a way to directly measure how the surgically-created filtration pathway is working, isolated from the
confounding effects of fluid dynamics elsewhere in the eye.
We also found that a monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF) displayed
antifibrotic effects in cell culture and rabbit models, potentially leading to another target for modulation of wound
healing after glaucoma surgery.
Expected future outcomes:
It is anticipated that the ideal physical parameters identified using this study's experimental and computational
models will lead to the development of new drainage devices and surgical techniques for glaucoma surgery. In
conjunction to existing anti-scarring treatments this could increase the long term success of filtration operations.
Name of contact: Professor Jonathan Crowston
Email of contact: crowston@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 533526
Start Year: 2009
CIA Name: Prof Leon Straker
End Year: 2012
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $538,136
Admin Inst: Curtin University of Technology
Grant Type: NHMRC Project Grants
Title of research award: RCT of the impact of electronic game use by children on physical activity and energy
expenditure
Lay Description (from application):
Increasing childhood obesity and reduced physical activity are major health issues in Australia. Three quarters of
Australian children play electronic games and this is widely thought to reduce their physical activity. Whilst the
effect of TV viewing is well understood, the impact of electronic games is not. This study will test whether access
to electronic games results in decreased physical activity in children. We need to understand the impact this
popular activity is having on child health.
Research achievements (from final report):
Data successfully collected from 87 families enabling testing for the first time the relative benefit of banning or
replacing sedentary electronic games.
Expected future outcomes:
Advice for health practitioners, educators and parents on whether banning electronic games or replacing sedentary
electronic games with active electronic games results in better activity outcomes.
Advice to gaming industry on desirable features of electronic games
Name of contact: Leon Straker
Email of contact: L.Straker@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350992
CIA Name: A/Pr Tony Butler
Main RFCD: Epidemiology
Admin Inst: Curtin University of Technology
Start Year: 2005
End Year: 2009
Total funding: $453,500
Grant Type: Career Development Fellowships
Title of research award: Improving and monitoring the health of prisoners in Australia
Lay Description (from application):
Not Available
Research achievements (from final report):
This award enabled me to pursue a broad range of research activities in regard to offender health leading to a
range of positive outcomes for this population. For example, Australia is now the only jurisdiction to collect
national health indicators for prisoners' health and the only jurisdiction worldwide to have implemented ongoing
national surveillance of bloodborne viruses and sexually transmitted infections. Work on establishing both these
project were possible due to the CDA. Other project have been pursued in other areas including mental health,
violence and tobacco smoking.
Expected future outcomes:
As a result of the CDA and the body of work attached to it, I was awarded a Future Fellowship in 2009 to continue
my work. The next evolution for this area is to establish a national offender health research centre.
Name of contact: Tony Butler
Email of contact: tbutler@nchecr.unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 373638
CIA Name: Dr Anne Smith
Main RFCD: Applied Statistics
Admin Inst: Curtin University of Technology
Start Year: 2006
End Year: 2009
Total funding: $138,375
Grant Type: Early Career Fellowships (Australia)
Title of research award: Characterisation of subgroups of adolescent low back pain & preventable determinants:
advanced statistical approaches...
Lay Description (from application):
Not Available
Research achievements (from final report):
This fellowship funded analysis of data about spinal pain in adolescents at 14 and 17 years in the Raine pregnancy
cohort study. The experience of spinal pain was found to be already common at 14 years, and to have significant
impact on a subgroup of adolescents by 17 years. The association of point and/or trajectory measures of a wide
range of physical, lifestyle and psychosocial risk factors with spinal pain and impact were established. Subgroups
of adolescence with spinal pain were identified for which preventation and management could be targetted. The
results suggest early and targetted prevention and management of spinal pain and disability is relevant and
achievable. Grant applications have been submitted to follow this cohort into adulthood.
This fellowship also funded other projects identifying early and modifiable risk factors for pain and disability in
young athletes, musicians and nurses.
Expected future outcomes:
Several opportunities for early intervention in childhood and adolescence to reduce the burden of chronic spinal
pain have been identified by this research, and we will apply for funding to assess the efficacy of targetted
interventions.
Name of contact: Anne Smith
Email of contact: Anne.Smith@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 323200
CIA Name: Prof Leon Straker
Main RFCD: Clinical Sciences not elsewhere classified
Admin Inst: Curtin University of Technology
Start Year: 2005
End Year: 2008
Total funding: $682,800
Grant Type: NHMRC Project Grants
Title of research award: Physical, lifestyle and psychosocial determinants of spinal pain development in
adolescents
Lay Description (from application):
This project aims to understand the development of back and neck pain in adolescence. By the age of 16 around
half of all adolescents have suffered back pain and one third have suffered neck pain. For many adolescents this
pain is disabling and over a third of sufferers miss school, miss recreation and seek medical help. The current
understanding of back and neck pain in adolescence is quite limited - restricting the effectiveness of initiatives to
prevent adolescents having to suffer spinal pain and of treatment of those adolescents unlucky enough to have an
episode. Better understanding and interventions for adolescent spinal pain will also have longer term implications
by reducing adult spinal pain. Four out of 5 adults will experience spinal pain. In the USA treating adult back pain
is the 4th largest health care cost. Many adults with chronic back pain had their first episode during adolescence.
A better understanding of spinal pain in adolescence may help prevent it developing into a lifelong disability. We
will collect information from 2,000 adolescents on their experience of back and neck pain and on potential
physical, lifestyle and psychosocial risk factors. We believe factors such as their posture, muscle capacity, TV and
computer use, mental health and social situation all combine to influence whether a person develops back or neck
pain. The project is unique as it will not only collect a broad range of information during adolescence, but will
also make use of a large database of health, developmental and psychosocial information already collected from
these children since birth.With a better understanding of the development of spinal pain we will be able to develop
guidelines to help prevent these problems. We will also be able to develop better treatment plans for sub-groups of
adolescents with a particular combination of risk factors. Together these initiatives will assist in understanding and
breaking the pathway to chronic spinal pain.
Research achievements (from final report):
This project funded the collection and partial analysis of information about back and neck pain in adolescents at
14 and 17 years in the Raine pregnancy cohort study. Spinal pain was found to be already common at 14 years of
age and to already be associated with disability at 17 years of age. Information on a wide range of physical,
lifestyle and psychosocial risk factors was also collected. Posture, fitness, obesity, motor competence, physical
activity, computer use, school bag carriage, diet, smoking and alcohol use, depression, externalising behaviours,
self worth, parental pain experience, socioeconomic status, family functioning and life stress events were all
related to spinal pain. Subgroups of individuals with spinal pain were also identified suggesting interventions
could be targetted. The findings refuted a common misperception that adolescent spinal pain is trivial. They also
suggested windows for interventions to reduce spinal pain risk (early life and adolescence) and arrest a trajectory
to chronic, disabling adult spinal pain. Grant applications have been submitted to follow this cohort into early
adulthood.
Expected future outcomes:
The publiction of the results of this project will correct a misperception about the importance of adolescent spinal
pain. We have identified several opportunities to reduce risks and will apply for funding to assess the efficacy of
targetting specific interventions.
Name of contact: Professor Leon Straker
Email of contact: L.Straker@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 533504
CIA Name: Prof Tony Butler
Main RFCD: Preventive Medicine
Admin Inst: Curtin University of Technology
Start Year: 2009
End Year: 2012
Total funding: $275,401
Grant Type: NHMRC Project Grants
Title of research award: Does Traumatic Brain Injury lead to offending behaviour?
Lay Description (from application):
Rates of reported traumatic brain injury (TBI) in offender and prisoner populations are extremely high (~80%). It
has been suggested that TBI may be responsible for half the crimes leading to incarceration. Criminal behaviour is
complex and the role of TBI in this conundrum is unclear. Our study will examine this question using datalinkage. Should we find a link between TBI and subsequent offending, this opens up the possibility of developing
interventions aimed at preventing this trajectory.
Research achievements (from final report):
This study has demonstrated that the link between exposure to traumatic brain injury and subsequent offending
behaviour is not a simple exposure and outcome relationship as many have assumed. What we demonstrated
through the careful selection of community and sibling controls is that while exposure to traumatic brain injury is
indeed associated with an increased risk of offending behaviours, when we examined sibling controls this
relationship does bear out. Thus, in logistic regression models adjusted for treatment for drug or alcohol abuse,
psychiatric illness, Aboriginality, and socioeconomic disadvantage, TBI was associated with increased offending
in both males (OR =1.7, 95% CI 1.5-1.9) and females (OR=1.5, 95% CI 1.2-1.9) compared with the unexposed
community group. However, when compared with unexposed siblings, no association between TBI and offending
was apparent in either sex (males OR = 1.1, 95% CI 0.9-1.3; and females OR = 0.9, 95% CI 0.6-1.2).
The results of this study do not support the hypothesis that TBI significantly increases the risk of subsequent
offending. The lack of an association between TBI and offending when siblings served as a comparison group
suggests that the risks both of offending and TBI may be influenced by common genetic, familial and
developmental factors.
Expected future outcomes:
We anticipate that future research will focus on the risk of offending in those exposed to traumatic brain injury but
will not view this in a simplistic cause and effect relationship.
Name of contact: Tony Butler
Email of contact: tbutler@kirby.unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 533502
Start Year: 2009
CIA Name: Prof James Semmens
End Year: 2011
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $404,579
Admin Inst: Curtin University of Technology
Grant Type: NHMRC Project Grants
Title of research award: The epidemiology, healthcare utilisation, treatment pathways and patient outcomes for
burn injuries in Western Australia
Lay Description (from application):
The aims of this research proposal are to investigate the patterns of burn injury, health service utilisation,
economic costs, treatment pathways, and outcomes for all patients hospitalized with burn injury in Western
Australia for the period 1999-2008. An important focus will also be on the developing preventative injury
education strategies. The proposal outlines a new collaborative initiative between the Burn Service of WA and the
WA Centre for Population Health Research at Curtin University.
Research achievements (from final report):
This study involved collaboration between burns specialists, epidemiologists, health economists and health
researchers to provide a unique clinical research program to support burns research. The project assessed the
clinical epidemiology, health service utilisation, economic costs, treatment pathways and outcomes for all patients
hospitalised with burn injury in WA for the period 1980-2008. The project contributed : 1) estimated the crude
and relative annual hospital admission and mortality rates for burn injury in Western Australia 1980-2008; 2)
evaluated the health utilisation patterns for burn patients during the index burn admission; 3) measured the crude
and relative longitudinal patterns of health care events and health outcomes encountered by patients during the
long-term management of their burn injury; 4) estimated the economic cost of the intensive resource utilisation
associated with acute and long term burn injury management; 5) disseminated outcomes to inform prevention
programs, treatment pathways, disaster response and education all have direct community impact.
The project examined trends in burns injury and important outcomes resulting from burns for obsteric outcomes,
cancer outcomes, rural versus remote injuries and age related injuries. The project produced 8 scientific papers
and 10 conference presentations.
Expected future outcomes:
The project has led to the establishment of the WA Burns Research Centre, based at the Unversity of Western
Australia and led by Professor fiona Wood. The research project has also provided the opportunity for
international comparison in Scotland ( the Scottish Information Services Division), Oxfor University (through the
Oxford Record Linkiage Unit, and the Swansea Data Linkage Unit (Wales, UK).
Name of contact: Professor Fiona Wood
Email of contact: Fiona Wood <fw@mccomb.org.au>
NHMRC Research Achievements - SUMMARY
Grant ID: 229011
Start Year: 2003
CIA Name: Prof Leon Straker
End Year: 2005
Main RFCD: Environmental and Occupational Health and Safety
Total funding: $207,353
Admin Inst: Curtin University of Technology
Grant Type: NHMRC Project Grants
Title of research award: Biomechanical and physiological responses of children and young adults to different
computer workstations
Lay Description (from application):
Computer use is increasing with 95% of Australian primary school children now using computers. Two out of
three children and three out of four adult workers report pain associated with computer use. This has lead to
concerns that increased computer use may be responsible for an increase in musculoskeletal disorders in young
people. Little is known about the physical consequences of children's use of computers. The information we have
on adult use is now out of date because of changes to computer technology and how computers are used. It is
therefore not possible to provide evidence-based recommendations for safe use of computers by young people.
Critical gaps in our knowledge include the appropriate desk design and computer display position. The proposed
studies will use recent advances in biomechanical and physiological measurement and modelling of
musculoskeletal stress to evaluate a range of desk designs and computer display positions for young adults,
preadolescentchilden and early school age children. The outcomes will include the first detailed description of the
physical stresses of computer use by children and preliminary guidelines for workstation design.
Research achievements (from final report):
Computer use by young Australians is becoming ubiquitous. This project provided the first detailed description of
the physical impact of workstation design features when young children (5-6years), pre-adolescents (10-12years)
and young adults (18-25years) worked with computers and with paper based technology. The project pioneered
the use of new measures of stress on the neck and shoulder which accounted for the variation in posture and
muscle activity. Variation is thought to be important for preventing the development of pain. The project was the
first to describe the posture of computer users in three dimensions. The project also pioneered the use of complex
biomechanical models to investigate the stress on muscles deep in the neck which are difficult to access for direct
measurement. Providing forearm support during computer work was found to decrease the stress on the neck and
shoulders. Positioning a computer display very high or very low was found to increase the stress on parts of the
neck and shoulders. Using tablet computers was found to be similar to working with books and paper. The use of
new measures of physical stress provided new insights into why neck pain is so common in computer users. The
knowledge gained from this project is the most comprehensive available and will guide the development of
evidence based guidelines for wise use of computers by young people.
Expected future outcomes:
We are expecting our research to be the benchmark for future research into the physical impact of computer use
by children. We are also expecting the guidelines we develop based on this project to be widely used by education
authorities and parents worldwide.
Name of contact: Professor Leon Straker
Email of contact: L.Straker@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 425550
Start Year: 2007
CIA Name: Dr Andrew Briggs
End Year: 2013
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $198,533
Admin Inst: Curtin University of Technology
Grant Type: Early Career Fellowships (Australia)
Title of research award: Understanding thoracic spine pain in adolescence and adulthood
Lay Description (from application):
Not Available
Research achievements (from final report):
This funding provided the Fellow with the opportunity to undertake novel and innovate clinical and policy-driven
research into musculoskeletal health in Australia. Broadly, five areas of work were covered over the funding
period, including:
o
Epidemiologic research into spinal pain, particularly mid-back pain, in children, adolescents and working
adults. Through systematic reviews, important data were collated and synthesised to describe the impact of this
spinal pain condition. These data complement other data in emphasising the significance of spinal pain conditions.
o
Clinical research examining the negative effects of low back pain on skeletal health, particularly bone
mineral density in the low back. Preliminary data were acquired to demonstrate the association between low back
pain and reduced low bone mineral density.
o
Clinical research examining musculoskeletal health within families in WA. A novel familial study was
undertaken to examine the familial links in musculoskeletal health, such as posture, low back pain, beliefs and
muscle strength. The same family cohort was used to examine health literacy among adults in WA.
o
Continued development and feasibility testing of a novel method to measure bone mineral density (BMD)
in the lumbar spine. While standard techniques for measuring BMD rely on estimating average BMD within a
vertebral body, our novel method enables the user to measure BMD within vertebral subregions. Emerging data
suggest the method is better able to identify individuals with and without osteoporotic fractures. Ultimately, the
method may be used in clinical practice to better identify individuals at risk of vertebral fracture.
o
Partnership-driven research between policy, clinical and academic domains to evaluate the implementation
of the Western Australian Models of Care for musculoskeletal health.
Expected future outcomes:
Future outcomes fall within two categories:
o
Innovation: further development and application of novel methods to measure bone mineral density in
clinical setting to better identify individuals at risk of fracture.
o
Expansion of partnership-driven research between policy makers, clinicians, and academics in the
implementation of health policy.
Name of contact: Dr Andrew Briggs
Email of contact: A.Briggs@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 229980
CIA Name: Prof Trevor Hearn
Main RFCD: Not Allocated
Admin Inst: Flinders University
Start Year: 2003
End Year: 2006
Total funding: $470,000
Grant Type: NHMRC Development Grants
Title of research award: Effects of pin biomechanics, coating material and surface roughness on the pin-bone
interface in external repair
Lay Description (from application):
Some fractures require external fixation, anchored with metal pins in the bone fragments. The reatment is
generally successful, although the pin tracts often loosen and become infected. This complication may jeopardise
fracture healing and must be treated. The purpose of this project is to determine what aspects of pin design
predispose to these problems at the pin-bone interface. Is it the way the pins are initially inserted, perhaps not
tightly enough so that the pin is unstable, or perhaps too tight, causing microcracks in the bone? Is it the material
of the pin, which might be improved with a bioactive coating? Is it the surface roughness which causes different
responses of bone cells? Would it help to have an antibiotic pin? This proposal is designed to answer these
questions. The biomechanics of the pin will first be studied with computer models and then tested in the
laboratory. The loosening and infection associated with different types of pin will then be studied biologically.
The results of the study will clarify the roles of pin biomechanics, coating and surface roughness, leading to
improvements in design and better outcomes in fracture patients.
Research achievements (from final report):
This project has established the foundations for a new device for the fixation of common fractures of the wrist.
Curently used fixation pins have had a high rate of infection and loosening, with instability of the pin-bone
interface as the primary precursor. The new design will optimize the stability of this interface over the time course
of fracture repair.
Expected future outcomes:
Increasing the stability of this interface will reduce infection rates and decrease need for further medical care.
Name of contact: Prof Trevor C Hearn
Email of contact: tnahearn@ozemail.com.au
NHMRC Research Achievements - SUMMARY
Grant ID: 426750
CIA Name: Prof Ian Gibbins
Main RFCD: Sensory Systems
Admin Inst: Flinders University
Start Year: 2007
End Year: 2009
Total funding: $499,860
Grant Type: NHMRC Project Grants
Title of research award: Synaptic environment of nociceptive inputs to the spinal cord
Lay Description (from application):
Pain affects everyone at some stage in their life. Usually, the pain subsides by itself as the underlying cause is
resolved. Thus, the damaged tissue heals or we move away from a potentially injurious stimulus and we become
free of pain. However, pain can persist for two main reasons: the underlying cause cannot be treated adequately
and the painful stimulus continues; or the pain is maintained long after the primary stimulus has resolved. This
ongoing pain often is resistant to alleviation by common analgesics. Therefore, a major aim of the pharmaceutical
industry is the development of new drugs to target persistent pain. This requires a thorough understanding of how
the nerves that detect painful stimuli transmit that information into the spinal cord, and then on to the brain, where
we construct a conscious perception of the pain. Various kinds of painful stimuli, such as tissue damage, noxious
chemicals, or extreme temperatures, are detected by different types of nerves. Each nerve type can be identified by
its characteristic chemical profile. Recently, we found that some of these nerves probably do not transmit their
messages to the spinal cord in the way everyone had thought. This means that there must be an alternative way for
many types of painful stimuli to be transmitted into the spinal cord. In this project, we will use a sophisticated
suite of modern microscopic and electrical recording techniques to find out what this alternative mechanism is.
Our central idea is that most types of painful stimuli simultaneously activate two types of sensory nerves. These
nerves then connect with specific nerve cells in the spinal cord before painful information is relayed to the brain.
Our proposal suggests a new mechanism for understanding how pain can develop from being an acute defensive
reaction to a chronic problem. In turn, this should lead to improved strategies for developing and testing new
analgesic drugs.
Research achievements (from final report):
During this project we identified and mapped a significant population of sensory nerves that previously have been
overlooked by other investigators. These nerves probably are responsible for a subset of painful sensations coming
from the skin and other areas of the body. One charactersitic of these nerves is that they use a different
combination of chemical neurotransmitters compared with other types of nerves that transmit painful stimuli.
Expected future outcomes:
Better understanding of mechanisms leading to chronic pain syndromes or intermittant pain that cannot be treated
by conventional analgesics.
Name of contact: Ian Gibbins
Email of contact: ian.gibbins@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 160062
CIA Name: Prof Jegan Krishnan
Main RFCD: Orthopaedics
Admin Inst: Flinders University
Start Year: 2001
End Year: 2003
Total funding: $188,450
Grant Type: NHMRC Project Grants
Title of research award: The design, development and clinical assessment of a new metacarpophalangeal joint
prosthesis
Lay Description (from application):
Rheumatoid arthritis is a crippling form of arthritis that affects many people in the community. It commonly
involves the finger joints in the hands resulting in deformity, pain and subsequent loss of function. There have
been implants designed for finger joint replacement, but unfortunately these implants have had only moderate
benefits and can break and lead to further joint destruction resulting in the worsening of deformity and pain. A
new implant for finger joint replacement has been developed. This implant has several potential advantages.
Firstly the unique design acts to prevent recurring deformity in the fingers with rheumatoid disease while allowing
functional motion. Secondly, it is thought that patients will return to function earlier and avoid the need for further
finger surgery as this implant design relies less on the tissues around it for stability. The purpose of this study is
to investigate the biomechanical and clinical benefits of this new implant for finger joint replacement. The new
design will undergo specific laboratory tests and be used in a clinical trial to quantify the therapeutic benefits it
provides to patients with rheumatoid arthritis.
Research achievements (from final report):
The reseach in the project assessed a newly developed implant for knuckle joint replacement. This joint was tested
biomechanically and manufacturing processes and the materials used to make the implant were refined
accordingly. Subsequent implant of this new joint into a person with rheumatoid arthritis showed that the joint was
effective in restoring function to the hand. One very important observation from this research was that the tools
available to assess hand function were limited, particularly for people with rheumatoid arthritis before and after
joint-replacement surgery. Therefore, considerable effort was made to improve and standardise the available tools
and to develop new and more appropriate tools and measurement devices.
Expected future outcomes:
Commercial development of the newly developed prosthesis is continuing with an Orthopaedic prosthesis
manufacturer.
The development and assessment of hand-function testing tools and devices is also expected to lead to new
instruments more appropriate to the rheumatoid hand.
Name of contact: Professor Jegan Krishnan
Email of contact: jegan.krishnan@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 160052
CIA Name: A/Pr Xin-Fu Zhou
Main RFCD: Cellular Nervous System
Admin Inst: Flinders University
Start Year: 2001
End Year: 2005
Total funding: $461,443
Grant Type: NHMRC Project Grants
Title of research award: Roles of brain-derived neurotrophic factor in plasticity of injured sensory neurons
Lay Description (from application):
The fundamental problem of how nerve cells respond to a nerve injury has long been studied by neuroscientists
and clinicians. After a nerve injury outside the brain or spinal cord, ie, in the periphery, some sensory nerve cells
die, some regenerate to reconnect to their targets, and some sprout to make abnormal connections. Recent
evidence from our lab and others indicates that the nerve sprouting is linked to chronic pain experienced by nerveinjury patients. However, how these changes occur still remains largely unknown. Our recent studies showed that
growth factors, particularly brain-derived neurotrophic factor (BDNF) which is made by the sensory nerve cells,
may play important roles in mediating these changes. This proposed project, directly evolved from our recent
exciting findings, aims to further examine roles and action mechanisms of BDNF and its relatives in regulating the
responses of sensory nerve cells to a nerve injury. We propose that after an injury, BDNF promotes survival of
some nerve cells, enhances sensory nerve regeneration in both periphery and spinal cord, and also mediates
abnormal nerve sprouting and is involved in neuropathic pain. With strong expertise and powerful tools in hand,
we have designed a series of experiments to investigate the roles and action mechanisms of BDNF and its related
molecules in these processes. Results from this project will help us understand mechanisms underlying the
responses of nerve cells to a nerve injury, and should provide much needed information which would help in
designing new methods for enhancing nerve cell survival and nerve regeneration as well as for inhibiting nerve
injury-induced chronic pain in nerve-injury patients.
Research achievements (from final report):
This project grant enable us to investigate the functional roles of brain derived neurotrophic factor and nerve
growth factor in the development of neuropathic pain, in the regeneration of injured spinal cord and nerve cell
death after nerve injury. We found that after nerve injury neuropathic pain is partially caused increased production
of neurotrophic factors. Suppression of these factors with specific antibodies can alleviate the pain. We found that
the neuropathic pain is caused by inflammation but not direct damage to sensory nerves. We also found that
increased production of neurotrophic factors plays a critical role in the regeneration of injured cord. These factors
can either protect nerve from death or enhance the death depending the microenvironment and expression levels of
their receptor p75.
Expected future outcomes:
Based on our findings, we can develop therapeutics for the treatment of neuropathic pain by using antagonizing
drugs to nerve growth factor or brain derived neurotrophic factor. We may also increase the production of BDNF
by the peripheral nerves or tissues to enhance the regeneration of the spinal cord.
Name of contact: Xin-Fu Zhou
Email of contact: xin-fu.zhou@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375109
CIA Name: A/Pr Xin-Fu Zhou
Main RFCD: Central Nervous System
Admin Inst: Flinders University
Start Year: 2006
End Year: 2008
Total funding: $472,771
Grant Type: NHMRC Project Grants
Title of research award: Roles of peripherally derived BDNF in regeneration of spinal cord and the mechanisms
Lay Description (from application):
Injury to the brain and spinal cord often leads to permanent disability due to lack of regeneration. The mechanism
why central nerve does not regenerate is not known. Neurotrophic factors are powerful molecules which can
overcome effects of inhibitory factors on regeneration. This project aims to investigate how neurotrophic factors
override the effects of inhibitory factors and how to improve the regeneration by increasing the production of
neurotrophic factors within nerves. Successful completion of this project will help understanding the mechanism
of how neurotrophic factors work on regeneration and developing the effective way to improve regeneration of the
injured spinal cord.
Research achievements (from final report):
We found that peripheral nerve lesion induced down-regulation of p75NTR and upregulation in satellite glia but
spinal cord lesion caused upregulation of p75 in sensory neurons. We showed that 85% of regenerating Fast Blue
labelled neurons did not express p75NTR but were surrounded by p75NTR+ satellite glia.
We also investigated the relationship between BDNF expression in DRG and regenerating neurons after spinal
cord injury with a prior conditioning lesion of sciatic nerve. We found that majority of regenerating neurons were
positive for BDNF and for trkC. We found that injection of exogenous BDNF into the sciatic nerve or into the
footpad promoted the regeneration of ascending sensory neurons after spinal cord injury. This work suggests for
the first time that peripherally derived BDNF may promote the regeneration of the spinal cord.
Sciatic nerve lesion triggered upregulation of BDNF in the injured spinal cord and in other systemic tissues such
as the pituitary gland. The enhanced regeneration of corticospinal neurons was blocked by antibodies to BDNF,
suggesting the peripherally derived BDNF may play a role in the regeneration.
Expected future outcomes:
We now expect that with the support of a commercial company we can expore the use of BDNF by peripheral
injection to promote regeneration of the injured spinal cord and to carry a clinical trial for the application of
BDNF in patients.
Name of contact: Xin-Fu Zhou
Email of contact: zhou0010@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 426758
Start Year: 2007
CIA Name: Prof Maria Crotty
End Year: 2009
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $572,543
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Title of research award: Individual Nutrition Therapy and Exercise Regime: A Controlled Trial of Injured,
Vulnerable Elderly (INTERACTIVE trial).
Lay Description (from application):
Hip fractures are a common and growing problem for older Australians. Unfortunately recovery is incomplete in
most people. In this study two factors believed to be important for recovery will be investigated - exercise and
nutrition. After a hip fracture the ability to walk is severely compromised, as are appetite and dietary intake.
These factors are likely to contribute to the loss of muscle mass and strength frequently observed amongst this
patient group. There is considerable evidence to suggest that this loss has serious consequences in terms of ability
to return to pre-injury levels of function, restriction in independence and ultimately transfer into a hostel or
nursing home. Given these facts it makes sense that an exercise program incorporating strength and functional
activities, and a nutrition program aimed at achieving nutritional requirements, will improve ability to walk, but
there is no conclusive evidence that this is so. Only a small number of studies have tested whether an exercise
program improves recovery after a hip fracture and these have mostly commenced weeks or months after the
injury when it is likely that there has been irreversible decline in muscle mass and strength. In contrast, most of
the nutrition studies commence soon after the injury but provide protein and calories insufficient to meet
requirements, provide supplements that patients find difficult to drink or provide the supplements for only a short
duration. This study will use the best quality research methods to test whether providing a 6-month
individualised exercise and nutrition program to hip fracture patients soon after injury improves walking and
other important health outcomes. Patients will be followed for 12 months to determine what difference the
exercise and nutrition programs make. If they help then health services will have the evidence they need to
recommend this type of program to the growing number of older Australians that suffer a hip fracture.
Research achievements (from final report):
The INTERACTIVE trial recruited 175 patients following hip fracture for 12 months. Each received either a
combined nutriton and exercise program or the equivalent attention via social visits. 12 month data was collected
for the last participant late 2010 and since this time considerable effort has been devoted to ensuring the integrity
of the data for analysis by an experienced Biostatistician. There have been some manuscripts published in peerreview scientific journals since the trial commenced and currently there are four manuscripts in draft form. It is
anticipated that each of these will be submitted by the end of 2011. The trial has seen the completion of one
research higher degree student and two others are currently analysing data for the purpose of their thesis, including
a comprehenisive cost effectiveness evaluation of the trial. This is the first cost effectiveness evaluation of a
nutrition and exercise trial following hip fracture and it is expected that the findings will have significant policy
implications. The investigators have identified an additional 6 potential manuscripts which will be prioritised for
drafting in early 2012.
Expected future outcomes:
The results of the trial are expected to inform current practice for hip fracture rehabilitation, particularly in relation
to the effectiveness of exercise programs and the costs associated with delivering a home based service to
vulnerable older adults.
Name of contact: Professor Maria Crotty
Email of contact: maria.crotty@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375100
CIA Name: A/Pr Judith Morris
Main RFCD: Autonomic Nervous System
Admin Inst: Flinders University
Start Year: 2006
End Year: 2008
Total funding: $472,771
Grant Type: NHMRC Project Grants
Title of research award: Neural circuits producing pelvic vasodilation in females
Lay Description (from application):
The reproductive organs and genitalia in males and females experience a large increase in blood flow during
sexual and reproductive activity. This increased blood flow (vasodilation) is a key component of penile and
clitoral erection, and enhances secretion from the lining of the internal reproductive organs. Vasodilation during
sexual activity is produced by a special sets of nerves receiving signals from the genitalia and the brain. In fact,
Viagra works by enhancing and prolonging the actions of these nerves. An important part of this neural pathway is
a group of nerve cells in the spinal cord that connects the central nervous system with peripheral nerves in the
reproductive organs - these are called preganglionic neurons. Recently we discovered that a major pathway from
the spinal cord to the pelvic blood vessels in females leaves the spinal cord at a different level (lumbar) from that
thought previously (sacral level). Currently there is no information on how these lumbar preganglionic nerves in
females are connected to other nerve pathways that are active during sexual activity, and how they integrate
signals from both the internal organs and the brain. We will use an array of modern cellular techniques together
with direct observation of dilation in isolated uterine arteries to discover how these nerve cells are wired up in
circuits in the spinal cord. This information is vital for us to understand the factors producing increased blood flow
in normal sexual activity, and how these might be altered in inflammation or in conditions where there could be
selective damage to one nerve pathway and not the other, such as after pelvic surgery, spinal cord damage at
different levels, or stimulation of the spinal cord for treatment of chronic pain. Our study also will help understand
referred pain and sensations of discomfort in abdominal and pelvic organs.
Research achievements (from final report):
We studied the nerve pathways that are important for increasing blood flow to the female reproductive organs
during sexual activity and the early stages of pregnancy. Using newly developed animal models we showed that a
previously under-recognised nerve pathway leaving the lumbar spinal cord and descending to the reproductive
organs can be activated by artificial stimulation of nerves from the genital region. However, we found that this
new pathway is normally inhibited by other nerves within the spinal cord during genital stimulation. It is unclear
at the moment how much this new pathway contributes to increased blood flow during normal sexual activity
when other nerve pathways at sacral spinal levels are also activated. However, our results indicate that the lumbar
nerve pathway is likely to be very important under conditions where the sacral nerves are damaged after essential
surgery or low level spinal cord injury. This pathway is also likely to be involved in some sorts of pelvic pain, and
may help to explain sexual and reproductive dysfunction during chronic inflammatory conditions. As the lumbar
pathway has not been widely recognised in previous medical research and clinical practice, our results present a
shift in thinking about neural regulation of the reproductive organs in health and disease.
Expected future outcomes:
This study should stimulate new research directions and promote use of our animal models to complement data
from current research. Once the significance of our findings have been clarified in animal studies it is likely that
they will impact on surgical and medical practice addressing a range of women's health issues.
Name of contact: Prof Ian Gibbins
Email of contact: Ian.Gibbins@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 375123
CIA Name: Dr Vladimir Zagorodnyuk
Main RFCD: Nephrology and Urology
Admin Inst: Flinders University
Start Year: 2006
End Year: 2008
Total funding: $408,862
Grant Type: NHMRC Project Grants
Title of research award: Sensory mechanisms in normal bladder and in cystitis
Lay Description (from application):
The function of the lower urinary tract is to store urine and release it at appropriate times. This requires neural
circuits in the brain, spinal cord and peripheral ganglia. When the bladder fills, sensory neurones fire and activate
these neural circuits to store urine or to empty the bladder. If sensory neurones are too easily excited (a process
called sensitisation ) this will lead to clinical disorders, including the common painful bladder syndromes, whose
cause is not known (interstitial cystitis, sensory urgency etc). These are characterised by pelvic pain, urinary
urgency, frequency and, in some cases, urge incontinence (loss of urine for no apparent reason) which results from
unstable or overactive bladder. Despite a large database of knowledge about the sensory innervation of the
bladder, many important gaps still exist. These gaps have restricted the development of new therapies. For
example, we have little idea about exactly which functional classes of sensory neurones signal filling of the
normal bladder or what different types of information they carry. This is vital information for understanding
which neurones are affected in disease states and whether they are all affected in the same way. We have
developed new methods that will allow us to identify the major classes of sensory neurones that innervate the
bladder, what they respond to and how they are activated. We will also determine whether some classes are
preferentially sensitised by inflammation and the most important mechanisms that are likely to underlie this. The
significance of this project is that it provides the basic scientific understanding of sensory innervation of the
bladder and will identify potential targets for selective pharmacological intervention in common bladder disorders.
Research achievements (from final report):
The major achievements of the project are the identification and characterization of five distinct classes of
extrinsic sensory neurones to the bladder which have different physiological and pathophysiological roles. These
include two stretch-sensitive afferents (muscle mechanoreceptors and muscle-mucosal mechanoreceptors), and
three stretch-insensitive afferents (mucosal high and low-responding mechanoreceptors and high threshold
vascular mechanoreceptors). Transduction by major classes of bladder afferents does not depend upon Ca2+sensitive exocytotic release of mediators, or endogenous release of ATP. Rather, benzamil-sensitive stretchactivated ion channels are present on their mechanosensitive endings and are involved in direct
mechanotransduction. Different classes of bladder afferents have distinct chemosensitivity to agonists and noxious
agents. It is likely that two classes of capsaicin-sensitive afferents, mucosal high-responding mechanoreceptors
and high threshold vascular mechanoreceptors, are potential nociceptors and targets for pharmacological
intervention in common bladder disorders. Discovery of TTX-resistant spontaneous release of acetylcholine from
autonomic cholinergic extrinsic and intrinsic nerves which affects bladder contractility is also important in
defining new strategies for the treatment of the overactive bladder syndrome.
Expected future outcomes:
This research is likely to lead to significant basic science advances in the field of autonomic neuroscience and will
be beneficial for developing new targets for parmacological treatment of common bladder disorders.
Name of contact: Vladimir Zagorodnyuk
Email of contact: vladimir.zagorodnyuk@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535080
CIA Name: Prof Ian Gibbins
Main RFCD: Sensory Systems
Admin Inst: Flinders University
Start Year: 2009
End Year: 2011
Total funding: $397,225
Grant Type: NHMRC Project Grants
Title of research award: Sensory neuronal pathways from the lower genital tract of females
Lay Description (from application):
Many women experience severe debilitating pain upon normally innocuous contact with their genitalia. The
causes of this pain are unknown. Therefore, this project will use a suite of sophisticated microscopic and electrical
recording techniques to identify the neural pathways that transmit sensation, including pain, from the female lower
genital tract. Our new data will help create a rational basis for understanding and treating the physical basis of
genital pain in women.
Research achievements (from final report):
We discovered an extraordinarily complex and dense innervation of the clitoris by large diameter endings that
must include low threshold mechanoceptors responding to gentle touch. Such endings are prominent in dermal
papilla of the clitoris but are rare elsewhere in vulval and perineal skin and are absent from hairy body skin. Each
large diameter ending is accompanied by at least one finer varicose sensory fibre containing calcitonin generelated peptide (CGRP), but not substance P (SP) that arise from dorsal root ganglion neurons with mid-sized cell
bodies typical of Adelta fibres. Neurons with this phenotype project both to the superficial dorsal horn and a well
defined region in the deep dorsal horn. These CGRP-containing neurons are most likely high threshold
mechanoceptors, and are the best candidates for mediating chronic genital pain.
We first used electrophysiological methods to define a novel ascending intraspinal pathway from pudendal nerve
sensory inputs to lumbar sympathetic outflows. We then used c-Fos labelling to identify neurons in the sacral
spinal cord activated by afferents from the lower genital tract. We found neurons in superficial and deep dorsal
horn that are activated by different degrees of mechanical stimulation of the clitoris and labia. Many c-Fos
labelled cells are associated with CGRP-containing sensory endings in the dorsal horn. Spinal sections have
provided evidence in support of our electrophysiological data that local inhibitory spinal circuits tonically
suppress reflex activation of spinal autonomic outputs.
Expected future outcomes:
We anticpate continuing to characterise the functional properties of sensory nerves innervating the female genital
tract including changs in their behaviour that may lead to pathological genital pain conditions.
Name of contact: Ian Gibbins
Email of contact: ian.gibbins@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 160091
CIA Name: A/Pr John Wakerman
Main RFCD: Not Allocated
Admin Inst: Flinders University
Start Year: 2001
End Year: 2005
Total funding: $215,299
Grant Type: SRDC - Research
Title of research award: Injury Prevention through Community Development Initiatives in Central Australia
Lay Description (from application):
Not Available
Research achievements (from final report):
The study has provided a detailed description and analysis of injury in Central Australia. Analysis of
hospitalisations and deaths due to injury show very high rates in the region, particularly in the Aboriginal
population. Land transport accidents were the most common cause of injury deaths for all residents of Central
Australia, accounting for 36% of all injury deaths. For Aboriginal residents, homicide and suicide followed with
similar rates, whereas for non-Aboriginal residents suicide was the second highest cause of injury death, followed
by falls. Assault and other interpersonal violence were by far the most common external cause of hospitalised
injury of Aboriginal residents of Central Australia, accounting for about 47% of episodes. Complications of care
and falls were other common categories of external causes of injury for Aboriginal residents. Falls and land
transport crashes were the most common external causes of hospitalised injury for other residents. There is a very
recent history of systematic racism and external injury to Aboriginal people in the region. This includes the Stolen
Generation and physical exclusion of Aboriginal people. Aboriginal perceptions of injury were much broader than
the standard public health definition of external injury. Aboriginal people also describe a linked concept of 'inside
injury' - a psychological or spiritual harm that can be caused by denial of culture or Aboriginal law, racism, failure
to acknowledge or support Aboriginal initiative, poor communication of health or criminal justice information,
sorcery, alcohol and other drugs. Tangentyere Council is at the forefront of injury prevention. Its Night Patrol and
Wardens Program were evaluated and found to be effective Aboriginal initiatives based on Aboriginal systems of
knowledge. They address both downstream factors (keeping people out of the criminal justice system) and
upstream factors (empowering both the organisation and individuals) in injury prevention.
Expected future outcomes:
A number of potential benefits arise from this study.Thy include improvements in communication from the health
and criminal justice systems; development of a regional public transport system to remote communities;
strengthening of the Tangentyere Night Patrol; further research into the economic benefits of the Night Patrol and
the concept of 'inside injury'; improvements in injury data collection.
Name of contact: John Wakerman
Email of contact: john.wakerman@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376028
CIA Name: Dr Paul Baldock
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2006
End Year: 2008
Total funding: $472,771
Grant Type: NHMRC Project Grants
Title of research award: Hypothalamic signalling in cortical and trabecular bone anabolic activity
Lay Description (from application):
Osteoporosis is a disease associated with an exponential rise in the number of fractures in the elderly. These
fractures are so common that around 1 in 3 women and 1in four men will be affected. They cause pain, disability
that can be permanent disability and are associated with premature death. Current treatments are able to
effectively increase bone strength in osteoporotic patients but can not return bone strength to normal. Some new
treatments can restore bone strength to some extent but these are limited by expense and safety concerns. We
have discovered a pathway in the brain that reduces bone formation and by blocking this pathway we can achieve
doubling of the amount of bone in key bone sites. This occurs due to a marked increase in the amount of new
bone formed. In fact, genetic manipulation of this pathway was able to double the speed at which bone is made by
the skeleton. Excitingly, these increases in bone were possible in adult mice, suggesting such changes could be
potential therapy for human patients. However, in order to be able to harness this pathway we must understand
what molecules within the brain are responsible for the signals that reach the bone. Our proposal aims to identify
the nerve signalling molecule(s) and the receptor for these signals within the brain that initiates the increase in
bone formation. This project ultimately aims to identify a target for new therapies that could cause this beneficial
effect by administration of a simple treatment, preferably by mouth in adult humans.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact: Dr Paul Baldock
Email of contact: p.baldock@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427632
CIA Name: Dr Paul Baldock
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2007
End Year: 2009
Total funding: $662,065
Grant Type: NHMRC Project Grants
Title of research award: Neuropeptide control of bone cell function
Lay Description (from application):
Osteoporosis is a disease associated with a progressive rise in the number of fractures in the elderly. These
fractures are so common that around 1 in 3 women and 1in 4 men will be affected. They cause pain, disability that
can be permanent and are associated with loss of independence even premature death. Current treatments are able
to partially restore bone strength in osteoporotic patients but can not return bone strength to normal. Some new
treatments can restore bone strength to some extent but these are limited by expense and safety concerns. We have
discovered a pathway in the brain that when blocked, results in a doubling of the amount of bone in key bone sites
and dramatic increases in bone strength. This occurs due to a marked increase in the amount of new bone formed.
In fact, genetic manipulation of this pathway was able to double the speed at which bone is made by the skeleton.
Excitingly, these increases in bone were possible in adult mice, suggesting such changes could be potential
therapy for human patients. We went on to test the effectiveness of this pathway in animal models of human
skeletal weakness and have shown that it is capable of remarkable benefits. However, in order to be able to
harness this pathway we must understand what molecules within the bone that are responding to the signals from
the brain. Our proposal aims to identify the nerve signalling molecule(s) and pathways for these signals within the
bone that initiate the increase in bone formation. This project ultimately aims to identify a target for new therapies
that could achieve this beneficial effect by administration in osteoporotic women and men
Research achievements (from final report):
This project was the first to link a centrally mediated pathway to bone. We had previously identified
hypothalamic actions of the neuropeptide pathway involving Neuropeptide Y (NPY) and its powerful control of
bone metabolism. The peripheral mechanism was unknown. This project defined the action at the osteoblast and
further reported it to be a peripheral action of NPY, which was notable for it was mainly considered a brain active
molecule.
Moreover, this work lays open the possibility of direct modulation of osteoblast activity by modulation of the local
NPY Y1 receptor. This is currently the focus of a NHMRC project grant [ID_535932]. Models developed in the
grant have enabled detailed expression profiling of Y1 action in osteoblasts and the potential for cross regulation
bet ween bone and fat cells.
This project also enabled assessment of the time course off NPY action during osteoblast differentiation. It
highlighted a far more complex and involved interaction between neural signalling and the cells of bone than
previously thought.
This information will be critical in considering NPY as a potential treatment for altered bone mass.
Expected future outcomes:
Curentl work is fi=ocussed upon preclinical models to assess the potential for Y1 receptor modualtion for control
of beon metabolism
Name of contact: Dr Paul Baldock
Email of contact: p.baldock@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325601
CIA Name: Prof Tuan Nguyen
Main RFCD: Endocrinology
Admin Inst: Garvan Institute of Medical Research
Start Year: 2005
End Year: 2007
Total funding: $363,000
Grant Type: NHMRC Project Grants
Title of research award: GENETIC PREDICTION OF FRACTURE IN A RISK-STRATIFIED POPULATION
Lay Description (from application):
Osteoporosis is a condition characterised by excessive bone loss and impaired bone quality, which ultimately
results in fracture with minimal trauma. Osteoporosis affects 27% of women and 11% of men aged 60 years or
above in the community, and costs Australia around $7 billion each year. Individuals with low bone mineral
density (BMD) have a significantly higher risk of fracture than those with normal BMD. In the long-term (14year) Dubbo Osteoporosis Epidemiology Study, more than half of individuals with osteoporosis (e.g., low BMD)
did not sustain a fracture, while approximately 60% of fracture cases had BMD above the high risk levels. Thus,
BMD alone is not a good discriminant of fracture versus non-fracture cases. It is widely known that the liability
to fracture is determined in part by genes. Previous studies, including from our group, have suggested a number
of candidate genes that are associated with fracture risk. The fundamental issue that this study is concerned is
that how and whether genetic markers could be used to facilitate case finding. It is proposed that common
variations of certain genes are associated with fracture risk independent of BMD. That is, they can identify
individuals at relatively high and low fracture risk after stratification for BMD. Hence, some markers may
identify those individuals likely (and unlikely) to fracture even with low (osteoporotic) BMD. Similarly, some,
possibly the same, markers may identify individuals at high risk of fracture despite relatively "good" (ie nonosteoporotic) BMD. It is further proposed that no single gene will achieve this outcome, but rather a small set of
such gene polymorphisms will provide clinically useful risk information. This effect is entirely analogous to the
use of clinical risk indicators (eg, age, weight, sex, family history, etc) to assess the risk of future fracture.
Research achievements (from final report):
1. We have genotyped 85 SNP, including the vitamin D receptor (VDR), collagen I alpha-1 (COLIA1), estrogen
receptor, beta-3 adrenergic receptor, and LRP-5 genes, for 2178 men and women in the Dubbo Osteoporosis
Epidemiology Study.
2. We have completed a genome-wide association study as part of a multi-centre collaborative study designed to
search for osteoporosis genes. From this study, we have identified a number of loci that were associated with
fracture risk of bone mineral density.
3. We have published 8 papers, including 4 original contributions, in international peer-reviewed journals such as
New England Journal of Medicine, Nature Genetics, Journal of Clinical Endocrinology and Metabolism. We have
published an important finding on the association between polymorphisms of the VDR and COLIA1 genes and
hip fracture, in which carriers of the VDR CC genotype (16% prevalence) and COLIA1 TT genotype (5%
prevalence) had an increased risk of hip fracture. Approximately 20% and 12% of the liability to hip fracture was
attributable to the presence of the CC genotype and TT genotype, respectively.
4. We have developed a prognostic model that incorporates genotypes for predicting fracture risk in an individual.
This prognostic model represents the first attempt in the world to translate genetic information into practical
clinical use. We are planning to make this model available worldwide through the internat implementation of the
model.
Expected future outcomes:
Development of prognostic model incorporating genetic data for predicting fracture risk
Name of contact: Tuan V. Nguyen
Email of contact: t.nguyen@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535932
CIA Name: Dr Paul Baldock
Main RFCD: Orthopaedics
Admin Inst: Garvan Institute of Medical Research
Start Year: 2009
End Year: 2011
Total funding: $469,740
Grant Type: NHMRC Project Grants
Title of research award: Manipulation of neural pathways for bone healing
Lay Description (from application):
Orthopaedic medicine utilises precise control of critical aspects of the bone healing response. This proposal looks
at a novel, and powerful neural-based method for controlling these processes. This will be done by modulating the
activity of the neuropeptide Y1 receptor, recently identified on osteoblastic cells and capable of powerful, inverse
regulation of bone formation activity. Harnessing these effects will provide a critical tool for existing surgical
practice.
Research achievements (from final report):
Fracture healing is a complex process involving coordination of numerous cell types and signalling pathways. In
order to aid our interpretation of NPY's effects on this process, we have first endeavoured to characterise the
baseline phenotypes of the models involved.
Aim1: The effects of NPY and osteoblastic Y1 receptor deletion have been analysed as a prerequisite to
understanding the fracture studies. We have also examined Y1 effects in fat cells, as an important potential side
effect of Y1 receptor modulation.
Fracture studies have been carried out for germline Y1 KO mice, which show a marked delay in fracture healing
compared to wild type mice. This exciting data provides critical data regarding Y1 modulation as a potential
therapy, and gives clues to the complex nature of neuropeptide signalling in bone. The repeat experiment using
osteoblast specific Y1 KO mice displayed no difference in healing evident from wild type, indicating a nonosteoblastic origin of the reduced callus in Y1R KO.
Aim2: Importantly, we have modelled chronic oral treatment of an NPY-modulating compound in mice for the
first time. BIBO 0334, a Y1 receptor antagonist has been fed to mice for 2 months, and has produced a skeletal
phenocopy of the germline Y1 KO. However, fracture healing in BIBO treated mice was not altered, indicating
this is a safe bone anabolic treatement for high fracture risk populations, such as osteoporotic individuals.
This is the first neuropapetide-based therapy shown to be affective in chronic treatment and in fracture.
Expected future outcomes:
This project has provided novel insights into the regulatory influence of the NPY system in bone and the possible
therapeutic role of NPY via control of Y1 signalling. Moreover, it has determined which aspects of bone healing
are most amenable to NPY-based therapy, and thus defined which specific areas of clinical need in bone repair
that might be genuine targets for further development.
Name of contact: Paul Baldock
Email of contact: p.baldock@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511187
CIA Name: Prof Mark Forwood
Main RFCD: Orthopaedics
Admin Inst: Griffith University
Start Year: 2008
End Year: 2012
Total funding: $493,817
Grant Type: NHMRC Project Grants
Title of research award: Cell biology of stress fractures: activation of remodelling at sites of non-union
Lay Description (from application):
Stress fractures are debilitating injuries. We characterised a model of stress fractures in rat ulnae, learning that
they heal by activated remodelling, that key genes are expressed in a temporal pattern, and that part of the fracture
remains un-healed, similar to many clinical cases. Now, we will examine cell localisation of important genes
necessary for remodelling, and test the efficacy of different growth factors to activate a healing response in the
non-healed section of the fracture.
Research achievements (from final report):
We demonstrated that chemical signals produced by bone cells, at the site of a stress fracture, are crucial for
regulating bone remodeling that heals stress fractures. In particular, specific molecules, called chemokines, are
produced by cells around the stress fracture and guide the bone cells to the site of stress fracture healing. We also
showed that drugs used to reduce pain (such as ibuprofen), or treat osteoporosis (such as bisphosphonates), slow
down the healing of stress fractures. Our discoveries are important because they guide physicians in the use of
drugs in people who may be experiencing a stress fracture, and also suggest potential therapies to accelerate
healing. Our results were used by a task force of the American Society of Bone and Mineral Research to highlight
the potential aetiology of atypical femoral fractures appearing in patients who have been treated with
bisphosphonates for long periods.
Expected future outcomes:
The observations regarding chemokine regulation of bone remodeling in stress fracture repair, suggest that
parathyroid hormone may be a beneficial treatment to accelerate healing when stress fractures fail to repair, or in
patients experiencing atypical femoral stress fractures while being treated with bisphosphonates
Name of contact: Prof Mark Forwood
Email of contact: m.forwood@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 231421
CIA Name: A/Pr Nigel Morrison
Main RFCD: Rheumatology and Arthritis
Admin Inst: Griffith University
Start Year: 2003
End Year: 2005
Total funding: $330,375
Grant Type: NHMRC Project Grants
Title of research award: Gene variants related to bone density and fracture.
Lay Description (from application):
Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone
density may permit advances in controlling osteoporosis. We have identified a variant that is related to bone
density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in
women. In addition, some people with bone fracture at the hip, or low bone density, have mutations in this gene.
The gene is a master regulator of the cells that make bone: this gives hope that it may be possible to alter bone
formation through this master regulator.
Research achievements (from final report):
The RUNX2 gene is expressed in both bone and cartilage and is therefore a candidate gene for both osteoporosis
(OP) and osteoarthritis (OA). Not only is RUNX2 important for OP and OA, this gene impacts on periodontal
disease, rheumatoid arthritis, osteomyelitis, loosening of prosthetic devices, and bone loss from malignant cancer.
At least 20% of the population will suffer from one of these conditions in a life time. Runx2 gene variants have
considerable effect on fracture and bone density (BMD). In an average sized school (say 1000 children), 5 will be
carriers of Q-mutants. In a community of 100,000 people, 377 will be carriers of the RUNX2 Q deletions that
confer -0.6SD lower BMD and 133 others will have the 30Q allele that confers -1.1 SD BMD. For every 1SD
decline in BMD, fracture increases two fold. Based on Australia's population, 102,000 people are carriers of Q
mutations and will start life with an increased fracture risk. OP and OA are major causes of morbidity and reduced
productivity due to the demographic trend of increased aged persons as a proportion of the total population.
Osteoporosis Australia estimates that the cost of OP-related fractures and hospitalisation will be $1 billion by
2010. Access Economics claims that the cost of OA to Australia in 2004 was $19.4 billion dollars. This project
has contributed to understanding the genetic influences of RUNX2 on bone and future work will cover influences
on OA.
Expected future outcomes:
Three journal publications are in the process of final editing for submission to top journals such as JBMR. These
papers cover the resubmitted paper on Q-repeat in RUNX2, the influence of 11-Ala polymorphims on fracture risk
and targets of RUNX2 in osteoblasts.
Name of contact: Nigel Morrison
Email of contact: N.Morrison@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 277002
CIA Name: Prof David Shum
Main RFCD: Learning, Memory, Cognition and Language
Admin Inst: Griffith University
Start Year: 2004
End Year: 2006
Total funding: $213,950
Grant Type: NHMRC Project Grants
Title of research award: Evaluation of rehabilitation strategies for prospective memory in individuals with
traumatic brain injury
Lay Description (from application):
Traumatic brain injury (TBI) resulting from motor vehicle accidents and other mishaps is a leading cause of death
and disability in young adults. Memory problems is one of the most common and debilitating symptoms reported
by people with TBI. Traditionally, the treatment of memory problems has focussed on retrospective memory or
the ability to recall or recognise previously learned information (e.g., remembering the name of a person, recalling
the content of yesterday's news stories). Little research has been conducted on problems with another type of
memory called prospective memory or the ability to remember to do something in the future (e.g., remembering to
attend an appointment, remembering to pay a bill before its due date). The treatment of prospective memory
problems in people with TBI is, however, very important for assisting them to return to work and successful
integration into the community. This is because the ability to remember to do things at the right time is essential
for work and for independent living. In addition, failure to treat this type of problems can be risky or even life
threatening (e.g., forgetting to take medication, forgetting to turn off an electrical appliance). This project aims to
evaluate the independent and combined effectiveness of two rehabilitation strategies, namely, promoting
awareness of memory problems and adopting compensatory strategies. In addition, this project aims to gauge
whether a better management of prospective memory problem will lead to better functioning in the community.
Research achievements (from final report):
Traumatic brain injury (TBI) resulting from motor vehicle and other causes is a leading cause of death and
disability in young adults. Memory impairment is one of the most common and debilitating problems reported by
people with TBI. Traditionally, the rehabilitation of memory impairment has focused on retrospective memory or
the ability to recall or recognise previously learned information. There has been little research on a new type of
memory called prospective memory or the ability to remember to do things in the future (e.g., remembering to
attend an appointment or take medication). This type of memory is important for successful independent living in
the community and its failure can be risky or life threatening. This project aimed to evaluate the relative
effectiveness of self-awareness training (training versus no training) and type of memory training (compensatory
versus remedial), alone and in combination, in improving prospective memory in individuals with TBI. Four
groups of participants with TBI took part in an 8-week rehabilitation programme and it was found that participants
in the compensatory condition showed better improvement in prospective memory than participants in the
remedial condition. The effect self-awareness training on prospective memory was not as strong. Interestingly,
compensatory memory training was also found to lead to improvements in psychosocial adjustment. Compared to
other studies, this study used a more powerful research design and included more participants. The results
obtained, therefore, are more reliable and generalisable.
Expected future outcomes:
By publishing the results of this study, it is envisaged that the memory rehabilitation programme developed in this
study will attract the attention of practitioners and researchers. Adoption of the programme in Australia and
overseas can help individuals with TBI to better manage and compensate for their prospective memory problems.
Name of contact: Professor David Shum
Email of contact: D.Shum@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 990761
CIA Name: A/Pr Andrew Gundlach
Main RFCD: Neurology and Neuromuscular Diseases
Admin Inst: Howard Florey Institute
Start Year: 1999
End Year: 2003
Total funding: $802,291
Grant Type: NHMRC Project Grants
Title of research award: Dynamics of neuropeptide systems in brain: Focus on novel galanin pathways and
receptors
Lay Description (from application):
Not Available
Research achievements (from final report):
This project aimed to characterize the distribution, regulation and function of the important galanin peptidereceptor systems in the central nervous system of the rat and mouse. Initial aims were to map the distribution of
galanin receptor subtypes in adult and developing brain; to characterise a newly identified galanin nerve pathway
in the inferior olive and cerebellar in the mouse; and to examine the effect of a range of experimental treatments
on galanin and galanin receptor expression in different classes of brain neurons, including effects of motor nerve
damage, cerebral ischemia and 'spreading depression' in the cortex, and homeostatic changes such as water
deprivation or salt-loading. Most of these aims were achieved and yielded important information about the
functional role of galanin signalling in the brain.
Thus, specific studies revealed: (i) the differential abundance and distribution of two main subtypes of galanin
receptor (GalR1 and GalR2) mRNA in postnatal developing and adult rat brain; (ii) the induction of GalR1
receptors in granule cells during the development of the mouse cerebellum; (iii) activity-dependent increases in
galanin in inferior olive neurons associated with drug-induced tremor; (iv) the distribution and regulation of
GalR1 receptors in vasopressin neurons in the hypothalamus; (v) the previously unknown distribution of galaninlike peptide (GALP) in neurons in the arcuate nucleus of hypothalamus and in specialized glial cells (pituicytes) in
the pituitary gland, along with GALP upregulation in these latter cells by osmotic stress; (vi) a delayed, transient
expression of galanin in cells in cerebral cortex identified as oligodendrocyte precursors, following activation by
acute waves of spreading electrical/metabolic depression; and (vii) the presence of galanin and GalR1 and GalR2
in cells within the 'proliferative zones' of the adult brain, where new neurons, glia and oligodendrocytes are
produced from neural stem cells.
Expected future outcomes:
These findings provide a solid framework for continuing studies of central galanin systems, including elucidation
of the role of galanin systems in brain injury, particularly in oligodendrocyte precursors, in developing brain and
in adult neural stem cells. Findings also suggest new avenues of further investigation of GALP biology and its role
in integrating metabolism and reproductive function.
Name of contact: Andrew Gundlach
Email of contact: a.gundlach@hfi.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219325
Start Year: 2002
CIA Name: Prof Roderick McClure
End Year: 2006
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $1,335,418
Admin Inst: Injury Prevention and Control (Australia) Ltd
Grant Type: NHMRC Partnerships
Title of research award: A research based solution to the public health problem of injury
Lay Description (from application):
Not Available
Research achievements (from final report):
The overall aims of the IPCA Research Partnership in Injury focused on the science that underpinned the
implementation of community based programs for the prevention of injury in each of the life stage categories and
in Indigenous communities. In each of these contexts, the contribution to knowledge made by the Partnership has
advanced the evidence base for the design, implementation and evaluation of these programs. Links between the
government, industry, researchers and the community, formalised in the IPCA model, has proved to have been
essential to the success of this research. The research activity has made important advances that explain not only
'what works' in injury prevention, but 'how to make it work' in population level programs.
The current Queensland Governement injury prevention policy focused on Childhood injury, Falls in older people
and Indigenous Injury is a direct result of the foundational research undertaken within three of the programs of the
Injury Partnership. A recent review commissioned by the Minister of Mines & Energy (QLD), made 39
recommendations on improvements to the reporting of injury and health issues in the mining industry, many of
which are based on evidence derived from IPCA research projects in the Mining Industry.
Expected future outcomes:
It is expected that over the next 5 years the research will be directly translated to reductions in the population level
indicators of injury-related health of children, young adults, adults in the workforce, older people, and Indigenous
Australians.
Name of contact: Professor Rod Mcclure
Email of contact: rod.mcclure@muarc.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 278802
Start Year: 2004
CIA Name: Dr Yeesim Khew-Goodall
End Year: 2006
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $496,500
Admin Inst: Institute of Medical and Veterinary Science
Grant Type: NHMRC Project Grants
Title of research award: A tyrosine phosphatase that regulates adherens junctions, cell migration and the
epithelial-mesenchymal transition
Lay Description (from application):
Cell-cell adhesion which physically glues cells together to form tissues and organs, also controls processes in
development, wound healing and cancer progression. I have identified a novel regulator of cell-cell adhesion that
regulates cell migration and cell morphology. Since these events are crucial during metastasis (the spread of
cancer) and during wound healing, understanding the function of this novel regulator may provide the basis for
new approaches to developing therapeutics. Specifically, in this proposal I aim to further our understanding of the
function of this novel regulator in normal physiology and to elucidate how its functions are regulated.
Research achievements (from final report):
In this study, we (i) demonstrated that the protein tyrosine phosphatase Pez is a regulator of epithelialmesenchymal transition (EMT), (ii) that its role in regulating EMT is crucial for the proper development of some
organs using a zebrafish model to study organ development and (iii) that it is a regulator of the growth factor
TGF-beta production leading to the EMT. In addition to its role in organ development, EMT is also a process
required for the initial stages of metastasis of solid tumours as well as a source of additional fibroblasts in fibrotic
diseases that lead to organ failure. Although TGF-beta level is well-known to be elevated in both cancers and
fibrotic diseases and play a role in the progression of both these diseases, little is known about the mechanisms
that lead to elevated TGF-beta levels in these diseases. Our findings implicate Pez as a potential protagonist of
both cancer metastasis and organ fibrosis and hence a potential therapuetic target for novel drugs to inhibit or
retard these processes. The findings from this study and reagents generated as a result led to a collaboration with a
colleague in which we identified a family microRNAs that could regulate EMT with implications for their use in
preventing or retarding metastasis.
Expected future outcomes:
We expect that in future we will establish a role for Pez in metastasis and fibrotic diseases and head towards
determining whether it is a worthy therapeutic target for controlling cancer progression and/or fibrotic diseases.
We will also establish the mechanism by which Pez upregulates active TGF-beta and this would impact on our
undestanding of developmental processes, homeostasis and diseases.
Name of contact: Yeesim Khew-Goodall
Email of contact: yeesim.khew-goodall@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 433027
CIA Name: A/Pr Hylton Menz
Main RFCD: Geriatrics and Gerontology
Admin Inst: La Trobe University
Start Year: 2008
End Year: 2009
Total funding: $730,975
Grant Type: NHMRC Project Grants
Title of research award: Randomised controlled trial of a tailored podiatry intervention to enhance mobility and
prevent falls in older people
Lay Description (from application):
Foot problems affect 1 in 3 people over the age of 65 years and are associated with reduced walking speed,
difficulty performing activities of daily living, impaired balance and increased risk of falls. Although a range of
health professionals provide treatment for foot disorders, the most common chronic foot problems in older people
(such as corns and calluses, nail disorders and toe deformities) are frequently managed by podiatrists using
treatments such as scalpel debridement of lesions, foot orthoses, exercise prescription and footwear modifications.
The 1995 National Health Survey reported that persons aged 80 years or over were most likely to have reported
visiting a podiatrist in the previous two weeks, followed by those aged 65-79 years. Similarly, the Australian
Department of Veterans Affairs, which provides podiatry services to veterans and their dependants, documented
606,706 episodes of podiatry care to 103,540 veterans in 1998-1999, at a cost of $23M. Podiatry therefore plays a
substantial role in the maintenance of foot health and mobility in older Australians. Despite the detrimental
effects of foot problems and the widespread utilisation of podiatry services by older people, very few studies have
been undertaken to ascertain the efficacy of podiatry treatments. Therefore, the aim of this study is to evaluate the
efficacy of an individualised podiatry intervention designed to reduce pain, enhance functional mobility and
prevent falls in older people. Given the high prevalence of foot-related disability and falls in older people and their
associated health care costs, the study findings will be of considerable public health importance. If found to be
clinically effective, the intervention could be easily implemented into a range of healthcare settings and adopted in
both state and federal falls prevention policies.
Research achievements (from final report):
The project investigated the effectiveness of a multifacated podiatry intervention to prevent falls in older people.
305 people aged over 65 years with disabling foot pain and an increased risk of falling were allocated to a usual
care control group or an intervention group. The intervention group received foot orthoses, footwear advice and
footwear cost subsidy, and a home-based exercise program. All participants were then followed for 12 months to
record the incidence of falls. At the end of the study, there were 36% fewer falls in the intervention group,
indicating that the multifacated podiatry intervention was effective in preventing falls in older people.
Expected future outcomes:
We plan to roll out the intervention to practicing podiatrists in both public and private sector settings and in
multidisciplinary falls prevention clinics and evaluate its effectiveness under 'real world' conditions.
Name of contact: Prof Hylton Menz
Email of contact: h.menz@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 234424
Start Year: 2004
CIA Name: A/Pr Hylton Menz
End Year: 2007
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $214,093
Admin Inst: La Trobe University
Grant Type: Early Career Fellowships (Australia)
Title of research award: Studies on foot and footwear risk factors for instability and falls in older people
Lay Description (from application):
Not Available
Research achievements (from final report):
The aim of this program was to determine the influence of foot problems and footwear characteristics on balance
and falls in older people. The core investigation involved a 12 month prospective study in which foot problems
and footwear characteristics were assessed in 176 people aged 65 years and over, and the incidence of falls was
tracked using monthly calendars. The findings of this study indicated that (i) foot pain, decreased ankle flexibility,
hallux valgus and weak toe plantarflexors are significant independent risk factors for falls, and (ii) risk of falling
indoors is increased in older people who go barefoot or wear socks only. This study is significant in that it has
identified potentially modifiable risk factors for falling in older people.
Expected future outcomes:
The results of this research have been used to inform an intervention study to assess the efficacy of a multifaceted
podiatry treatment to improve balance and prevent falls in older people. If this intervention is found to be
effective, it has the potential to reduce the burden of falls-related injury in older people.
Name of contact: Dr Hylton B. Menz
Email of contact: h.menz@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 234423
CIA Name: Dr Jill Cook
Main RFCD: Sports Medicine
Admin Inst: La Trobe University
Start Year: 2003
End Year: 2005
Total funding: $97,125
Grant Type: Early Career Fellowships (Australia)
Title of research award: Is neovascularisation the source of pain in patellar tendinopathy
Lay Description (from application):
Not Available
Research achievements (from final report):
Tendon injury occurs across the lifespan, in active people in recreation and in the workplace. Tendon injury
causes pain when the tendon is loaded, decreasing physical activty and interfering with employment. Tendon
injury results in pathology that is resistant to repair. New blood vessels (neovascularisation) are a key pathological
change in tendon injury.
Early investigations suggested an association between vessels and tendon pain. This program of research
confirmed this association and revealed that it was the presence of vessels not blood evident on imaging that
determines the pain. This has been confirmed in research from other groups that have shown nerves associated
with vessels may be the source of pain. The research also showed that measurement of vascularity with Doppler
ultrasound was reliable, and that the pre-imaging activity may be crucial in demonstrating maximal vascularity.
Additionally, it was determined that abdominal obesity was the greatest risk factor for tendon pathology and pain,
but abdominal adiposity was not associated with vascularity.
The benefits from this research include better understanding of the role of vascularity in tendon pain and how it
changes over time. There is also an understanding of the role of imaging in identifying tendon vascularity and the
factors that affect images of tendon vessels. Treatment to decrease vascularity can be directed appropriately to
affected tendons.
This research also identified abdominal adiposity as a strong but potentially modifiable factor associated with
tendon pathology. In this age of increasing obesity, this finding may have important implications for changing the
prevalence of tendon injury.
Expected future outcomes:
Understanding the role of local factors in producing tendon pathology and pain as well as the identification of
systemic factors will allow treatments directed at modification of both. Better outcomes for those with tendon pain
will result in greater levels of activity and better overall health..
Name of contact: Jill Cook
Email of contact: j.cook@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512159
CIA Name: Prof Mark Connor
Main RFCD: Peripheral Nervous System
Admin Inst: Macquarie University
Start Year: 2008
End Year: 2010
Total funding: $397,399
Grant Type: NHMRC Project Grants
Title of research award: Effects of muscle inflammation on sensory neuron excitability
Lay Description (from application):
Muscle pain is a common and poorly treated health problem for many Australians. This project examines the
properties of nerves that sense muscle pain and looks at how these change during inflammation, a common cause
of muscle pain. We are looking specifically at jaw muscles, which are one of the most common sites of chronic
muscle pain. By understanding how muscle nerves are changed by injury, we hope to be able to develop
treatments to prevent or reverse these changes.
Research achievements (from final report):
In this study we have found that experimental inflammation of jaw muscle in mouse produces an increase of the
capacity of the nerves to the muscle to make serotonin, an important mediator of pain. We first established that
the inflammation produced changes in way the jaw muscle nerve cells sense tissue damage, and then rather
unexpectedly found that this was also associated with an increase in the amount of the enzymes that make
serotinin. For the first time we established that the nerve cells innervating the face expressed all of the enzymes
needed for making serotonin, and we showed that levels of these enzymes differ between male and femnale rats,
and also change in female rats across their estrus cycle. The finding that the nerves which sense pain may also
make a substance involved in modulating pain intensity will focus attention on whether the nerves themselves are
more than simply passive sensors of tissue damage, and whether they may contribute to the chronic pain
associated with jaw muscle inflammation. Our work higlights the possibility of using drugs which limit serotonin
production or which act to modify serotinin receptors as potential treatments for jaw muscle pain.
Expected future outcomes:
Development of new pharmacotherapies aimed at modulating serotinin synthesis by trigeminal neurons, with a
view to relieving jaw muscle and perhaps other facial pain. This will require understanding of the role of sesnory
nerve-derived 5-HT.
Name of contact: Mark Connor
Email of contact: mark.connor@mq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 331966
CIA Name: Dr Penelope Jeffery
Main RFCD: Oncology and Carcinogenesis
Admin Inst: Mater Medical Research Institute, Brisbane
Start Year: 2006
End Year: 2009
Total funding: $276,750
Grant Type: Early Career Fellowships (Australia)
Title of research award: Cell surface mucins modulate epithelial cell growth and apoptosis of normal mucosal
wound repair and epithelial cancers
Lay Description (from application):
Not Available
Research achievements (from final report):
This fellowship has enabled the recipient to undertake an intensive full-time training program in biomedical
research. The trainee has acquired skills in the manipulation and study of animal models of disease and advanced
techniques in immunology and molecular biology. The fellow has also developed skills in scientific writing and
the success of this is evident by the fact that the fellow received an NHMRC project grant (as the chief
investigator A) and several smaller grants during the course of her training fellowship. The fellow helped to
phenotype a unique mouse model that was created in her laboratory and that has shown to have an increased
susceptibility to inflammatory bowel disease (IBD). The fellow has also used other models of this disease to test
potential new agents for the treatment of IBD and has translated these findings by using immune cells taken from
IBD patients and examining the mechanisms underpinning the anti-inflammatory effects of novel agents. These
impacts are significant as novel treatments for IBD are urgently required and the work arising from this fellowship
has garnered interest from the pharmaceutical industry.
Expected future outcomes:
This work will continue as the fellow has secured future funding. The novel agents identified during the
fellowship as being anti-inflammatory in mouse models of IBD will be further studied with the goal of employing
them in clinical trials with IBD patients.
Name of contact: Penny Jeffery
Email of contact: pjeffery@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 282400
Start Year: 2004
CIA Name: Prof Stephen Jane
End Year: 2006
Main RFCD: Genetic Development (incl. Sex Determination)
Total funding: $496,500
Admin Inst: Melbourne Health
Grant Type: NHMRC Project Grants
Title of research award: The role of GRHL-3, a mammalian homologue of Drosophila grainyhead, in neural
tube development
Lay Description (from application):
Spina bifida and anencephaly are two common human congenital malformations that form part of a wide
spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of
spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from
limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault
and failure of normal brain development and die within the first few hours of life. These abnormalities occur
frequently (1/1000 live births) and are a direct result of failure of the neural tube to close during embryogenesis.
NTDs are influenced by both environmental and genetic factors. The best characterised environmental factor is the
dietary supplement folate, which when administered before conception results in a reduction in the incidence of
spina bifida. The genetic complexity is evidenced by the array of mouse genetic mutations that give rise to NTDs.
One of these mouse mutations, known as Curly tail (ct), has served as the major animal model of human NTDs.
This is because the ct mice are resistant to folate administration (like most of the cases of spina bifida currently
seen in patients) and because the mice seem to have normal development in virtually all other organ systems.
Ironically, the genetic mutation that causes the curly tail phenotype has remained undiscovered for over 50 years.
We have now identified the gene mutated in the curly tail mice. This gene is highly conserved in humans
suggesting that it will play a similar role in neural tube development in man. The gene, known as GRHL-3, is a
descendant of a fly gene critical for development of the nervous system in that organism. The studies we propose
here will examine the developmental pathways involved in normal neural tube closure in mice and humans and
will impact on our understanding of these devastating congenital malformations.
Research achievements (from final report):
During the tenure of this grant, we demonstrated that the mammalian gene Grhl3 is essential for formation of the
barrier function of skin and that this protective pathway is conserved over 700 million years of evolution from fly
to man. This work was published in Science, and was the subject of an invited review in Current Opinions in
Genetics and Development. This discovery paves the way for novel interventions in the area of infant prematurity
and wound repair.
Expected future outcomes:
We will expand on this work to further examine the pathways that regulate skin protective function.
Name of contact: Stephen M. Jane
Email of contact: jane@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 544920
CIA Name: Prof David Small
Main RFCD: Cell Neurochemistry
Admin Inst: Menzies Research Institute
Start Year: 2009
End Year: 2011
Total funding: $618,950
Grant Type: NHMRC Project Grants
Title of research award: How amyloid causes neurodegeneration: the role of transthyretin in familial
amyloidotic polyneuropathy
Lay Description (from application):
This project seeks to understand the biochemical basis of nerve degeneration in a disease known as familial
amyloidotic polyneuropathy. This disease is caused by a protein known as transthyretin, which is abnormally
deposited around nerves and causes nerve damage. The project is highly likely to provide clues which help us
understand some related dementia causing diseases like Alzheimer's disease and prion diseases such as scrapie
and mad cow disease.
Research achievements (from final report):
This research has helped us to understand the mechanisms that cause a rare disease known as familial amyloidotic
polyneuropathy. However, the real significance of this work is that the mechanisms which underlie familial
amyloidotic polyneuropathy may be the same as those that cause Alzheimer's disease. Understanding these
mechanisms is vital for the identification of new drug targets for the treatment of Alzheimer's disease and related
disorders.
Expected future outcomes:
This research has increased our understanding of the cause of a neurodegenerative disease. Ultimately, therapies
targetting this cause may be developed which can be used to effectively treat the disease.
Name of contact: David Small
Email of contact: d.h.small@menzies.utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 403000
CIA Name: Dr Velandai Srikanth
Main RFCD: Epidemiology
Admin Inst: Menzies Research Institute
Start Year: 2006
End Year: 2008
Total funding: $528,331
Grant Type: NHMRC Project Grants
Title of research award: A population-based study of cerebrovascular mechanisms underyling gait, balance and
cognition in older people
Lay Description (from application):
Mobility problems, falls and dementia are among the major problems affecting older Australians with significant
consequent disability. Treatment of such disorders carries an estimated annual cost of around 4 billion dollars.
This study will examine the role of age-related brain changes in causing problems with walking, balance and
cognitive abilities in the general community. The clarification of the role of the ageing brain in causing such
disorders will guide efforts directed at preventing the occurrence of falls and dementia.
Research achievements (from final report):
The primary aim of this study is to examine in detail the effect of age-related brain changes termed as white matter
hyperintensities on key aspects of brain function, namely gait, balance and cognition in an older population. A
primary finding of this study has been that such changes, when present in large amounts, predict a high risk of
future falling in older people. These brain changes have also also associated with poorer gait in older people.
These initial findings suggest that we may need to find ways to treat or prevent the occurrence of such lesions in
order to prevent falling in older people.
Expected future outcomes:
Further publications are expected over the next year regarding the location-specific effects of such lesions on gait
and cognitive function.
Name of contact: Dr. Velandai Srikanth
Email of contact: velandai.srikanth@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490025
CIA Name: Prof Adrian West
Main RFCD: Central Nervous System
Admin Inst: Menzies Research Institute
Start Year: 2008
End Year: 2010
Total funding: $478,068
Grant Type: NHMRC Project Grants
Title of research award: Interactions between injured neurons, astrocytes and metallothionein
Lay Description (from application):
We have found that the protein, metallothionein, which protects the brain after injury or during neurodegenerative
disease acts in a more complex way than previously thought, including a direct action on injured neurons as well
as on the originating cell, astrocytes. Elucidating each component of metallothionein action will help us
understand how cells interact in the brain after injury, and excitingly, offers an opportunity to develop an
enhanced therapeutic strategy based on this protein.
Research achievements (from final report):
This project investigated how different types of brain cells interact following injury, with a focus on how a protein
produced by brain cells, metallothionein, can protect neurons from death and promote regenerative growth. We
discovered that metallothionein is released by astrocytes following injury and it promoted regenerative growth of
neurons by interacting with a specific class of cellular receptor. This has clear therapeutic potential since future
treatments could exploit this pathway using either metallothionein or synthetic analogues of metallothionein. We
also discovered that metallothionein could cause glia cells (astrocytes, microglia) to assume a pro-regenerative
role following injury.
Expected future outcomes:
Based on this work, we are investigated a new class of synthetic agents based on metallothionein which promote
recovery from brain injury.
Name of contact: Adrian West
Email of contact: Adrian.West@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 544913
CIA Name: Prof Roger Chung
Main RFCD: Cellular Nervous System
Admin Inst: Menzies Research Institute
Start Year: 2009
End Year: 2011
Total funding: $408,739
Grant Type: NHMRC Project Grants
Title of research award: How does the LRP receptor megalin promote regenerative neuronal growth?
Lay Description (from application):
Promoting the regenerative growth of neurons to allow recovery from traumatic brain injury or Alzheimer's
disease is a major goal of neuroscientists. This project continues the Chief Investigators' work in which they have
discovered the regenerative potential of a protein and focuses on how this protein interacts with a key neuronal
receptor, megalin, which appears to drive the regenerative process. This work will identify new targets for
therapies for a range of nervous system disorders.
Research achievements (from final report):
The aim of this project was to determine the precise mechanisms through which the protein metallothionein can
promote the regeneration of injured nerves following traumatic brain injury. Through a systematic series of
experimental approaches, we determined the identity of the receptor and the precise biochemical pathway that is
activated by metallothionein to promote regenerative sprouting of injured neurons. In addition, we found that
metallothionein can also modify the behaviour of non-neuronal cells, to make them more permissive to
regeneration of injured neurons. Finally, using our experimental models we identified a new molecule that
appears to be a key driver of nerve regeneration, and we are currently evaluating this new neuroregenerative
pathway. These important discoveries will greatly benefit the scientific community towards developing
therapeutic strategies to treat traumatic brain injury.
Expected future outcomes:
These important outcomes may lead to the development of new therapeutic agents that promote the regeneration
of nerves following traumatic brain injury.
Name of contact: Dr Roger Chung
Email of contact: rschung@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 544925
CIA Name: Prof James Vickers
Main RFCD: Neurology and Neuromuscular Diseases
Admin Inst: Menzies Research Institute
Start Year: 2009
End Year: 2011
Total funding: $400,885
Grant Type: NHMRC Project Grants
Title of research award: Determining the cellular mechanism underlying diffuse axonal injury following brain
trauma
Lay Description (from application):
Traumatic head injury causes transient stretch injury to the nerve cell processes within the brain. This leads to a
poorly understood series of cellular changes within nerve cells which may ultimately lead to their breakage and
subsequent neurological disability. This project seeks to understand how this nerve cell damage forms, and
explores new potential interventions which may protect the brain.
Research achievements (from final report):
Acute axonal stretch and shear in the central nervous system, leading to a pattern of secondary 'diffuse axonal
injury' (DAI), has been proposed to be a major cause of on-going disability following mild to severe forms of
brain injury. This project grant was based on a novel in vitro method for causing mild-moderate transient axonal
shear strain that leads, over 2-3 days, to secondary DAI-like axotomy. Our investigation determined that transient
axonal stretch injury in vitro induces an initial acute increase in intracellular calcium, principally derived from
intracellular stores, which was followed by a delayed increase in calcium over 48 hrs post-injury. This progressive
and persistent increase in intracellular calcium was also associated with increased frequency of spontaneous
calcium fluxes as well as cytoskeletal abnormalities. Pharmacological inhibition of calcium-activated enzymes,
such as phosphatases, resulted in reduced secondary axotomy. These results demonstrate that stretch injury of
axons induced an initial substantial release of calcium from intracellular stores with elevated intracellular calcium
persisting over two days. These long-lasting calcium alterations may provide new insight into the earliest neuronal
abnormalities that follow traumatic brain injury as well as the key cellular changes that lead to the development of
diffuse axonal injury and secondary degeneration.
Expected future outcomes:
These results provide important new insights into the cascade of pathological brain changes that follow traumatic
brain injury. The research has also indicated potential new approaches to interfere in the sequene of cellular
changes that follow axon stretch injury, and we are continuing research on these areas.
Name of contact: James Vickers
Email of contact: James.Vickers@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 403035
CIA Name: Dr Tania Winzenberg
Main RFCD: Preventive Medicine
Admin Inst: Menzies Research Institute
Start Year: 2006
End Year: 2009
Total funding: $305,500
Grant Type: Early Career Fellowships (Australia)
Title of research award: Chronic disease prevention: investigating how to improve bone mass, fracture risk and
obesity at different life-stages.
Lay Description (from application):
Not Available
Research achievements (from final report):
With the award of this GP Training Fellowship, Dr Winzenberg has undertaken a range of projects investigating
chronic disease prevention in both adults and children, focussing work initially on prevention of osteoporosis and
other musculoskeletal conditions. With the recognition of the range of issues shared across prevention other
chronic diseases, this work expanded to also consider prevention of cardiovascular diseases. Key outcomes of
her work include:
*demonstrating that informing women of their fracture risk could lead to them making lifestyle changes to
improve not only their own bone health, but potentially that of their children as well;
*providing definitive evidence that calcium supplements in healthy children have only minor effects on bone
mineral density and do not affect body weight, thus clarifying that calcium supplements have only a limited place
as a public health intervention;
*developing an easy-to-take dosage regimen to treat vitamin D deficiency in adolescents;
*identifying the previously unrecognised issue of poor accessibility of the bone mineral testing (an important test
for osteoporosis diagnosis and management) in rural areas;
*defining general practitioners' views of their role in assessing their patients' physical activity levels and
determining how well the methods GPs have to do this perform in practice. This showed that GPs perform
targeted assessments of their at-risk patents but that a commonly short questionnaire to assess physical activity
performs less well than GPs' usual assessment processes. The need for further research in how to best help GP's
assess their patients' physical activity was highlighted in these studies.
Expected future outcomes:
Dr Winzenberg is investigating further ways to improve children's bone health including determining if vitamin D
supplementation is effective in either healthy children or children who have sustained a broken bone. She is also
studying whether informing people of their risk of cardiovascular disease might cause them to improve their
lifestyle, as seen with fracture risk feedback.
Name of contact: Tania Winzenberg
Email of contact: tania.winzenberg@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490305
CIA Name: A/Pr Geoffrey Isbister
Main RFCD: Toxicology (incl. Clinical Toxicology)
Admin Inst: Menzies School of Health Research
Start Year: 2008
End Year: 2010
Total funding: $715,730
Grant Type: NHMRC Project Grants
Title of research award: A Randomised Controlled Trial of Factor Replacement Therapy in Snake Bite
Coagulopathy
Lay Description (from application):
This proposal seeks funding to undertake a controlled trial of clotting factor replacement in snake bite
coagulopathy after the administration of a neutralising dose of antivenom. The aim is to determine if factor
replacement will result in a rapid return of clotting function in patients and therefore reduce the potential risk of
major bleeding. This study will have international implications because globally snakebite coagulopathy is a
major cause of morbidity and death like in Australia.
Research achievements (from final report):
The study has changed the treatment of snake envenoming in Australia by reducing the amount of antivenom
required, the monitoring and observation of patients with snake bite and the indications for treatment. This has led
to a 3 to 4 fold reduction in antivenom use with the consequent decrease in risk of allergic reactions to antivenom
and huge cost savings in less antivenom having to be stored in hospitals around the country. The existence of a
large multicentre study of snakebite with a 24 hour research number has also (inadvertently) improved the clinical
care of patients because doctors all around the country have consulted about cases and received the most up to
date and current advice. A number of subgroup analyses have been published of different types of snakes which
has improved our understanding of the clinical effects for each type of snake (eg. brown, tiger, black snakes etc.),
the distribution of bites by these snakes (distribution of the snakes) and the role and dose of antivenom in each
type of snake envenoming.
Expected future outcomes:
The analysis of the randomised controlled trial in the next few months will define the use, risks and benefits of
fresh frozen plasma in snake bite coagulopathy for Australian snakes and will have potential value to the treatment
of snake bite world wide because fresh frozen plasma is more readily available than antivenom.
Name of contact: Geoff Isbister
Email of contact: geoff.isbister@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 194272
CIA Name: Prof David Morgan
Main RFCD: Biomechanics
Admin Inst: Monash University
Start Year: 2002
End Year: 2004
Total funding: $196,410
Grant Type: NHMRC Project Grants
Title of research award: Adaptation of muscle to eccentric exercise and its clinical applications 194272
Lay Description (from application):
Work in this laboratory has concentrated on Delayed Onset Muscle Soreness (DOMS), the soreness felt for
several days after unaccustomed exercise. This is particularly so when the exercise involves stretching of active
muscle, called eccentric exercise, at longer muscle lengths. DOMS is due to microscopic muscle damage. A rapid
training effect, leading to reduced soreness from a subsequent bout of similar exercise, has been identified by us as
due to a specific structural adaptation. This results in the optimum length for tension generation moving to longer
muscle length so that the muscle is less likely to be damaged during subsequent stretches. Hypothesizing that
gross muscle tears arise from the microscopic damage, we have begun investigating whether eccentric exercise
training can prevent hamstring muscle injuries. We have shown that eccentric exercise shifts the optimum length
for contraction in human hamstring muscles. We are now examining athletes with past injuries, known to be likely
to re-injure. Other experiments are designed to show that sports that cause injury do indeed include eccentric
exercise of the hamstring muscles. We are also investigating the effectiveness of eccentric exercise in treating
apparently normal children who compulsively walk on their toes. We have built monitoring equipment and are
monitoring both conventional and exercise based treatments designed to shift muscle optimum length to longer
lengths to allow the children to place their heels on the ground. Finally, most muscles contain different fibre types,
distinguished mainly by their speed of contraction. It has been suggested that they are not all uniformly
susceptible to damage from eccentric exercise, a result not predicted by our theory. However, we hypothesize that
secondary factors, particularly the length for generating optimum tension, may be responsible for these
differences. We plan to test this idea by measuring properties of different types of motor units.
Research achievements (from final report):
N/A
Expected future outcomes:
The eccentric exercise program for the idiopathic toewalkers has formed the backbone of a highly successful
management program that will be promoted to health professionals around the world.
Extending better understanding of how to perform eccentric exercises without risk of injury or excessive soreness
is expected to result in an increased usage for injury prevention.
Name of contact: David Morgan
Email of contact: David.Morgan@ieee.org
NHMRC Research Achievements - SUMMARY
Grant ID: 334076
CIA Name: A/Pr Cynthia Whitchurch
Main RFCD: Medical Bacteriology
Admin Inst: Monash University
Start Year: 2005
End Year: 2007
Total funding: $346,250
Grant Type: NHMRC Project Grants
Title of research award: Analysis of a chemosensory complex that controls twitching motility and virulence in
Pseudomonas aeruginosa
Lay Description (from application):
Pseudomonas aeruginosa is a common bacterium which causes serious life-threatening infections of individuals
with cystic fibrosis, AIDS or who have suffered severe burns or are undergoing cancer chemotherapy. Infection
by this pathogen requires the controlled expression of a large number of virulence factors including extracellular
enzyme, toxins and structures for the attachment and colonisation of host tissues. We have identified a complex
multicomponent regulatory system which coordinates the expression of many of the virulence determinants of this
pathogen. This project aims to dissect the intermolecular interactions and signalling events which input into,
occur within, and output from this regulatory system. This knowledge will provide a platform for developing
rational strategies for the production of new antimicrobials for fighting infections by this and related pathogens.
Research achievements (from final report):
We have mde signficant progress toward deciphering how Pseudomonas aeruignosa responds to extracellular cues
to control colonisation and virulence factor production
Expected future outcomes:
We expect to identify and characterise protein-protein interactions of Chp chemonsensory sytem of Pseudomonas
aeruginosa and to determine how this system controls twitching motility, extracellular DNA production and
virulence factor production in response to environemetal cues
Name of contact: Cynthia Whitchurch
Email of contact: Cynthia.Whitchurch@uts.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284345
Start Year: 2004
CIA Name: A/Pr Stephen Bernard
End Year: 2006
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $311,000
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Title of research award: A trial of prehospital rapid sequence intubation in patients with severe head injury
Lay Description (from application):
In Australia, major trauma is a leading cause of death in people between the ages of one and 44 years. In addition
to mortality, there is a high morbidity rate and quality adjusted life-years lost from injury is vast. In broad terms,
major trauma is defined as those injuries with the highest severity, requiring time critical medical care. Over 10%
of major trauma patients have a severe head injury and approximately 40% of these patients die and another 40%
have significant long-term morbidity. Following severe head injury, it is common for patients to have decreased
oxygen levels and this is associated with a significant increase in brain damage. To prevent or treat this, patients
with severe head injury require endotracheal intubation (a tube is placed in the airway to provide oxygen to the
patient) as soon as possible following injury. However, in most patients with severe head injury, endotracheal
intubation requires the use of drugs to facilitate placement of the endotracheal tube. The usual technique involves
the administration of both a sedative drug and an appropriate muscle-relaxant. This technique is known as rapid
sequence intubation (RSI). However, it is unknown whether RSI should be undertaken by paramedics early after
injury or be delayed until arrival at the hospital. Since better evidence of improved outcome is required to justify
the possible risk and considerable expense of training ambulance paramedics in the skill of RSI, it is proposed that
a randomized, controlled trial of RSI in adults with severe head injury be conducted. This trial will compare rapid
sequence intubation with standard airway management (no intubation) by ambulance paramedics for major trauma
patients with severe head injury. This study will assess differences in patient outcome at 6-months post injury.
The study will involve head injury patients treated by paramedics in Victoria.
Research achievements (from final report):
This clinical trial enrolled 312 patients. It was found that paramedic rapid sequence intubation is associated with
an increase in favorable outcomes from 31% to 46% at 6 months post injury.
Expected future outcomes:
It is proposed that mild hypothermia might be induced after intubation to improve neurological outcomes after
severe head injury
Name of contact: A/Prof Stephen Bernard
Email of contact: stephen.bernard@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 544304
CIA Name: Prof Stephen Jane
Main RFCD: Dermatology
Admin Inst: Monash University
Start Year: 2009
End Year: 2011
Total funding: $579,138
Grant Type: NHMRC Project Grants
Title of research award: Defects in epidermal morphogenesis in Grainyhead-like gene deficient mice
Lay Description (from application):
The cells of the skin play an essential role in the development of the mammalian embryo. They are critical for
forming a protective barrier against infection and external toxins, for preventing excess fluid loss, for repair of
defects and wounds , and for the generation of hair. Our laboratory has identified a family of genes that are critical
for these processes. The aim of this study is to determine the relationship between these genes to further our
understanding of the skin and its functions
Research achievements (from final report):
This project examined the role of the Grainy head-like factors in epidermal morphogenesis. We made
excellent progress in understanding the role of Grhl3 in both embryonic epidermal development and in
adult epidermal homeostasis. We also made inroads in deciphering interactions between the family
members in epidermal development.
Expected future outcomes:
These studies pave the way for further developments in understanding and management of disease processes that
involve defective epidermal migration such as failed wound repair and neural tube defects.
Name of contact: Stephen Jane
Email of contact: stephen.jane@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 124331
CIA Name: Prof Peter Rogers
Main RFCD: Obstetrics and Gynaecology
Admin Inst: Monash University
Start Year: 2000
End Year: 2004
Total funding: $759,928
Grant Type: NHMRC Project Grants
Title of research award: Endometrial angiogenesis
Lay Description (from application):
The lining of the uterus is unusual compared to other parts of the adult body in that new blood vessels grow and
then breakdown during menstruation every month. The aim of this project is to understand what controls the
growth and regression of these uterine blood vessels. This information is of immediate relevance to a number of
clinical problems where an ability to either promote or prevent blood vessel growth would be of major advantage.
For example, increased blood vessel growth would accelerate wound healing, while blocking blood vessel
growth would prevent the growth and spread of cancers. Another disorder that could be controlled through
preventing blood vessel growth is endometriosis, a disease where cells from the lining of the uterus grow inside
the abdomen causing pain and infertility. Endometriosis affects upto 10% of women.
Research achievements (from final report):
The primary focus of this research project was to better understand how new blood vessels form in the lining of
the uterus. A fundamental knowledge of uterine blood vessel growth is relevant to a large number of common
women's health problems, including endometriosis, menorrhagia (excessive menstrual blood loss), breakthrough
bleeding (irregular menstrual bleeding associated with hormone replacement therapy and hormonal
contraceptives), endometrial cancer, fibroids, infertility and establishment of a normal placenta during pregnancy.
Expected future outcomes:
This project has increased fundamental knowledge that underpins our understanding of uterine function in both
normal and diseased states. Future work will build on this knowledge base to develop better treatments and
outcomes for a number of diseases that affect the uterus, including endometriosis, endometrial cancer, fibroids and
inadequate placental function.
Name of contact: Peter A W Rogers
Email of contact: Peter.rogers@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509349
CIA Name: Prof Russell Gruen
Main RFCD: Surgery
Admin Inst: Monash University
Start Year: 2008
End Year: 2011
Total funding: $314,312
Grant Type: Career Development Fellowships
Title of research award: Refining methods for obtaining, synthesising and interpreting research evidence in
surgery
Lay Description (from application):
Research evidence plays a crucial role in improving clinical care. However the main forms of evidence and the
tools that facilitate evidence use - namely randomised controlled trials (RCT) & structured systematic reviews of
existing research - have had limited application in surgery for a variety of reasons. This project aims to promote
the use of research evidence in surgical decision making by developing tools tailored to the predominance of nonRCTs in surgery & surgeons' information needs.
Research achievements (from final report):
In this 4 year period I have advanced various aspects of science in health services, surgery and trauma care. I have
published major articles on topics ranging from the sustainability of health services, to the early management of
severe injury, and how to measure the performance of trauma care and trauma systems. I have benefited from
good mentorship and support, and have developed an international network of collaborators and researchers on
similar topics, and have attracted significant project and program funding to support this work into the future.
During this period of NHMRC support I became a full professor and head of department.
Expected future outcomes:
I am continuing on with an NHMRC Practitioner Fellowship and will continue to develop a world class research
program and work on using research to improve care of injured people globally.
Name of contact: Professor Russell Gruen
Email of contact: r.gruen@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436767
CIA Name: Prof Sally Green
Main RFCD: Therapies and Therapeutic Technology
Admin Inst: Monash University
Start Year: 2007
End Year: 2009
Total funding: $682,134
Grant Type: NHMRC Project Grants
Title of research award: Improving the care for people with acute low back pain by allied health professionals:
cluster RCT.
Lay Description (from application):
The project focuses on the NHMRC Clinical Practice Guidelines (CPG) for the management of acute low back
pain, and more specifically the key messages of non-referral to x-ray and advising patients to stay active. A
mixed design approach will be used in line with the framework for evaluating complex interventions (MRC 2000).
A qualitative approach using semi-structured interviews with physiotherapists, chiropractors and the patients of
both will be conducted to identify the barriers and enablers to implementation of the evidence-based clinical
practice guideline. The interviews will be underpinned by a theoretical framework grounded in behavioural
theory. Information from the interviews will be used to develop a survey to canvas views of a larger population
of chiropractors and physiotherapists. The results of the interviews and survey will inform the development of a
targeted implementation strategy suitable for use in private physiotherapy and chiropractic clinics. Potential
interventions include educational strategies, patient and practitioner information via various media, reminder
systems and peer leadership.
Research achievements (from final report):
This project evaluated an intervention designed to assist allied health practitioners (physiotherapists and
chiropractors) better manage people with acute low-back pain. This research has led to further articulation of the
complexities of research that aims to improve clinical practice in line with research evidence, and thus has
furthered understanding in the field of implementation science. This project has also extended the methodology of
desinging theory-based behaviour change interventions and the assessment of intervention fidelity. The project has
strengthened partnerships between the Australian-based project team and international leaders in implementation
research.
Expected future outcomes:
Allied health professionals ordering fewer plain x-rays for patients with acute low-back pain can lead to reduced
health care costs and decreased number of people exposed to harmful radiation. The increased use of health
professionals advising patients with acute low-back pain to stay active in line with evidence from research should
result in improved health care outcomes.
Name of contact: Professor Sally Green
Email of contact: sally.green@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546005
CIA Name: Prof Euan Wallace
Main RFCD: Foetal Development and Medicine
Admin Inst: Monash University
Start Year: 2009
End Year: 2011
Total funding: $511,295
Grant Type: NHMRC Project Grants
Title of research award: Preventing Prenatal Brain Injury in Fetal Growth Restriction
Lay Description (from application):
Intrauterine fetal growth restriction (IUGR) is a serious complication of pregnancy associated with increased
perinatal morbidity and mortality. In particular, IUGR infants have a high risk of perinatal brain injury which is
likely to arise from damage before birth. Our aim is to use an ovine model of IUGR to define the causes of that
brain injury and to develop new therapies that could be offered to women to protect their unborn baby.
Research achievements (from final report):
In this project we demonstrated that impaired fetal growth was associated with injuries to the developing brain
that resulted in disability of the newborn. We went on to show that this brian injury was related to oxidtive stress
in the growth restricted fetus and that treatment of the pregnant mother with melatonin - a powerful antioxidant reduced oxidative stress in the developing fetus and prevented brain injury. The melatonin treatment improved
developmental outcome of the newborns. The project was udnertaken using an experimental sheep model of
growth restriction. However, the results show for the first time that it is possible to treat an unborn baby before it
is born and prevent brain injury.
Expected future outcomes:
The results of this project have been used to design a clinical trial where the treatment will be offered to pregnant
women whose baby is severely growth restricted.
Name of contact: Professor Euan Wallace
Email of contact: euan.wallace@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384103
Start Year: 2006
CIA Name: Dr Lesley Day
End Year: 2008
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $1,157,574
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Title of research award: Tai Chi for independent living: RCT of efficacy of Tai Chi in delaying disability
among older people.
Lay Description (from application):
This study addresses the issue of disability among our ageing population. Preservation of function among our
older citizens, and their capacity to live independently, is of significant social, public health and economic benefit.
The aims of this study are to (1) test the efficacy of Tai Chi in delaying disability among older people, prior to its
onset, (2) investigate the mechanisms by which Tai Chi intervenes in the disability pathway, (3) determine the
cost-benefits of Tai Chi for older people. The study will recruit 670 people over 70 years of age and randomly
assign them to receive either Tai Chi, or a stretching and relaxation program, for a period of 48 weeks. The groups
will then be compared to determine if there is any difference in the development of disability as well as a range of
functional outcomes such as strength, balance, depression, arthritic symptoms, life satisfaction, and falls. This
will be the first study world-wide to test the impact of any exercise program on delaying the manifestation of
disability among older people. Robust evidence that Tai Chi can in fact delay disability will have immediate and
significant implications for the maintenance of independence among older people at a critical time for our ageing
population. Translation of these research results to practice will decrease demand for support services for
community dwelling older people, and for places in supported accommodation facilities. Older people will have
improved quality of life, and government and non-government agencies will experience reduced demand for
limited resources. This internationally significant study will also contribute to understanding the mechanisms by
which disability develops, and create the valuable opportunity for continuing research on attrition of effect and
long term adherence to exercise programs.
Research achievements (from final report):
This was the first study world wide to attempt to test the impact of any exericse program on delaying the
manifestation of disability among older people. A total of 503 older people, in the very early stage of disability,
were recruited and received one of two different exercise programs for a 48 week period. Disability outcomes, and
a number of explanatory factors, were monitored. Preliminary results following an interim analysis after 24 weeks
of exericse, suggest that the initial promise of the program may not be realised. However, data on the impact of
the full exericse program has not yet been analysed. There may be important messages regarding the participation
of older people in exercise programs.
Expected future outcomes:
Future analysis will test whether the full 48 week exericse program has an impact on delaying disability onset, and
on improving a number of health related outcomes.
Name of contact: Lesley Day
Email of contact: lesley.day@muarc.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236858
CIA Name: Prof Julian Rood
Main RFCD: Medical Bacteriology
Admin Inst: Monash University
Start Year: 2003
End Year: 2003
Total funding: $78,500
Grant Type: NHMRC Project Grants
Title of research award: Two-component regulatory systems involved in toxin production in Clostridium
perfringens
Lay Description (from application):
The bacterium studied in this project causes gas gangrene, a severe and often fatal infection of traumatic or
surgical wounds. The project involves the detailed analysis of the process by which this bacterium controls the
production of the toxic proteins that are required for disease to occur. The emphasis is to determine the
mechanism by which this regulatory process is mediated. Research in this laboratory has identified two genes
whose protein products are the key links in this regulatory network. The objectives of the project will be to
determine which part of the regulatory protein interacts with the target toxin gene, to start to determine the
structure of the regulatory protein so that the precise biochemical mechanism of action can be ascertained, to
determine the components of the DNA target that are essential for binding activity, and to identify other genes that
are involved in the regulation of both the toxin genes and other genes that may be implicated in the disease
process. These studies will be facilitated by the availability of the complete genome sequence of this pathogenic
bacterium. The project will make a major contribution to our knowledge of how bacteria that cause disease are
able to control the production of the toxins that are critical to the disease process. If we are to learn how to more
effectively control and treat bacterial infections then it is very important that we understand the complex
regulatory networks that tell bacteria when to produce its disease-causing products.
Research achievements (from final report):
These studies will involve a bacterium that causes gas gangrene by invading a wound, growing and producing
potent toxins. The future directions of this research predominantly involve the elucidation of the precise
mechanism by which two proteins combine to transmit an environmental cell signal into increased production of
the protein toxins that are important in this disease. Specifically, these studies will concentrate on the protein to
protein interactions between each element of this important regulatory cascade. Determination of the crystal
structure of one of these proteins will be an important part of this process. Using this knowledge, we may be in a
better position to develop novel methods of antimicrobial treatment.
Expected future outcomes:
N/A
Name of contact: N/A
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 194242
CIA Name: Dr Lesley Day
Main RFCD: Epidemiology
Admin Inst: Monash University
Start Year: 2002
End Year: 2005
Total funding: $665,930
Grant Type: NHMRC Project Grants
Title of research award: Risk factors for serious farm-work related injury among adult males
Lay Description (from application):
This study addresses occupational injury among male adult farm workers. The health and safety performance of
agricultural industries is among the worst in Australia. A recently published study of work-related fatalities from
1989 to 1992 found that rural industries ranked third, with a fatality rate 3-4 times that for all industries. The rural
industries accounted for 80 deaths annually. Best estimates place the cost of farm injury between $0.5 and $1.29
billion per year. This study is designed to contribute to farm injury prevention by: (1) identifying factors
associated with a higher risk of serious injury among adult farm workers and (2) determining the proportions of
the farm workforce who are exposed to various injury risks. The study will recruit 300 seriously injured or killed
farm workers from regional Victoria and collect information about themselves, their working life and the property
on which they work. This information will be compared with 600 randomly selected farm workers who are not
seriously injured to determine which personal, work and environmental factors place farm workers at higher risk
of injury. The study will lead to the development of new or more refined prevention strategies and programs. A
study of this kind has not been conducted before in Australia and would contribute to a continuing scientific basis
for selection of interventions for farm injury and targeting of prevention programs, at a time of increasing
momentum in agricultural health and safety.
Research achievements (from final report):
This study has led to a greater understanding of the factors leading to farm injury which is required to underpin the
development of new or more refined intervention strategies. For example, we found that although owners and
managers comprise the greater proportion of injury farmers, employees and contractors were at increased risk of
injury. A greater understanding of the individual and farm characteristics associated with an increased risk of farm
injury is likely to lead to better targeting of prevention programs. A study of this kind has not been conducted
before in Australia and will provide a continuing scientific basis for selection of interventions for farm injury and
targeting for prevention programs, at a time of increasing momentum in agricultural health and safety.
Expected future outcomes:
If the study results are used to inform prevention programs, the expected future outcome is a decrease in the rates
of serious farm work related injury among men in Australia.
Name of contact: Lesley Day
Email of contact: lesley.day@muarc.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436659
Start Year: 2007
CIA Name: Dr Ian Smyth
End Year: 2009
Main RFCD: Genetic Development (incl. Sex Determination)
Total funding: $475,517
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Title of research award: The role of the Frem proteins in development and disease
Lay Description (from application):
Rare genetics diseases can often provide us with insights into some of the fundamental mechanisms which control
how we develop and live healthy lives. We have identified a family of genes called the Fras and Frem genes and
some of these are mutated in a disorder called Fraser Syndrome. Fraser Syndrome patients have profound defects
in the normal development of their skin and kidneys. We are studying the function of these genes with a view to
understanding not just how Fraser Syndrome develops, but how our organs develop normally. The genes involved
in FS contribute to the "extracellular matrix" which is effectively the scaffolding which our cells use when
developing into our organs. The extracellular matrix is also important in maintaining our adult tissues and
responding to damage. It can act as a physical support and as a key controller of how ours cells react to growth
factors and to each other. This proposal will explore how the Fras and Frem genes mediate these interactions to
control normal development and also to determine how their mutation gives rise to disease. In doing so we hope
to gain insights into more common diseases which affect both the kidney and the skin.
Research achievements (from final report):
During the course of this project we have furthered our understanding of the role of the Fras and Frem genes in
development. Specifically we have detailed gene expression in a number of developmental animal systems
uncovering gene expression interactions with relevance to human disease caused by mutations in these genes. We
have developed a novel imaging technology to explore developmental defects in these genes and have applied this
to the analysis of a number of different organ systems. We have shown that the Fras and Frem genes can control
Pdgf signalling and the implications of this finding to the study of tissue inflammation are ongoing. Wehave also
shown that mutations in these genes contribute to defects in craniofacial development including orofacial clefting
and craniosynostosis.
Expected future outcomes:
Better understanding of disease features associated with the Fras and Frem genes and the application of imaging
modalities based around Optical Projection Tomogrpahy to better understand features of developmental disease in
model organisms
Name of contact: Ian Smyth
Email of contact: ian.smyth@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 194417
Start Year: 2002
CIA Name: Prof Rachelle Buchbinder
End Year: 2004
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $269,020
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Title of research award: Efficacy of physiotherapy after hydrodilatation for the painful stiff shoulder: a
randomised placebo-controlled trial
Lay Description (from application):
Shoulder disorders are common, being third only to back and neck complaints as musculoskeletal reasons for
medical consultation and they account for 10% of all physiotherapy referrals. The stiff painful shoulder affects up
to 2-5% of the general population, being more common in middle age and diabetes. It causes significant pain and
disability that restricts activities of daily living as well as work and leisure. Forty percent of sufferers will
continue to have symptoms and restricted movements beyond 3 years and 15% will have persistent disability.
Because this disease is prevalent, it imposes a considerable burden on the Australian health care system. Shoulder
hydrodilatation is a common conservative treatment option that has been shown by our research group to have
short-term but not long-term benefits. Physiotherapy may be prescribed following hydrodilatation on the basis
that it may maintain the initial benefits seen with hydrodilatation. However, there are no studies to either support
or refute this hypothesis. Thus, this novel research project will answer important questions about the efficacy of a
physiotherapy program in addition to hydrodilatation for the stiff painful shoulder. We will determine whether
physiotherapy offers a benefit over hydrodilatation alone and if so, whether this benefit is sustained. In addition
we will determine whether the additional costs of physiotherapy represent good value for money. The results of
this project can then be easily and immediately translated into clinical practice as recommendations can be made
about the usefulness of physiotherapy for this patient population. The results will be of major benefit not just to
the physiotherapy profession but to the medical profession who must justify patient referral to physiotherapy.
Research achievements (from final report):
This research project will answer important questions about efficacy of a physiotherapy program in addition to
hydrodilatation for the stiff painful shoulder. Our trial will determine whether physiotherapy offers a benefit over
hydrodilatation alone and if so, whether this benefit is sustained. The standardised physiotherapy we developed
can be taught to physiotherapists. In addition, if there is a benefit, it will show whether the additional costs of
physiotherapy represent good value for money. Our results will be able to be immediately translated into clinical
practice since we will be able to make recommendations about the usefulness of physiotherapy for this patient
population. The results will be of major benefit not just to the physiotherapy profession but to the medical
profession who must justify patient referral to physiotherapy.
Expected future outcomes:
The results of our study will be widely disseminated to ensure timely take up of the findings into clinical practice.
We expect to do this via publications, presentations and by updating our Cochrane systematic review of
physiotherapy for shoulder pain. The results will also be used to inform our future research agenda in terms of
finding effective treatments for shoulder pain.
Name of contact: Rachelle Buchbinder
Email of contact: rachelle.buchbinder@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 546238
CIA Name: A/Pr James Friend
Main RFCD: Surgery
Admin Inst: Monash University
Start Year: 2009
End Year: 2009
Total funding: $187,213
Grant Type: NHMRC Development Grants
Title of research award: The NanoNautilus : A Breakthrough in the Successful Treatment of Strokes and Other
Cerebrovascular Diseases
Lay Description (from application):
Strokes are one of the biggest killers of Australians and are becoming increasingly so every year. Bleeding from
the brain involves extremely delicate and dangerous medical treatments. The development of NanoNautilus [TM]--a remote-controlled steerable microcatheterusing world-first miniaturization technology---will revolutionise
current practises and greatly reduce the current risk with medical intervention.
Research achievements (from final report):
Strokes are one of the biggest killers of Australians and are becoming increasingly so every year. Bleeding from
the brain involves extremely delicate and dangerous medical treatments. This project helped develop the
NanoNautilus [R]---a remote-controlled steerable microcatheter using world-first miniaturization technology,
where we developed our triple-axis micromotor and mounting technology to the point where the device can be
taken forward in further animal trials for actual application in navigating the arteries of the brain. Two patent
applications to PCT have resulted from this grant, as have four published journal papers at a minimum. Ex-vivo
and animal trials in pigs are ongoing. Our chief achievement is in creating and validating a novel microtechnology
for navigating the neurovasculature, overcoming significant technical hurdles in achieving controllable motion of
a catheter tip.
Expected future outcomes:
The future of this work is the use of the technology as a complete device in human trials at the Royal Melbourne
Hospital's Neurointervention Centre.
Name of contact: James Friend
Email of contact: james.friend@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334060
CIA Name: Prof Sally Green
Main RFCD: Primary Health Care
Admin Inst: Monash University
Start Year: 2005
End Year: 2007
Total funding: $426,000
Grant Type: NHMRC Project Grants
Title of research award: Implementing Clinical Practice Guidelines in General Practice: A Cluster Randomised
Controlled Trial
Lay Description (from application):
Evidence based clinical practice guidelines have the potential to improve clinical practice through providing
health care workers with the most reliable information on which to base their treatment decisions. Many
governments and organisations are investing significantly in the development of guidelines for common and
important clinical disorders. To date, however, we do not fully understand how to increase the uptake of
guidelines and facilitate health care workers to change their practice in line with the guideline's recommendations.
This project aims to work with general practitioners to develop a method or strategy to increase the uptake of
guidelines for the treatment of acute low back pain, particularly to reduce the number of patients who are
unnecessarily x-rayed, and to increase advice to stay active. The effectiveness of the developed strategy will be
tested by randomly assigning general practice clinics to either receive the intervention or to have access to the
guidelines without any extra interventions (such as training and reminders) to help doctors change their practice.
Both the doctor's practice, and patient outcomes of pain and disability will be measured to determine not only if
the doctors followed the guidelines, but whether this resulted in an improvement in patient outcome. The findings
of this study will help us understand the best ways to improve adhesion to guidelines and so has the potential to be
applied to other conditions presenting to general practice where there are recommendations not currently being
implemented into practice.
Research achievements (from final report):
This project evaluated an intervention designed to assist general practitioners better manage people with acute
low-back pain. The study has shown that the GPs who received the intervention intended to order less x-rays and
intended to give advice to stay active more often to their patients with acute low-back pain.
This research has led to further articulation of the complexities of this kind of research that aims to improve
clinical practice, and has thus furthered understanding in the field of implementation science. This project has also
extended the methodology of the development of theory-based complex interventions, and the assessment of
complex intervention fidelity. Also, this project will inform healthcare policy by providing some answers about
the implementation of guidelines in general practice. Finally, the project has strengthened partnerships between
the Australian-based project team and international colleagues.
Expected future outcomes:
GPs ordering less x-rays for patients with acute low-back pain can lead to reduced healthcare costs and decreased
number of people exposed to harmful radiation. The increased use of GPs giving patients with acute low-back
pain advice to stay active should result in improved healthcare outcomes. Methods development have contributed
to our understanding of translation of research into practice.
Name of contact: Professor Sally Green
Email of contact: sally.green@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299950
CIA Name: Prof Lenore Manderson
Main RFCD: Care for Disabled
Admin Inst: Monash University
Start Year: 2004
End Year: 2007
Total funding: $251,743
Grant Type: NHMRC Project Grants
Title of research award: Social aspects of amputation among an aging population in urban and rural Victoria
Lay Description (from application):
In recent years, social scientists have shown increasing interest in how individual and social structural factors
inter-relate to produce wellbeing. An associated interest has been the role of social networks and social support for
individuals with chronic disease, enabling them to manage ongoing illness or impairment, live fulfilling lives and
experience wellbeing. To explore these issues in an Australian context, this project focuses on people who have
had amputations from trauma, advanced disease (e.g. cancer) or complications of chronic disease (e.g. diabetes).
The study aims to increase our understanding of how people live with particular diseases and health conditions,
the impact of these conditions on body image, self-esteem, social relationships and societal participation, and how
structural, contextual and environmental factors affect individual functioning and disability. By including people
of different gender, ethnicity, age and area of residence, the study is concerned with how life circumstances and
socialization (including ideas of gender) influence outcome. The findings will contribute to our knowledge of
adaptation and provide information relevant to improved care for people from different backgrounds. The study is
significant because of the increase in chronic disease (relative to infectious disease) in contemporary industrialised
societies, particularly with an aging population. The policy context of this work is government interest in
maximising the independence and wellbeing of people who are aged and/or with chronic disease, while
minimising the economic costs. The research is also significant to international agencies and consumer
organisations concerned with reducing discrimination against and inequality of people with impairments. The
study will contribute to the WHO classification of disability, and efforts to promote and protect the rights and
dignity of persons with disabilities.
Research achievements (from final report):
This research explored social and psycho-social factors impacting upon an individual's adaptation to lower limb
amputation, with a particular focus on health service delivery. Data highlighted the importance of providing
formal psycho-social support during the in-patient rehabilitation phase to assist patients with their experiences of
grief and loss, such as from a psychologist. Currently, rehabilitation services tend to provide services to people at
high risk of developing mental health co-morbidities only; this data suggested that many recent amputees
experience sub-clinical levels of mental illness, particularly depression. The process of adaptation to amputation
would be enhanced by such support services, which may reduce the incidence of future mental health problems.
Findings have also assisted in the establishment and maintenance of the condition-specific peer support group,
limbs4life, including material on life post-amputation.
Expected future outcomes:
Data will be used to inform future service delivery models and provide an assessment about the efficacy of the
rehabilitation process. In-depth knowledge about the processes of adaptation will be used to shape program
development and assist in community rehabilitation and lay condition-specific models of social support.
Name of contact: Narelle Warren
Email of contact: Narelle.Warren@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436629
CIA Name: Prof David Cooper
Main RFCD: Intensive Care
Admin Inst: Monash University
Start Year: 2007
End Year: 2011
Total funding: $360,313
Grant Type: Established Career Fellowships
Title of research award: Practitioner Fellowship
Lay Description (from application):
I am an intensive care physician, clinician and researcher, interested in studying new therapies to improve
outcomes in patienst with acute trauma, sepsis and lung injury. A main focus is independent phase 111 clinical
trials in critically ill patients
Research achievements (from final report):
In 2011, I published two pivotal clinical trials in NEJM, one as first author. I had 70 papers in the past 5 years, and
23 in 2011. My h-index is 25. Both trials published in NEJM in 2011 (DECRA and PROTECT) have impacted
clinical practice (Marion D. Lancet Neurol. 2011 Jun;10(6):497-8). The publication of the DECRA trial (N Engl J
Med. 2011 April; 364(16): 1493-502) was described as a "fundamental event in the history of decompressive
craniectomy for traumatic brain injury" (Hutchison P, B J Neurosurg 2011; 25(3): 441-442), and as "one of the
most important clinical trials of a novel therapy for severe TBI, and a class 1 study which should be considered as
foundation for an evidence based guideline" (Lancet Neurol. 2011 Jun;10(6):497-8). DECRA was the first
randomised controlled trial of any neurosurgical technique in neurotrauma. It will change clinical practice and is
likely to save Australian health care 1-200 million dollars annually.
Expected future outcomes:
I will lead 2 main research programs: Improving outcomes after traumatic brain injury; and Optimising patient
blood management in critical care. Three NHMRC currently funded multicentre clinical trials (two as CIA) and
the CRE grant (CIA) provide the major components and main funding support for these programs. Organising an
international conference in Italy on clinical trials in intensive care.
Name of contact: D J (Jamie) Cooper
Email of contact: jamie.cooper@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 284354
CIA Name: Prof Rachelle Buchbinder
Main RFCD: Endocrinology
Admin Inst: Monash University
Start Year: 2004
End Year: 2007
Total funding: $586,250
Grant Type: NHMRC Project Grants
Title of research award: Efficacy and safety of vertebroplasty for treatment of painful osteoporotic spinal
fractures: a randomised trial
Lay Description (from application):
Painful spinal or vertebral fractures are a substantial and growing public health problem and are a burden on the
health care system. In Australia, 20-25% of women and 15-20% of men over the age of 50 will develop one or
more fractures of their spine in their lifetime. Up to a half of these fractures will result in severe pain and
disability. While the fractures generally heal within weeks or a few months, some are so painful that they require
narcotic pain control, hospitalisation, and/or long-term nursing home care. Other problems include chronic pain,
spinal deformities, loss of height and mobility and restricted breathing. Vertebroplasty is a new procedure
consisting of injection of a type of 'bone cement' into the vertebrae to mend the break. It is an exciting treatment
because for some people, this results in an immediate and sustained improvement in pain. Although rare,
complications such as rib fracture, cement leakage and fractures in other vertebrae do occur. One particular
concern is that the mechanical changes to the spine caused by the bone cement may cause long-term
complications such as an increased risk of future fractures of treated or adjacent vertebrae. So far, there is very
little evidence of the efficacy and safety of this new technology. Importantly, it has not been compared with usual
medical care for fractures. In medical research it can be difficult to properly evaluate an exciting and 'apparently'
effective treatment that doctors and patients demand. The main aim of this project is to determine whether
vertebroplasty is an effective and safe treatment compared to usual medical care. We have a unique opportunity to
evaluate vertebroplasty through a strong collaborative effort between the 3 centres currently offering this
procedure in Melbourne. If vertebroplasty can be demonstrated to be an effective, safe and cost-effective
treatment for painful osteoporotic spinal fractures this will be a valuable addition to current treatment options.
Research achievements (from final report):
Painful vertebral fractures complicating osteoporosis are a substantial and growing public health problem leading
to severe morbidity and an increased burden on the health care system. Vertebroplasty is becoming an
increasingly accepted treatment for vertebral fractures despite the lack of scientific evidence of its benefit. The
outcome of our proposed research will be to establish whether vertebroplasty is efficacious, safe, and costeffective compared to placebo for painful osteoporotic spinal fractures. If positive, we will have scientific
evidence to support the currently uncorroborated widespread endorsement of this intervention. If, on the other
hand, our results indicate that its efficacy is no greater than placebo (and it may do more harm), then the resources
spent on performing these procedures might be put to better use. We have published an editorial outlining our
concerns about use of vertebroplasty without high quality evidence of its benefit.
Expected future outcomes:
We will determine the short term efficacy and safety of vertebroplasty for alleviating pain and improving function
for acute painful osteoporotic vertebral fractures and examine if there is excess risk of further vertebral fractures
within two years.
Name of contact: Professor Rachelle Buchbinder
Email of contact: rachelle.buchbinder@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284278
CIA Name: Prof Uwe Proske
Main RFCD: Central Nervous System
Admin Inst: Monash University
Start Year: 2004
End Year: 2006
Total funding: $287,250
Grant Type: NHMRC Project Grants
Title of research award: Changes in motor control and kinaesthetic sensations after eccentric exercise.
Lay Description (from application):
It is a well-known observation that after a period of intense exercise we are unsteady on our feet and are clumsy
when attempting to make precision movements. Such impressions are particularly marked after eccentric
exercise, during which the contracting muscles are forcibly lengthened. Activities such as walking downhill,
skiing and horse riding involve eccentric exercise. The debilitating consequences of this kind of exercise are
attributed, not just to the post-exercise effects of fatigue, but to loss of muscle force from damage to fibres.
Eccentric exercise also leads to longer term effects. The breakdown of the damaged tissue leads to sensations of
stiffness and soreness the next day. This application proposes experiments aimed at studying a number of effects
of eccentric exercise on motor control, and establishing the muscle, spinal and brain levels at which they occur.
Three studies are planned. In the first, the question will be explored whether we are less able to use the motor
areas of our brains to execute voluntary contractions after exercise. So fatigue is not just a matter of exhausted
muscles but perhaps also exhausted brains. We will use brain and spinal cord stimulation to explore this point.
Then we plan to listen to single motor units, the basic elements of muscle control, to try to understand the
mechanism by which the brain minimises the debilitating effects of fatigue. Finally we want to examine subjects'
ability to locate their limbs in space as a means of providing a basis for the clumsiness we experience after
intense exercise. These are all important issues relevant to clinical medicine and rehabilitation as well as sports
science and exercise.
Research achievements (from final report):
We have studied human position and movement sense in a number of ways and obtained significant new data.
When in an arm-matching task one arm is loaded with a heavy weight, the blindfolded subject is able to match its
position just as accurately as they did with the unloaded arm. When one arm was exercised to fatigue, this
disturbed the subject's ability to match the positions of their two arms. The degree of disturbance was correlated
with the level of fatigue. Matching errors suggested that subjects perceived their fatigued muscles to be longer
than they actually were. These findings are unexpected and they compliment earlier observations on the paralysed
anaesthetised hand. Clearly mechanisms within the brain are involved in determining arm position when the arm
muscles are active, as in bearing a load. Such a conclusion represents a major shift in present-day thinking in this
area. It has implications for the interpretation of the neural basis of certain neurological conditions such as
schizophrenia and Parkinson's disease.
Expected future outcomes:
Important implications of this work relate to the effects of fatigue in sport and exercise. A fatigued athlete can be
uncertain of the position of their limbs if they are not expressly looking at them. The effects of exercise in
disturbing proprioception also has implications for the elderly. Proprioception is an important indicator of the risk
of falls in the elderly.
Name of contact: Uwe Proske
Email of contact: uwe.proske@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 545865
CIA Name: Dr Kathleen Burman
Main RFCD: Motor Control
Admin Inst: Monash University
Start Year: 2009
End Year: 2011
Total funding: $554,656
Grant Type: NHMRC Project Grants
Title of research award: Plasticity of sensorimotor representations in adult primate cortex
Lay Description (from application):
Cells in some regions of the brain, collectively known as the sensorimotor cortex, control our capacity to
purposefully move the arms and hands. Damage to these regions in adults causes severe deficits. However,
rehabilitative training can restore some control over the muscles. To understand how the brain circuits change to
compensate for injury, and what effect rehabilitation may have on these changes, I will study cellular alterations in
the movement control pathways in the cerebral cortex.
Research achievements (from final report):
This project focused on how the non-human primate brain reorganises after injury to the areas responsible for
sensation and movement, including a close examination of the connections of premotor areas. The results have
provided limited support for the idea that focal ischemic lesions followed by spontaneous recovery of arm
movement promote massive rearrangements in cortico-cortical sensorimotor pathways. The tracer experiments
indicate that parietal somatosensory areas 1 and 2 are directly linked to the ventral premotor cortex in both normal
and lesioned animals. However, they suggest differences in the density and distribution of connections from the
granular and retroinsular cortices to the ventral premotor cortices, with lesioned animals showing a more robust
projection. These results suggest that rodent studies alone may not provide the best information for strategies
aimed at improving motor function in humans recovering from stroke. Our results also add to our understanding of
the organisation of motor areas in the non-human primate brain.
Expected future outcomes:
These results enhance our understanding of the finer organisation of motor areas in the non-human primate and
how the brain controls movement and may lead to better strategies for managing stroke recovery in humans.
Name of contact: Kathleen Burman
Email of contact: kathleen.burman@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334002
CIA Name: Prof Jennie Ponsford
Main RFCD: Neurosciences not elsewhere classified
Admin Inst: Monash University
Start Year: 2005
End Year: 2007
Total funding: $328,050
Grant Type: NHMRC Project Grants
Title of research award: Fatigue, attention and sleep disturbance after traumatic brain injury
Lay Description (from application):
Traumatic brain injury (TBI) is a major cause of disability in young people. A major obstacle to the rehabilitation
of these young people and their return to work or study is their susceptibility to fatigue post-injury. Sleep
disturbance is also often reported following TBI and this may accentuate fatigue. Suprisingly, little research has
been conducted on the nature, causes or progression of fatigue and sleep disorders following TBI and their
possible interrelationships. This study aims to investigate the incidence and extent of fatigue in a large group of
people who have experienced a TBI compared to a control group, how fatigue changes over time and its impact on
daily life. The study will also address whether higher fatigue levels are associated with decreased attention and
speed of information processing. Changes in sleep patterns will also be investigated using both subjective
measures, such as sleep quality and daytime sleepiness, and objective physiological measures, such as the time of
dim light melatonin onset and polysomnography, comparing the head injured group with controls. The
interrelationships between fatigue and sleep changes will then be examined and also their association with injury
severity, the location of the brain injury, the time since the injury, age, the presence of any cognitive impairments
and the incidence of depression. The project has the potential to provide valuable information to healthcare
professionals on the diagnosis of fatigue and sleep disorders in head injury patients. The investigation of the
nature, causes and impact of fatigue and sleep disorders could also provide a basis for therapy. For example,
fatigue and problems with attention and slowed information processing can be minimized by restructuring lifestyle
demands and simple and effective treatments are available for many sleep disturbances, such as bright light
therapy and/or exogenous melatonin.
Research achievements (from final report):
This project has provided valuable information to health care professionals about fatigue and sleep changes
following TBI, whilst also providing information as to which assessment tool/s best identify fatigue and sleep
disturbances following TBI. The identification of an association between fatigue and deficits of attention and
speed of information processing has provided a basis for structuring lifestyle demands to minimize demands on
these processes and thereby minimize fatigue. An association was also identified between depression and fatigue,
highlighting the fact that if depression is treated appropriately, then fatigue might also be alleviated. Examining
the nature and extent of sleep disturbances has highlighted the need for the development of treatments for daytime
somnolence, a further source of fatigue, debilitation, and reduced feeling of wellbeing following TBI. Simple and
effective treatments are available for many sleep disturbances. For example where changes in the circadian system
are demonstrated, bright light therapy and/or exogenous melatonin may be administered.
Expected future outcomes:
On the basis of these study findings, we have now developed a proposal for an intervention study to alleviate
fatigue, daytime sleepiness and sleep disturbance, comparing the effectiveness of cognitive behaviour therapy,
and/or light therapy with treatment as usual.
Name of contact: Professor Jennie Ponsford
Email of contact: jennie.ponsford@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 456097
Start Year: 2007
CIA Name: Dr Terrence Haines
End Year: 2009
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $524,137
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Title of research award: Randomised controlled trial of multimedia patient education approaches to preventing
in-hospital falls
Lay Description (from application):
In hospital falls are one of the most frequently occurring adverse events in Australian hospitals. They are the
cause of considerable patient morbidity, stress to family members and care givers, and health care resource use.
However, there are many potential causes of in-hospital falls which has made minimising them a difficult task for
hospitals around the country. Recent evidence has indicated that a patient intervention strategy is useful for
preventing in-hospital falls as a part of a multi-factorial falls prevention program. This research aims to
investigate the effectiveness and economic benefit of two approaches to providing patient education for the
prevention of in-hospital falls. Patients at high risk for falls will be recruited from the Princess Alexandra
Hospital and be randomly allocated to either a DVD + 4 sessions of face-to-face education with an occupational
therapist program, to a DVD alone education program, or to a usual care with no additional education control
condition. Patients will be followed up until their discharge from hospital and the number of in-hospital falls they
incur will be compared between groups. It is expected that both the DVD + 4 sessions of face-to-face education
with an occupational therapist program, to a DVD alone education program will be effective in reducing falls and
that the DVD alone education program will demonstrate the greater cost-effectiveness in reducing falls.
Stemming from this research, it is anticipated that a cost-effective resource for preventing in-hospital falls will be
developed and evaluated such that it can be used in hospitals Australia wide.
Research achievements (from final report):
The patient education program developed as a part of this research reduced falls amongst cognitively intact
hospital inpatients by 50% across acute and subacute hospital wards. This is the first time a single intervention
has been shown to reduce falls in a hospital population internationally. This program has been the subject of
keynote addresses at national and international conferences and has now been translated into practice in several
hospitals around Australia, Hong Kong and the United Kingdom.
This project advanced the methodology of conducting falls research in hospitals by demonstrating that hospital
incident reporting systems under-report falls by ~30%, creating a considerable source of bias in some studies.
This study advanced the methodology of conducting meta-analyses in fields where the outcome of interest is a
recurrent event by demonstrating that standard meta-analysis approaches create confidence intervals that are too
narrow.
This study demonstrated that hospital patients face a high burden of falls once they have been discharged from
hospital, but have little idea of effective intervention strategies, so are unable to effectively self-manage.
Expected future outcomes:
Further work build on this study is currently underway to better understand risk taking by older adults, to examine
the economic efficiency of hospital falls prevention programs and to develop programs to prevent falls once older
adults are discharged from hospital.
Name of contact: Terry Haines
Email of contact: terrence.haines@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 236859
CIA Name: Prof Julian Rood
Main RFCD: Medical Bacteriology
Admin Inst: Monash University
Start Year: 2003
End Year: 2003
Total funding: $136,750
Grant Type: NHMRC Project Grants
Title of research award: Pathogenesis of clostridial myonecrosis
Lay Description (from application):
The aim of this project is to provide a better understanding of the mechanisms underlying the development of gas
gangrene, an often fatal disease of particular significance to elderly and diabetic patients, who are particularly
susceptible following injury, or surgery, or in some cases when suffering from colon cancer. Although research
has been carried out on this disease for many years prompt surgical removal of the infected tissue, often including
amputation of a limb, is still commonly used to ensure the patient's survival. This project involves the study of the
two bacteria that are the major causes of the disease. We aim to find out how the bacteria mediate the disease, in
particular to determine which toxic factors produced by the bacteria are involved. The normal host response to a
bacterial infection is a rapid influx of white blood cells to the infected tissue, which is part of the normal
inflammatory response. These cells engulf and degrade the bacteria, clearing the infection. However, a major
characteristic of gas gangrene pathology is that very few white blood cells infiltrate the infected tissue. We aim to
determine why the host fails to mount an inflammatory response to this bacterial infection. We will achieve this
objective by developing a better understanding of the role of the bacterial toxins in the development of this morbid
disease. It is hoped the results from this study will enable the development of more effective therapeutic and
prophylactic treatments for this disease and also provide a foundation for studies into the modulation of the host
response by other bacterial species.
Research achievements (from final report):
The research will continue as originally proposed with a focus on elucidating the mechanism by which pathogenic
bacteria can mediate gas gangrene, an often fatal disease of particular significance to the elderly or to diabetics.
These patients are particularly susceptible following injury, or surgery, or in some cases when suffering from
colon cancer. Continued studies will aim to determine how the toxic factors produced by the bacteria are involved
in the disease process. The normal host response to a bacterial infection is a rapid influx of white blood cells to the
infected tissue, which is part of the normal inflammatory response. These cells engulf and degrade the bacteria,
clearing the infection. However, a major characteristic of gas gangrene pathology is that very few white blood
cells infiltrate the infected tissue. Further studies will determine why the host fails to mount an inflammatory
response to this bacterial infection. It is hoped that the results from this study will enable the development of more
effective therapeutic and prophylactic treatments for this disease and also provide a foundation for studies into the
modulation of the host response by other bacterial species.
Expected future outcomes:
N/A
Name of contact: N/A
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 465142
CIA Name: Dr Yuanyuan Wang
Main RFCD: Rheumatology and Arthritis
Admin Inst: Monash University
Start Year: 2007
End Year: 2010
Total funding: $282,008
Grant Type: Early Career Fellowships (Australia)
Title of research award: The effect of sociodemographic and lifestyle factors on the risk of primary and revision
joint replacement.
Lay Description (from application):
Not Available
Research achievements (from final report):
The project explored the ethnic disparity in total joint replacement utilization in Australia, and examined
associations between lifestyle factors including obesity, physical activity, and diet, and the risk of total joint
replacement for osteoarthritis. The research on the disparities of joint replacement utilization is crucial to healthy
policy in terms of the issue of equity: health service and resources should be fairly distributed on clinical needs,
but not by patient's cultural or socioeconomic background. The findings of the research identify the potentially
modifiable risk factors for osteoarthritis, contribute better understanding of the pathogenesis of osteoarthritis, and
inform novel preventive strategies for osteoarthritis. For example, muscle mass was shown to be beneficial to knee
cartilage, and fat mass to be detrimental to knee cartilage and associated with an increased risk of total joint
replacement. It may be that for effective prevention of osteoarthritis, weight loss programs should focus on both
fat mass reduction and muscle maintenence: simple weight loss alone may be insufficient. Thus, these may
facilitate more effective strategies to prevent osteoarthritis in the future.
Expected future outcomes:
Patient-related factors associated with the risk of revision joint replacement and the effect of adult weight gain on
the risk of total joint replacement will be further explored. Extension of this work may provide a stronger basis to
enable intervention studies to be conducted to reduce the risk of osteoarthritis.
Name of contact: Yuanyuan Wang
Email of contact: Yuanyuan.Wang@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 180404
CIA Name: Prof James Cooper
Main RFCD: Intensive Care
Admin Inst: Monash University
Start Year: 2002
End Year: 2006
Total funding: $269,750
Grant Type: Established Career Fellowships
Title of research award: Saline of Albumin Fluid Evaluation (Safe) study
Lay Description (from application):
Not Available
Research achievements (from final report):
This Practitioner Fellowship enabled completion and publication of two pivotal multicentre trials testing
resuscitation fluids in critically ill patients. These were published in JAMA and NEJM. A Victorian collaboration
tested prehospital hypertonic saline resuscitation in head injury patients, established that it did not improve long
term patient outcomes, and prevented widespread introduction on Australian ambulances. Second, an ANZICS
Clinical Trials Group (CTG) collaboration (the SAFE trial) found that contrary to previous research, albumin and
saline fluid resuscitation in intensive care patients were equally effective and safe. This finding enabled practice
change in Australia towards increased use of saline - with substantial cost savings. A substudy from SAFE, also
published in NEJM in 2007, found that saline resuscitation was associated with better survival in head injury and is changing clinical practice internationally in head injury patients.
During the Fellowship period, Dr Cooper obtained 5 further new NHMRC project grants for major clinical trials,
and established a new bi-national Intensive Care Research Centre (NHMRC Enabling Grant funded) at Monash
University. He also became Vice-Chair (and currently Chair) of the ANZICS CTG.
Expected future outcomes:
The multicentre clinical trials enabled by the Fellowship have translated to improved management of critically ill
patients internationally. Fluid resuscitation, management of severe head injuries, of septic shock, and prevention
of venous thrombosis have all been improved. The Research Centre will train a new generation of clinican researchers in intensive care medicine.
Name of contact: Prof David J (Jamie) Cooper
Email of contact: j.cooper@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400937
CIA Name: Prof Caroline Finch
Main RFCD: Epidemiology
Admin Inst: Monash University
Start Year: 2006
End Year: 2011
Total funding: $1,160,492
Grant Type: NHMRC Project Grants
Title of research award: A randomised controlled trial of exercise programs for preventing knee injuries
Lay Description (from application):
The promotion of physical activity, either through organised sport or active recreation, is a key public health
strategy in this country. However, there is a risk of injury during this participation and efforts need to be
undertaken to reduce this risk so that spor is safe for all. Sports injury prevention efforts to date in Australia have
been severely hampered by a lack of evidence supporting currently advocated countermeasures. This concern has
been recognised by both the NHMRC and the Commonwealth Department of Health and Ageing. It is imperative
that we formally evaluate the effectiveness of sports injury countermeasures in the context of broad community
level participation in sport, in contrast to previous research focussed on professional sport, and begin to deliver the
preventive measures to the community. Australian football is a popular sport throughout Australia and it is
associated with more medically-treated injuries than any other sport. Knee injuries are particularly common and
can have severe consequences. One of the most commonly recommended knee injury prevention strategies is a
well-designed exercise training program. Despite their potential to significantly reduce injury rates, the
effectiveness of exercise training programs to prevent knee injuries in football, and indeed in most other sports,
has not previously been assessed but has been identified as a priority research area by the NHMRC. This project
will determine the effectiveness of exercise training programs for preventing knee injuries in community-level
football players by monitoring injury rates, player behaviours and player attitudes before and after the training
programs are implemented.
Research achievements (from final report):
Because of the large amount of running and other game-specific manoeuvres necessary to play football,
footballers can sustain injuries to their lower limbs. Lower limb injuries are the most common football-related
injury and can have significant impact for players in terms of need for treatment and being unable to play the
game for a time. While it is well known from laboratory-based studies that strengthening and conditioning the
muscles and control of ligaments around the knee could potentially prevent these injuries, this evidence has not
previously been applied directly to community football. This study developed the first exercise training program
specifically for community footballers to reduce their risks of lower limb injury. The program was delivered and
trailed in two large football leagues in Victoria and Western Australia. The research team worked with
community football coaches and their training support staff to encourage players to undertake the guided exercise
program. The project has led to the refining of an "ideal" exercise training program that other coaches could
implement with their players to prevent lower limb injuries in the future. If players start, in their preseason, to
prepare for their football season using this training program, they are likely to have a reduced risk of injury and
will be able to play fully over the following playing season, with good performance and fitness benefits.
Expected future outcomes:
Our improved understanding of what motivates coaches to deliver, and players to adopt, exercise training
programs means that we can now deliver a program which is more likely to be successful in the future because it
is highly relevant for, and acceptable to, the culture of community football.
Name of contact: Caroline Finch
Email of contact: caroline.finch@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384366
Start Year: 2006
CIA Name: Dr Peter Kent
End Year: 2008
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $120,510
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Title of research award: A prospective cohort study of recent-onset low back pain in primary care.
Lay Description (from application):
Not Available
Research achievements (from final report):
This Fellowship funding was for an Australian researcher's participation in a large multi-national study of people
seeking care for low back pain, organised by a UK-based research group. The aim of that study was to identify
whether clinically important subgroups of low back pain exist with previously unrecognised treatment needs. That
UK-based study did not proceed.
As the aim of that study was still scientifically sound, the study protocol was redesigned in Australia to include
fewer countries and a more practical method. Developing a more practical method required: reviewing the
literature for evidence-based predictors of the outcomes of care; identifying best-practice statistical method for
analysing subgroups and creating a new conceptual framework for that method; and developing more efficient
questions to gather information from patients.
New research collaborations were established with research groups in Denmark and USA. Funding applications
for the Australian and Danish components of the project were submitted. The Danish component was successfully
funded as the main development site. Mid-way through the 4-year Fellowship, the project migrated to Denmark
and the Fellowship ceased.
Since the Fellowship ceased, the Danish collaborators have applied innovative information technology to the
project to allow multilingual, resource-efficient collection of information from patients. The first 1,500 people
entered the study during 2009 and another 5,000 are likely to during 2010.
Expected future outcomes:
This ambitious project is likely to identify modifiable risk factors for poor outcome from low back pain, and the
way those factors interact. It is also likely to provide a rich source of testable hypotheses about what treatment
particular groups of people respond to and do not respond to.
Name of contact: Peter Kent
Email of contact: peter.kent@slb.regionsyddanmark.dk
NHMRC Research Achievements - SUMMARY
Grant ID: 465103
CIA Name: A/Pr Belinda Gabbe
Main RFCD: Epidemiology
Admin Inst: Monash University
Start Year: 2007
End Year: 2011
Total funding: $471,059
Grant Type: Career Development Fellowships
Title of research award: Improving the measurement and monitoring of long term outcomes following trauma.
Lay Description (from application):
Not Available
Research achievements (from final report):
Traumatic injury remains a leading cause of the global burden of disease and is one of the seven National Health
Priority Areas. Advancements in the treatment of injuries has led to a global reduction in injury-related death
increasing the importance of measuring the burden of non-fatal injury, including the degree of functional loss,
ongoing disability and lost quality of life experienced by survivors. The key focus of the research undertaken
during this Career Development Award was the development, validation, and implementation of a methodology
for capturing long term disability outcomes following injury via trauma registries, one of the most detailed source
of injury-specific data available globally. Uptake of this methodology by the Victorian State Trauma Registry and
Victorian Orthopaedic Trauma Outcomes Registry has resulted in the largest repository of long term injury
disability outcomes and the only injury-specific monitoring systems to routinely collect data on long term
outcomes other than mortality. Additional observational and qualitative studies undertaken during this Award
have focused on the individual and societal impacts of injury, experiences with the delivery of trauma care, and
comparing outcomes of different treatment approaches and systems of care. The research has resulted in an
improved understanding of the course of recovery of following serious injury, factors contributing to good and
poor outcomes, and the impact of specialised trauma centre care on the quality of survival of injured patients.
Expected future outcomes:
This research will allow population-based monitoring of the long term outcomes following injury, including the
capacity to measure the impact of changes in delivery of care on patient outcomes. The data collected will also
provide contribute to validation and improvement of measurement of the global burden of non-fatal injury.
Name of contact: Belinda Gabbe
Email of contact: belinda.gabbe@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 236880
CIA Name: Dr Lesley Day
Main RFCD: Epidemiology
Admin Inst: Monash University
Start Year: 2003
End Year: 2009
Total funding: $706,500
Grant Type: Established Career Fellowships
Title of research award: Application of epidemiological methods to injury prevention research
Lay Description (from application):
Not Available
Research achievements (from final report):
This Fellowship supported a program of injury research directed towards two high risk populations- the farm
workforce, and older people. Key achievements in the farm safety area include the development of a tractor safety
rating system (STARS), the evaluation of guidelines for the retrofitting of safe access platforms for the prevention
of tractor run-over injuries, and the identification of novel risk factors for serious farm work related injury. These
three projects provide evidence to underpin prevention programs. The uptake of STARS and the guidelines for
retrofitting safe access platforms would contribute to the reduction of the two leading causes of tractor related
fatalities. The identification of being an employee or contractor, not having attended farm training courses, and
machinery age as risk factors for serious farm work related injury provides direction for strategic prevention
programs. The key achievements in the area of older persons' falls prevention included the testing to two popular
falls interventions - tai chi, and a multifactorial risk factor referral program- neither of which were found to be
effective in the groups in which they were tested. A train the trainer package for the NoFalls Exercise Program,
shown to be effective in previous research, was developed and 100 trainers, and 500 exercise class leaders were
trained across Australia. In addition, modelling of the impact of proven falls interventions if delivered at the
population level provides a foundation for decision making regarding public investment in falls prevention
programs.
Expected future outcomes:
Falls among older people, and the associated functional decline and injury, is a major challenge to the health and
quality of life of our ageing population. The work of the Fellowship in testing falls interventions, supporting
ongoing delivery of a successful falls intervention, and policy modelling, will continue to inform policy and
practice in this area.
Name of contact: Lesley Day
Email of contact: lesley.day@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334010
CIA Name: Prof Rachelle Buchbinder
Main RFCD: Rheumatology and Arthritis
Admin Inst: Monash University
Start Year: 2005
End Year: 2009
Total funding: $404,425
Grant Type: Established Career Fellowships
Title of research award: Practitioner Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The achievements of this research award have included the completion of several randomised controlled trials that
I have led including an important study investigating the value of vertebroplasty (an injection of bone cement) for
painful spinal fractures due to osteoporosis that has been increasingly used despite a lack of strong evidence
supporting its use. Not only did this trial fail to demonstrate significant benefits for vertebroplasty compared to a
sham procedure, it was also widely cited as exemplifying the dangers of adopting new treatments into routine
clinical pracice before they have been properly evaluated. The results of the completed trials are all immediately
implementable into clinical practice and have the potential to improve health outcomes. Another achievement of
this award has been the involvement I have had with other colleagues in establishing the Australian Rheumatology
Association Database (ARAD), a highly productive and valuable resource that is providing important information
about the long-term benefits and risks of the newly available biological drugs for inflammatory arthritis sufferers
in Australia. This research award has made it possible for me to expand my activities related to my role as Joint
Coordinating Editor of the Cochrane Musculoskeletal Group with the completion of many new revews. Together
with my linguistic colleagues I have also developed a novel linguistic framework for improving the quality of
written patient materials about medication, and together with other colleagues I have also established a program of
research in the field of health literacy.
Expected future outcomes:
The expected future outcomes of my work include improvements in evidence-informed management of various
musculoskeletal conditions, clarification of the long-term benefits and risks of exposure to biological drugs for
inflammatory arthritis, improvements in written patient information and recognition of the importance of health
literacy to good health.
Name of contact: Rachelle Buchbinder
Email of contact: rachelle.buchbinder@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 314502
CIA Name: Prof James Cooper
Main RFCD: Intensive Care
Admin Inst: Monash University
Start Year: 2005
End Year: 2007
Total funding: $490,500
Grant Type: NHMRC Project Grants
Title of research award: Multi-centre randomised trial of early decompressive craniectomy in patients with
severe traumatic brain injury
Lay Description (from application):
Despite optimal neurosurgical and intensive care therapy, many trauma patients with severe brain injury
(typically young males) have very poor long term neurological outcomes. Current knowledge suggests that a key
contributor to secondary brain damage which occurs after injury and to poor neurological outcomes is brain
swelling and subsequent increase in brain pressure. Present intensive care therapies to control brain pressure are
often not effective, and favourable neurological outcomes occur in only 20-30% of these patients. Small studies
suggest that a surgical operation called decompressive craniectomy (DC) may decrease brain pressure and
improve neurological outcomes in these patients. DC involves temporarily surgically removing a piece of skull
bone (during the swelling period) and replacing it when the swelling has subsided. DC is done under general
anaesthetic in unconscious patients and is used occasionally at present, although due to insufficient research the
benefits are controversial. The proposed study is a multi-centre randomised controlled study of best current
therapies plus early decompressive craniectomy vs best current therapies alone in selected unconscious patients
with severe head injury. The study outcome is patient neurological function measured 6 months after the injury.
A study of this type is required before early DC could become a routine therapy in Australia. Next of kin will
sign informed consent for the study and then also for the surgery if patients are randomised to surgery. The study
will be managed at the Alfred Hospital/Monash University in Melbourne and includes fifteen collaborating ANZ
neurotrauma centres over 3.0 years. There are >200 patients in Australia annually in this category with potential
for DC to increase favourable outcomes in >40 patients annually. Lifetime costs for these patients with severe
disability are > $2.4 million, so there may be substantial economic and social impact.
Research achievements (from final report):
Traumatic brain injury is a potentially devasting injury that predominantly affects young males. Approximately
10% of patients admitted with severe traumatic brain injury have a diffuse injury and persistent brain swelling that
is difficult to control with best medical managment. Over the past decade, mangement of these patients has been
shifting from barbiturate coma to decompressive craniectomy. This is a well established neurosurgical procedure
in which a large piece of skull bone is removed, stored for 1-2 months and then replaced.This project (NEJM
2011; 364:1493-1502) assessed for the first time in adults the effectiveness of this procedure. Patients with severe
diffuse traumatic brain injury that were suitable for the project were randomly assigned to receive best medical
care or decompressive craniectomy and best medical care. The results showed that surgery was extremely
effective in decreasing intracranial pressure (a measure of brain swelling), markedly decreased medical therapies
required for treatment of intracranial pressure, shortened ventilation time and shortened length of stay in
ICU.However despite these positive short term effects, the findings in relation to patient's functional outcome at 6
months were the reverse of what was expected. The group of patients who received surgery were more likely to
have a poorer outcome (death or dependent) compared to those who received best medical care. These results have
enormous significance as the functional outcomes of future patients with severe diffuse traumatic brain injury can
be substantiallyimproved by choosing best medical care rather than decompressive craniectomy for management
of raised intracranial pressure.
Expected future outcomes:
Further analysis of results will provide additional information about the use of decompressive craniectomy in
certain sub groups of patients.
Name of contact: Prof Jamie Cooper
Email of contact: Jamie.cooper@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 237024
CIA Name: Dr Belinda Gabbe
Main RFCD: Epidemiology
Admin Inst: Monash University
Start Year: 2003
End Year: 2006
Total funding: $261,500
Grant Type: Early Career Fellowships (Australia)
Title of research award: Outcomes of major trauma and sports injuries
Lay Description (from application):
Not Available
Research achievements (from final report):
Traumatic injury remains a leading cause of the global burden of disease. Reducing the burden of injury remains
a priority public health issue and requires detailed knowledge of its incidence and outcomes. The most commonly
used outcome measure in injury is the mortality rate. However, the vast majority of injured people survive. The
percentage of preventable deaths is now very low with improvements in trauma care increasing the probability of
surviving even severe injuries. This has placed a greater emphasis on determining the morbidity associated with
injury and, in particular, establishing the degree of functional loss, ongoing disability and lost quality of life
experienced by survivors. Despite acknowledgement that the greatest cost burden of injury exists in these aspects
of morbidity, routine measurement of injury outcomes other than mortality is rare, particularly in Australia.
Trauma registries, like other disease registries, provide the basis for monitoring the incidence and outcomes of
injury but have been under-utilised with respect to measuring outcomes other than mortality. The research
undertaken during this fellowship focused primarily on establishing the needs of trauma registries with respect to
outcomes measurement, evaluating existing measures of functional outcome and implementing functional and
quality of life measures into the population-based Victorian State Trauma Registry and the Victorian Orthopaedic
Trauma Outcomes Registry. The routine monitoring of post-hospital discharge outcomes will enable monitoring
of trauma outcomes over time, the identification of sub-groups of injury at higher risk of poor outcomes, and
provide the information necessary to drive improvements in trauma care.
Expected future outcomes:
The future outcomes of this research will be ongoing monitoring of the long term outcomes following injury, an
improved understanding of the burden of injury, and the ability to inform trauma care policy, delivery and injury
prevention research in order to reduce the public health burden of injury
Name of contact: Belinda Gabbe
Email of contact: belinda.gabbe@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 380832
CIA Name: Prof Claude Bernard
Main RFCD: Cell Neurochemistry
Admin Inst: Monash University
Start Year: 2007
End Year: 2009
Total funding: $325,911
Grant Type: NHMRC Project Grants
Title of research award: Targetting Nogo A as a means to promote CNS axonal regrowth
Lay Description (from application):
Unlike the peripheral nervous system, regenerative nerve fiber growth and structural plasticity are limited in the
adult mammalian central nervous system (CNS), following injury. Although lesioned axons can sprout
spontaneously, this regeneration attempt is transitory and no significant re-growth occurs over long distances.
Consequently, injury to the CNS often leads to permanent disability. In many cases, it has been shown that it is
not the absence of growth-promoting molecules in the CNS but rather the presence of axon outgrowth inhibitors,
including components of both CNS myelin and astroglial scars that limit regeneration. Given that axonal injury is
an important pathological determinant of permanent disability in multiple sclerosis (MS), we have recently
investigated the role of the CNS neurite outgrowth inhibitor, Nogo A in the development of a chronic form of
murine MS-like disease. We showed that targeting Nogo A by active and passive immunization blunts clinical
signs, demyelination and axonal damage associated with this model of MS. These results identify Nogo A as an
important determinant of the development of autoimmune-mediated demyelination and suggest that its blockage
may help to maintain and/or to restore the neuronal integrity of the CNS after autoimmune insult in disease such
as MS. The principal goal of this application is to study the mechanism by which blockade of Nogo A improves
clinical outcome in disease like MS and to determine whether neurite sprouting accounts for such an
improvement. Targeting Nogo A and/or its receptor, has the potential to not only regulate/modulate the process of
autoimmune mediated demyelination but could lead to the first therapy ever offered to patients that helps damaged
nerves regenerate after axonal injury following neurodegeneration due to insult or disease.
Research achievements (from final report):
The motor deficit that characterized multiple sclerosis (MS) patients results from the degeneration and loss of both
large and small caliber axons. The molecular mechanisms that underlie axonal degeneration are relatively
unexplored in both MS as well as its animal model, experimental autoimmune encephalomyelitis (EAE). We have
shown that the axonal growth inhibitor, Nogo-A, plays a central role in the pathophysiology of EAE. A
downstream effector of axonally-dependent Nogo-A-receptor signaling, is Rho-kinase (ROCKII). ROCKII is
known to phosphorylate and thereby inactivate CRMP-2, a critical determinant of tubulin assembly and axonal
growth. Therefore, we examined the protein levels of ROCKII-phosphorylated CRMP-2 (pThr555-CRMP-2) in
the spinal cord of C57BL/6 mice during the course of MOG35-55-induced EAE. Levels of axon-specific pThr555CRMP-2 were increased at the onset and peak stages of EAE-disease. This increase directly correlated with a
decrease in the levels of CRMP-2-bound tubulin. Furthermore, we found increased immunoreactivity to pThr555CRMP-2 in degenerating axons at and near the site of EAE lesions. This suggest that phosphorylation of CRMP-2
at the Thr555 site inhibits the normal physiological function of CRMP-2 in spinal cord axons and is associated
with axonal degeneration. Further clinical observation of Nogo Receptor 1 knock-out (ngr1-/-) mice revealed a
significant delay in EAE onset when compared with wild-type littermate controls. Extensive immune-phenotypic
analysis revealed no immunological defect in ngr1-/- mice. While there was an increase in total levels of CRMP-2
in ngr1-/- mice, the levels of pThr555-CRMP-2 was twelve-fold lower when compared with MOG35-55-EAEinduced wild-type littermates at peak stage of disease.
Expected future outcomes:
Demyelination is a major event in neurodegenerative disorders. Given that ROCKII mediated phosphorylation of
CRMP-2 downstream of Nogo receptor activation may play a role in the potentiation of axonal degeneration in
EAE.
Therefore the Nogo signal transduction pathway may be a promising target for promoting repair of axons in
neurodegenerative diseases, such as spinal injury, trauma and MS.
Name of contact: Bernard
NHMRC Research Achievements - SUMMARY
Email of contact: claude.bernard@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436815
CIA Name: A/Pr Cristina Morganti-Kossmann
Main RFCD: Neurosciences not elsewhere classified
Admin Inst: Monash University
Start Year: 2007
End Year: 2009
Total funding: $397,535
Grant Type: NHMRC Project Grants
Title of research award: Role of post-traumatic hypoxia in the exacerbation of cerebral inflammatory response
elicited by brain injury
Lay Description (from application):
Traumatic brain injury is the major cause of death in the young population below the age of 40 years.
Approximately 25% of patients that survive head injury remain with permanent neurological disabilities with
considerable family, professional and economic costs. Extensive research has shown that not all brain damage
occurs at the time of injury, but rather evolves over the hours and days following trauma. Secondary injury may
result from various factors including hypoxia (insufficient oxygen) as a consequence of respiratory distress that
occurs in about 50% of patients with severe head trauma. Hypoxia is known to significantly worsen the
neurological impairment and potentially lead to death. Brain injury and hypoxia have the ability to separately
trigger cerebral inflammation. A dual role has been attributed to inflammation: to promote tissue repair but also
add further damage through the release of neurotoxic substances. We hypothesise that hypoxia occurring after
traumatic brain injury enhances the inflammatory response in the brain and aggravate tissue damage as well as
neurological dysfunction. This hypothesis will be tested on a rat model of brain injury whereby the animals will be
exposed to moderate-severe hypoxia immediately after trauma. The production of multiple inflammatory
mediators will be quantified in the brain tissue and also in cerebrospinal fluid. The concentration of these
mediators will be compared with the levels of cellular injury proteins known to increase following injury to
determine whether a correlation exists. In a clinical study on patients, we will measure the same inflammatory
mediators and proteins in the cerebrospinal fluid and blood of individuals with severe head injury. The suitability
of these factors for potential use as diagnostic/prognostic markers of either hypoxia or injury will be determined.
Research achievements (from final report):
Epidemiological data have shown that a hypoxic event following head injury is associated with mortality and
disability in humans. However, the mechanisms exacerbating brain damage and neurological function after brain
trauma remain obscure. In this study we demonstrated that a hypoxic event following traumatic brain injury (TBI)
in a rat model of diffuse brain damage worsens neurological deficit and exacerbates neuroinflammation by means
of brain infiltration of blood macrophages, accumulation of microglia and glial activation. The synthesis of the
cytokines TNF, IL-1 and IL-6 was more elevated in the cortex of TBI-hypoxic rats than animals with TBI or
hypoxia alone. Most importantly, in this model of diffuse TBI, hypoxia enhanced axonal pathology in the corpus
callosum and brain stem up to 2 weeks post-injury.
In the clinical study based on patients (up to 36) with severe head injury, the occurrence of hypoxia immediately
after the accident showed a trend towards a protracted increase in the concentration of cytokines TNF, IL-2, IFN,
GM-CSF in the cerebrospinal fluid over 6 days as compared to patients with TBI without hypoxia. In addition,
when surrogate markers of brain damage were quantified in the blood of these patients, S-100 and myelin basic
protein were found more elevated in TBI-hypoxic group as compared to TBI normoxic individuals, whereas the
biomarker neuronal specific enolase was not different between the groups.
Collectively these studies corroborate in two distinct systems the detrimental effects of post-TBI hypoxia mostly
with enhanced brain inflammation. The use of the standardised animal model allowed us to deepen our
understanding of the role of hypoxia on neurological deficit, tissue damage and neuroinflammation at cellular and
humoral level. The identification of injury markers reflecting exacerbated brain damage may have significant
applications in the clinic.
Expected future outcomes:
This study has spurred further investigations in patients and rat model of TBI on the activation of the kynurenine
pathway which metabolises tryptophan, producing quinolinic acid, a potent neurotoxin. Electrophysiological and
therapeutic studies on the animal model will elucidate functional changes leading to neurological impairment and
strategies to improve outcomes after TBI-hypoxia.
NHMRC Research Achievements - SUMMARY
Name of contact: Cristina Morganti-Kossmann
Email of contact: cristina.morganti-kossmann@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 284402
CIA Name: Dr Donna Urquhart
Main RFCD: Orthopaedics
Admin Inst: Monash University
Start Year: 2004
End Year: 2008
Total funding: $268,650
Grant Type: Early Career Fellowships (Australia)
Title of research award: The characterisation of orthopedica trauma and the evaluation of outcome
Lay Description (from application):
Not Available
Research achievements (from final report):
Musculoskeletal conditions are major contributors to pain and disability in Australia, with more than 6.1 million
people affected. Moreover, with aging of the population and the obesity epidemic, these figures are expected to
rise. As a result, musculoskeletal conditions have been declared a National Health Priority. This research program
was aimed at investigating risk factors, outcomes and treatment strategies for musculoskeletal conditions,
including the two most common muscloskeletal conditions, low back pain and osteoarthritis.
Some of the key findings from our research program included; identifying that both high levels of back pain and
disability are associated with obesity in community-based women and that while knee malalignment is associated
with progression of knee osteoarthritis, there is insufficient evidence to support a relationship with the
development of this condition. With respect to outcomes, we found a large percentage of patients after
musculoskeletal injury have ongoing pain and disability and a reduced capacity to return to work 6 months after
their trauma and that partial and revision hip replacements are resource intensive for the public and private healthcare systems, respectively. Moreover, we found that there is no clear evidence to support the use of two common
treatment strategies, anti-depressants and radiofrequency deinnervation, for the management of low back pain.
This work has the potential to guide health and medical researchers in future epidemiological research into low
back pain and osteoarthritis, inform health services in the outcomes and resource utilisation associated with these
conditions, and assist clinicians in the selection of treatment strategies in the management of musculoskeletal pain
and disability. Ultimately, the findings of this research program will assist in the future development of innovative
strategies to prevent and manage chronic pain and disability associated with musculoskeletal conditions.
Expected future outcomes:
The findings of this research program will assist in the future development of innovative strategies to prevent and
manage chronic pain and disability associated with musculoskeletal conditions.
Name of contact: Donna Urquhart
Email of contact: Donna.Urquhart@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436620
CIA Name: Dr James BOURNE
Main RFCD: Sensory Systems
Admin Inst: Monash University
Start Year: 2007
End Year: 2009
Total funding: $460,947
Grant Type: NHMRC Project Grants
Title of research award: Development and maturation of the visual cortex
Lay Description (from application):
Much of the human brain is devoted to vision, which requires the integrated activity of many interconnected areas
of the cerebral cortex. Damage to these areas is a relatively common complication of preterm delivery and- or
perinatal conditions including trauma and infection. The severity of both the short- and long-term effects of these
lesions appears to be related to the time of the damage. The aim of this project is to investigate the way in which
the multiple visual areas of the brain develop and become 'wired' together in the period following birth. We will
also determine if there are mechanisms which allow alternate routes to be found for processing visual information
while the brain is still establishing connections between its multiple areas. This will allow us to understand the
anatomical and physiological bases of the deficits caused by early damage to the visual areas of the brain, and
perhaps point to strategies that will lead to improved recovery of visual function.
Research achievements (from final report):
Much of the human brain is devoted to vision, which requires the integrated activity of many interconnected areas
in the neocortex. Damage to these areas is a relatively common complication of preterm delivery and/or perinatal
conditions including trauma and infection. The severity of both short- and long-term effects of these lesions
appears to be related to the time of the damage. This project has demonstrated the ways in which the visual
cortical areas develop in sequence and how they purposefully interact following birth. Furthermore, at the micro
level it has enabled us to define the cellular networks that are involved in plasticity. The outcomes of this research
allow us to understand the anatomical and physiolgical bases of the deficits caused by damage to the visual
cortical areas of the brain early in life. The potential benefits are the development of strategties that afford
improved recovery of visual function.
Expected future outcomes:
The corollary of the outcomes achieved in this present study have been the design of potential strategies using
specific molecules that can afford rewiring of connections.
Name of contact: Dr James Bourne
Email of contact: james.bourne@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384414
CIA Name: Prof John Bateman
Main RFCD: Orthopaedics
Admin Inst: Murdoch Childrens Research Institute
Start Year: 2006
End Year: 2008
Total funding: $457,518
Grant Type: NHMRC Project Grants
Title of research award: Molecular mechanisms of cartilage degeneration in osteoarthritis
Lay Description (from application):
Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of
joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that
covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint
replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely
due to our incomplete understanding of the molecular changes and pathways involved in both the onset and
progression of cartilage breakdown. Powerful new genomic approaches allow simultaneous screening of changes
in a broad profile of genes, particulalrly in humans and mice following complete sequencing of their genomes. By
applying this new technology in the earliest stages of cartilage degeneration in OA, the role of novel genes and
the pathways involved in the onset of this disease process can be discovered. However, to investigate changes at
the initiation of disease, tissue from animal rather than human joints must be used due to the difficulty in obtaining
pre-symptomatic human cartilage. In order to maximise the number of genes screened, cartilage from a novel
surgically induced model of OA in mice will be used in this study. We have developed micro dissection and linear
mRNA amplification methods to overcome inherent problems with tissue availability from this small animal
species. Successful completion of these studies will for the first time allow identification of the complex changes
that occur in early OA. An important and likely outcome of this research will be identification of novel matrix
proteins and regulatory molecules that will provide critical information for the development of new diagnostic and
therapeutic approaches to OA.
Research achievements (from final report):
This is the first study to comprehensively determine the gene expression patterns of cartilage during the initiation
and progression of osteoarthrtitis. It has identified new genes that may play a role in either the onset or
development of joint disease. Because these studies have identified possible new molecular pathways that may be
involved in OA, the information obtained in these studies has potential for the development of novel biomarkers
ans therapeutic approaches
Expected future outcomes:
The novel OA candidate genes identified in this study will be examined in detail ongoing studies. The outcome of
these studies is likely to be a more complete elucidation of OA disease mechanisms.
Name of contact: John Bateman
Email of contact: john.bateman@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 216744
Start Year: 2002
CIA Name: A/Pr Cathy Catroppa
End Year: 2006
Main RFCD: Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)
Total funding: $127,815
Admin Inst: Murdoch Childrens Research Institute
Grant Type: Early Career Fellowships (Australia)
Title of research award: Long-term residual impairments in executive skills following childhood traumatic brain
injury (TBI)
Lay Description (from application):
Not Available
Research achievements (from final report):
-Through-out the approval time for this project a number of aims have been achieved. All assessments for those
agreeing to participate in the 7-10 year post-injury follow-up have been completed. Data entry has also been
completed. A number of manuscripts are also in progress, with a few of these ready for submission. Key findings
have also been disseminated at both national and international conferences.
-With regard to the pilot intervention component, the intervention was developed and a number of those eligible
for intervention have completed the program, and this data is now to be analysed, and a manuscript will follow.
Potential benefits:
: A clearer understanding of the long-term outcomes from paediatric TBI.
: A clearer understanding of the preditors of outcome following TBI in childhood.
: Development and evaluation of a pilot intervention program aimed at improving/preventing common residual
difficulties.
: The potential to invite other TBI children to take part in the intervention program.
Expected future outcomes:
- Improved quality of life for children who have sustained a TBI.
- Improved quality of life for families of children who have sustained a TBI.
Name of contact: Cathy Catroppa
Email of contact: cathy.catroppa@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 264597
CIA Name: Prof Kerr Graham
Main RFCD: Clinical Sciences not elsewhere classified
Admin Inst: Murdoch Childrens Research Institute
Start Year: 2005
End Year: 2009
Total funding: $2,000,000
Grant Type: Centre of Clinical Research
Excellence
Title of research award: Clinical Gait Analysis and Gait Rehabilitation
Lay Description (from application):
Substantial portions of the Australian population have some difficulty walking. People affected include children
with cerebral palsy, people who've had injuries playing sport and older people with Parkinson's disease,
osteoarthritis or who have had a stroke. The cost of managing arthritic conditions alone was estimated at $2.2
Billion for 2001. Gait analysis uses high technology video cameras, force transducers, muscle activity sensors and
computers to record how people walk and is now being used more and more commonly across Australia. The
technology is very similar to that now being used to capture how people move for the movie industry. The
technology allows us a better understanding of how people are moving and therefore of what treatments they are
likely to benefit from. Melbourne now has four Gait Analysis facilities working with different patient groups and
each with an international reputation for its work. These groups have combined to form the CCRE in Gait
Analysis and Gait Rehabilitation under the leadership of Professor H Kerr Graham (Royal Children's Hospital)
and Professor Bob Iansek (Kingston Centre, Southern Health).
Research achievements (from final report):
We have acheived our goal of generating much new knowledge about walking in healthy people and in those who
have difficulty walking due to diseases such as cerebral palsy, arthritis, Parkinson's disease and stroke. We have
made significant contributions to improving the methods of measuring walking and in better understanding the
biomechanics underlying how we walk. We know more about the effects of interventions to improve walking,
such as surgery, physiotherapy and orthotics. We have trained a large group of clinicians from medicine, surgery
and allied health backgrounds to conduct clinical research within this specialised field. We have also guided a new
group of academic researchers who have completed post-graduate research higher degrees in the disciplines of
medicine, physiotherapy, biomechanics, engineering, podiatry and prosthetics. We have led specialised
educational events to train clinicians and researchers to better understand and interpret clinical gait analysis
measurements. Our team have shared this knowledge widely and effectively, through conference presentations,
specialty meetings, peer-reviewed publications and clinical seminars. Our clinical colleagues have adopted some
of this new knowledge, with translation into the clinical management and measurement of people with gait
disorders.
Expected future outcomes:
Our multidisciplinary team of trained clinical researchers will continue to contribute high quality research in this
field. Knowledge gained will translate into better outcomes for people who have difficulty walking.
Name of contact: Professor Kerr Graham
Email of contact: kerr.graham@rch.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284518
Start Year: 2004
CIA Name: Prof Vicki Anderson
End Year: 2006
Main RFCD: Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)
Total funding: $338,900
Admin Inst: Murdoch Childrens Research Institute
Grant Type: NHMRC Project Grants
Title of research award: Long term outcome from early childhood brain injury: 10 year follow up
Lay Description (from application):
The primary aim of this project is to further improve our understanding of the long-term consequences of
childhood traumatic brain injury (TBI). Over the past decade our research team has ascertained a sample of
children sustaining TBI, and systematically followed their progress over a 5-year period. The project has an
international reputation, and is unique in terms of length of follow-up, prospective design and representative, wellmaintained sample. Our findings challenge the traditionally held view that children are resilient and recover fully
from early brain insult. Rather, we have shown that, up to 5 years post-TBI, many children experience
impairments in physical, cognitive and behavioural function. These impairments result in educational, vocational,
social and emotional problems, limiting the child's capacity to meet developmental expectations and achieve
adequate quality of life. The implication is that these problems will lead to life-long disability, resulting in high
levels of individual, family and community burden. However, with follow-up data limited to 5 years, there
remains a possibility that ongoing developmental processes may support an extended recovery period in childhood
TBI, in comparison to the 2-year period cited in adult models. The review of this sample, 10 years post-injury,
provides an unprecedented opportunity to address this possibility and to document recovery/outcome as children
move into adolescence and adulthood. Not all children experience problems post-injury. However, predicting
individual outcome remains a significant challenge, with particular clinical relevance to treatment and follow-up.
Thus, the second aim of the proposed study is to examine factors that contribute to recovery and outcome.
Research achievements (from final report):
This significant 10-year research project is one of the first internationally to explore outcomes of childhood head
injury in a prospective longitudinal study. The cohort in the current wave of data collection included 19/35
control and 40/96 traumatic brain injury (TBI) participants. Those who were able to be located agreed to
participate in the current wave of the study. Almost all participants consented to the complete research protocol,
providing data in the forms of Neuropsychological test results, parent-completed questionnaires, an MRI scan, and
a cheek swab for genetic testing of ApoE. In return for their assistance, all participants were provided with the
results of the MRI scan with recommendations as necessary, and a detailed report of the Neuropsychological
assessment written by a qualified Psychologist. The extensive dataset is up-to-date, and statistical analysis and
writing for publication is currently underway.
The information we obtain from the data analysis will help both children who have already sustained a TBI and
will help future cases of childhood TBI in several ways. These include educating care providers, clinicians and
the medical community broadly about common outcomes of childhood TBI, and providing suggestions about
principles to be incorporated into clinical best-practice. Children will be better able to contribute to society in the
long-term and have a better quality of life.
Expected future outcomes:
As this longitudinal study provides ground-breaking research into consequences of childhood head injury it has
already established a strong international profile for the investigators, and has generated great interest within the
research and medical communities. We anticipate publishing in internationally-recognised high-impact journals
in which previous waves of this research have been reported
Name of contact: Dr Cathy Catroppa
Email of contact: catroppc@tpg.com.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334337
CIA Name: Prof Vicki Anderson
Main RFCD: Mental Health
Admin Inst: Murdoch Childrens Research Institute
Start Year: 2005
End Year: 2007
Total funding: $277,000
Grant Type: NHMRC Project Grants
Title of research award: A prospective study of concussion in children and adolescents: Diagnosis, recovery and
risk factors for poor outcome.
Lay Description (from application):
Concussion is one of the most common neurological injuries and represents a significant public health issue in
Australia. The most common consequences of concussive injuries are reduced attention, slowed response speeds
and memory impairment. These cognitive processes are critical for performing common day-to-day activities in
childhood and adolescence (e.g. acquiring new knowledge and skills, attending to school work). Approximately
20% of concussive injuries occur during participation in organised sport. In adult populations, there are now
evidence-based guidelines for the diagnosis and management of concussion in sport. Few well-controlled studies
exist to identify the frequency and outcome of such injuries in child and adolescent populations, and there are
currently no guidelines for diagnosis and management of concussion in children. Further, the academic and social
consequence of concussion for the child remains unknown. This study will investigate the cognitive and
behavioural outcomes of concussion in young children and adolescents and will use this information to modify
and validate currently available adult concussion diagnosis and management paradigms for application with this
population. This study will also investigate risk factors for poor outcome following concussion in children and
adolescents, and provide age-appropriate data for use in the medical, behavioural and educational management of
concussed children and adolescents. A total of 3000 children aged between 10 and 18 years will be recruited to
participate in this study. All participants will undergo a baseline evaluation consisting of memory and attention
tests, a behavioural rating scale, and measures of educational ability. Participants parents will also provide general
health and demographic information. Children who are concussed during the year will be re-assessed within 48
hours of injury and again at 5 days, 10 days and 30 days post-injury to track recovery.
Research achievements (from final report):
This study examined the effect of concussion on cognitive functioning and physical symptoms in children and
adolescents. One of the most important achievements to come out of this study was the collection of a large
amount of data on cognitive functioning in healthy children and adolescents. This information represents a
significant contribution to the scientific literature and our results on attention and memory skills in children and
adolescents, recently presented at a major international conference, place our group at the forefront of
international research. Consistent with our original aims, we demonstrated that recovery from concussion is
different for children and adolescents than for adults as cognitive symptoms were most impaired approximately 10
days post-injury. However, our results on physical symptom endorsement were consistent with adult data, more
physical symptoms were endorsed in the days immediately after the injury. Finally, we demonstrated that a large
percentage of children who sustained a concussion during the study had previously had one or more concussions
indicating the potential risk for future injury associated with concussion. The results of this study represent a
significant contribution and have important potential for the development of evidence-based interventions and
age-appropriate guidelines governing safe return-to-play. During the course of the study we developed close
relationships with major sporting organisations, such as Cricket Victoria and Basketball Victoria. As a result of
this, our results will be incorporated into training sessions, a number of which have already been conducted, to
better educate coaches about the effect of concussion in sports.
Expected future outcomes:
We have 2 manuscripts in preparation and expect them to be in submission in the coming months. We anticipate
presenting the results at a major international conference early next year. In addition, this work has led to the
development of other research projects which have attracted high-profile international collaborators.
Name of contact: Prof Vicki Anderson
Email of contact: vaa@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284519
Start Year: 2004
CIA Name: Dr Peter Anderson
End Year: 2006
Main RFCD: Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)
Total funding: $255,475
Admin Inst: Murdoch Childrens Research Institute
Grant Type: NHMRC Project Grants
Title of research award: The role of psychosocial factors on recovery following early brain insult.
Lay Description (from application):
Early brain insult (EBI) is a major cause of developmental delay and long-term disability. However, outcome
following EBI is variable and dependent on multiple injury-related and non-injury-related factors. To date, most
research has focussed on injury-related variables such as age at insult, nature of brain pathology, and size and site
of brain lesion. These injury-related factors predict short-term recovery following EBI, however they have been
found to account for a surprisingly modest portion of variance in long-term outcome. Thus, non-injury-related
factors must also contribute to outcome following EBI. Research now suggests that psychosocial characteristics
(social status, environmental conditions, parenting characteristics, family dynamics) influence long-term outcome
following EBI, however these studies have focussed on bivariate relationships, relied on specific patient groups
limiting the generalisability of findings, and utilised small to moderate samples that are inadequate when
investigating complex interactive relationships. As a consequence, the role of psychosocial factors on recovery
following EBI is still unclear. The objective of this project is to undertake a large-scale investigation of the
independent and interactive contribution of social status, environmental conditions, parenting characteristics and
family dynamics on outcome following EBI. The aim is to identify the psychosocial characteristics that predict
outcome, mediate recovery, and buffer the impact of injury-related factors in children with EBI. Understanding
these complex inter-relationships is crucial for rehabilitation purposes, as many psychosocial characteristics are
fluid and at least partially modifiable. Based on this project's findings we intend to devise and trial appropriately
focussed intervention programs that aid recovery and minimise long-term disabilities.
Research achievements (from final report):
The objective of this study was to undertake a large scale investigation of the independent and interactive
contribution of social status, environmental conditions, parenting characteristics, and family dynamics on longterm outcome following early brain injury. Thus the aim was to identify the psychological characteristics that
predict outcome, mediate recovery, and buffer the impact of injury-related factors in children with early brain
injury.
This project has recruited a large sample of children with documented brain pathology (head injury, prematurity,
cerebral infection, tumour, hypoxia, and stroke). These children were aged 10-15 years at the time of testing, and
have a documented brain insult (CT/MRI/ultrasound) sustained more than 2 years prior to assessment. We have
recruited and assessed over 150 children, and this will be the largest sample of its kind to assess these issues. The
outcome measures used in the study assess general intelligence, adaptive functioning, behavioural and emotional
status, social skills and academic achievement. Social-demographic factors measured to assess their role in
recovery following early brain injury include parental occupation, parental education, family income, and type of
schooling (private/public). The environmental factors assessed include the parenting characteristics, parenting
mental health, family structure, family functioning, and family burden.
While the data has been entered and clean, final analyses is only just beginning. Thus, no papers have yet been
published from this data, however this is a unique dataset and numerous papers will emanate from this study over
the next 2 years. Findings from this study will assist clinical services identify children and families at greatest risk
for poor outcome, enabling more targeted intervention and allocation of limited resources.
Expected future outcomes:
The results from this study will provide rich information as to why some children recover well following early
brain insult while others struggle. This information will then be used to devise and trial appropriately focussed
intervention programs that aid recovery and minimise long-term disabilities.
Name of contact: Dr Peter Anderson
NHMRC Research Achievements - SUMMARY
Email of contact: peter.anderson@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 437205
CIA Name: Prof Peter Drummond
Main RFCD: Peripheral Nervous System
Admin Inst: Murdoch University
Start Year: 2007
End Year: 2009
Total funding: $345,473
Grant Type: NHMRC Project Grants
Title of research award: Involvement of adrenergic receptors in neuropathic pain
Lay Description (from application):
After nerve or tissue injury including burns, some people will suffer from a condition called neuropathic pain.
This is a condition where chronic pain is endured, often totally unrelated to the initial injury or induced by events
that would normally not be painful. Our project will determine whether this abnormal pain response is due to an
abnormal communication between the nerves that carry pain signals (sensory nerves) and nerves that form part of
the sympathetic nervous system, which is part of autonomic (or involuntary) nervous system. We believe that this
abnormal communication is due to an increase in the expression of special receptors called adrenergic receptors,
on the sensory nerves. Our project will look at these receptors in the skin of animals that have had pain conditions
induced, and also in skin samples from patients who suffer from neuropathic pain that can be classified as
sensitive to sympathetic stimulation. By better understanding how neuropathic pain is derived, we can open the
door to novel treatment approaches in these difficult to treat conditions.
Research achievements (from final report):
Neuropathic pain is a difficult and costly health problem. It is a common condition that is often misdiagnosed and
difficult to treat because we do not understand the primary factors that drive the disease. The studies in this project
concentrated on clarifying the biological basis of a link between the pain processing system and the sympathetic
nervous system which is thought to contribute to certain forms of neuropathic pain.
We discovered that pain-signalling nerves contain a molecular target for noradrenaline, the chemical messenger
released by the sympathetic nervous system, that controls blood flow through the skin. We also found that
activation of this molecular target, termed the alpha-1 adrenoceptor, increases the excitability of pain-signalling
nerves and ultimately sends pain messages to the brain. In addition, we identified an increase in the expression of
these receptors on nerve fibres that survived an injury to the sciatic nerve.
Together, these findings help to explain the link between the pain-processing system and the sympathetic nervous
system. They also introduce a novel target for analgesia that could potentially alleviate pain in the skin of patients
with neuropathic pain.
Expected future outcomes:
The next step is to find out whether an antagonist to the alpha-1 adrenoceptor suppresses pain when taken orally
or when applied in a topical preparation to the skin of patients with neuropathic pain. Topical application is the
preferred aproach as this would avoid unwanted side-effects of oral medication.
Name of contact: Dr Peter Drummond
Email of contact: p.drummond@murdoch.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157305
Start Year: 2001
CIA Name: A/Pr Julie Bernhardt
End Year: 2004
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $127,599
Admin Inst: National Stroke Foundation
Grant Type: Early Career Fellowships (Australia)
Title of research award: Walking handicap and falls in stroke survivors
Lay Description (from application):
Not Available
Research achievements (from final report):
This research award has led to the development of a new model and direction of stroke rehabilitation research with
the potential to: 1) unite researchers and clinicians from across Australia; 2) answer an important and timely
research question about stroke rehabilitation models of care and 3) reduce the burden of stroke experienced by
patients, carers and the broader community. The preliminary work for this research program led to new knowledge
about physical activity patterns of patients very early after stroke. This was published in the prestigous journal
Stroke. After identifying the routine high levels of bed rest (and low levels of activity) early after stroke, we
worked closely with collaborators in Norway to develop a very early model of rehabilitation suitable for testing
here in Australia. We chose Norway because this research group have demonstrated consistently better outcome
after stroke than other stroke units worldwide. Furthermore, preliminary evidence from their centre suggests that
very early rehabilitation is a major contributor to these outcomes. In the past 2 years we have: 1) gathered together
a small team to work on AVERT (A Very Early Rehalitation Trial); 2) developed the trial methods for AVERT
ensuring best practice randomised controlled trial methods are employed, 3) obtained approval from two hospitals
to conduct the trial, 4) commenced the Phase 2 safety and feasibility study, with 60 patients recruited to date, 5)
obtained over $200,000 in funding from a range of sources and 6) developed 10 collaborative centres here in
Australia and a collaborative centre in Glasgow UK, all interested in conducting Phase 3 of the trial at their
hospital. The preliminary work from this research program has been presented at National and International
conferences, with two further publications in preparation. Once Phase 3 funding is secured, we will conduct the
largest stroke rehabilitation trial (with economic evaluation) ever over the coming 5 years.
Expected future outcomes:
We expect AVERT to be a landmark study in the field of stroke rehabilitation research, regardless of outcome. If
early rehabilitation reduces death and dependency, leads to fewer and less severe complications, better quality of
life for patients and is cost effective (as we hypothesise), then we expect the practice to be adopted across
Australia, ultimately reducing the buden of stroke.
Name of contact: Julie Bernhardt
Email of contact: J.Bernhardt@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 388920
CIA Name: Dr Craig Harrison
Main RFCD: Endocrinology
Admin Inst: Prince Henry's Institute of Medical Research
Start Year: 2006
End Year: 2008
Total funding: $507,271
Grant Type: NHMRC Project Grants
Title of research award: Activin type II receptor antagonists: mechanism of action and biological applications
Lay Description (from application):
Activin is a member of the TGF- family of growth and differentiation factors. Over-expression in mice leads to
muscle and liver wasting, scarring during wound healing, disturbances to the reproductive system and various
endocrine disorders. Activin's biological activity is promoted by its binding in series to two receptors termed Type
I and II. Previous studies by this investigator have shown that selective modification of activin's protein structure
can result in activin forms (in this instance called activin-M108A) which bind to Type II receptors but fail to
promote binding to the Type I receptor. This has led to the hypothesis that activin-M108A may compete for native
activin binding to Type II receptors and thus prevent activin's recruitment of the Type I receptor with the
consequence that activin's biological activity is inhibited. It is proposed to test this hypothesis by producing
sufficient amounts of activin-M108A and testing its inhibitory effects in several mouse models of liver damage,
muscular degeneration and ovarian and testicular disease. If activin-M108A, or related modified forms of activin,
decrease the morbidity and mortality associated with these murine diseases, then we envisage that these activin
type II receptor antagonists will also be beneficial for the treatment of related human conditions.
Research achievements (from final report):
Activins are important regulators of diverse cellular functions, differentiation and proliferation that, of necessity,
are precisely constrained by multiple mechanisms. Despite these constraints a deregulated activin signalling
pathway has been implicated in a variety of disorders, including fibrosis, cachexia and cancer. We developed the
first activin type II receptor antagonist (activin-M108A) and showed that it is capable of blocking signalling in
vitro by activin and the related protein, myostatin. However, when assessed in the rat pituitary cell culture system,
activin-M108A was a poor antagonist of follicle stimulating hormone (FSH) release and in our preliminary animal
studies, no suppression of FSH was observed in ovariectomized rats (despite a robust suppression of FSH
observed upon addition of the known activin antagonist, inhibin). The major reason for the lower than anticipated
potency of activin-M108A is its significantly reduced affinity for the activin receptor complex. Therefore our
primary objective of utilizing activin-M108A as an activin/myostatin antagonist in vivo was not realized.
Subsequent studies, however, have made important contributions to the understanding of the mechanism of action
of key activin inhibitory molecules, including follistatin, betaglycan and inhibin. In addition, we have developed
second generation activin antagonists that are more effective than activin-M108A. These compounds could be
used to block activin signalling in disease models.
Expected future outcomes:
Our continuing studies have generated a more specific and potent activin A antagonist. Based on these studies, we
are also developing reagents that will specifically block other TGFbeta proteins. Given the importance of TGFbeta
proteins in development and the maintenance of tissue homeostasis, and their dysregulation in many disease
pathologies, this will be a significant achievement.
Name of contact: Craig Harrison
Email of contact: craig.harrison@princehenrys.org
NHMRC Research Achievements - SUMMARY
Grant ID: 443210
CIA Name: A/Pr Graham Kerr
Main RFCD: Geriatrics and Gerontology
Admin Inst: Queensland University of Technology
Start Year: 2007
End Year: 2009
Total funding: $680,793
Grant Type: NHMRC Project Grants
Title of research award: Dynamic postural stability and falls prediction in older people during walking in realworld environments.
Lay Description (from application):
The increased occurrence of falls with advancing age (33-50% of people aged >65 years) is a significant cause of
mortality (1014 deaths in 1998), morbidity, and disability, affecting not only the individuals concerned, but the
health care system (45,069 fall related hospitalizations in 1998 in Australia) and the broader community (National
falls Prevention Initiative, 2004). Although there are a number of falls risk tests, most rely on determination of
body sway while standing when the body is static rather than in motion. Given that up to 70% of falls occur during
walking and performing transfers, there is a clear need to develop tests of falls risk prediction that incorporate
indices of postural stability measured during more dynamic activities. Test development needs to be underpinned
by clear evidence of how age-related sensory and motor deficits affect postural stability during walking. The
studies outlined in this application will develop and utilise new accelerometer-based technologies to determine the
fundamental mechanisms underlying balance control during walking in older people. Specifically, this project will
aim to develop a clear understanding of how changes in factors as vision, neuromuscular function (strength,
stiffness) and proprioception contribute to the overall decline in stability and balance during walking in older
people. Combined with physiological assessment measures developed by the research team, the research will
allow the development of a more definitive predictive test of stability and falls risk. This test will be able to be
used by health professionals for assessment of older people to determine the most effective therapeutic and/or
exercise interventions to target those individuals at risk. This technology will also be adaptable to a biofeedback
device to allow individuals to monitor their own stability.
Research achievements (from final report):
This research has developed new accelerometer-based technologies and innovative tests of trunk stiffness to
determine the fundamental mechanisms underlying balance control during walking and standing in older people.
These tools were used to investigate critical issues that have an impact on dynamic postural control and falls risk
in older people. In addition, visual factors that contribute to increased risk of falls were examined, particularly
those related to decreased contrast sensitivity and visual blur. The research was extended to include people with
neurodegenerative disease, partcularly Parkinson's disease, to determine similarities and differences in falls rick
factors with older people. This research has resulted in precitive tests for falls risk in older people.
Expected future outcomes:
This research will provide prospectively validated accelerometer systems, in combination with physiological
parameters, for more accurate prediction of older people at risk of falling. The results will also inform evidenced
based best-practice approaches for interventions to reduce the risk of falls in older people and people with
neurodegenerative diseases.
Name of contact: Graham Kerr
Email of contact: g.kerr@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 497268
CIA Name: Prof Adekunle Oloyede
Main RFCD: Biomechanical Engineering
Admin Inst: Queensland University of Technology
Start Year: 2008
End Year: 2011
Total funding: $230,633
Grant Type: NHMRC Development Grants
Title of research award: Development of a smart arthroscopy system and prototype probe for joint tissues
Lay Description (from application):
This project relates to the ever growing use of arthroscopy in the management of joint defects. An innovative
probe that will combine all the molecular, microstructural and biomechanical characteristics of joint articular
cartilage and bone for the purposes of diagnosis, treatment, treatment-related decisions, comparison of the
effectiveness of treatment methods and post treatment evaluation will be developed. This system will produce
spin-offs for arthroscopy of other soft tissues and bodies.
Research achievements (from final report):
The aim of the research was to conduct further research into the assessment of cartilage viability. The expected
outcome was a prototype proof-of-concept (POC) probe that combines near infrared, ultrasound and mechanical
loading technologies into one easily applied probe. The potential benefit is an advancement in the field of
arthroscopy that removes subjectivity and hence unnecessary surgery for patients with related cost reduction to the
national health budget. The innovative POC probe has been developed with a new interface that both controls data
acquisition and all related analysis of raw data, outputting parameters that enable precise surgical decisions. The
POC probe was demonstrated on December 4th 2009.
The new stand-alone graphical user interface (GUI) application was built in the MATLAB environment. It
implements multivariate statistical protocols such as partial least squares regression (PLSR), principal component
analysis (PCA) and principal component regression (PCR) from the statistics toolbox. Accepting raw data in any
of three different formats (.csv, .xls, .txt), this application implements the necessary statistical protocol based on
user preferences and outputs the required parameter for assessment.
Expected future outcomes:
Further resolution of the ultrasound and NIR spectra information for precise mapping of layer-by-layer property of
a piece of cartilage. We are also going to incorporate the new IP system that has been developed into an existing
arthroscope so that we can carry out preliminary clinical tests. It has also been decided that the IP would be better
protected by secrecy with blackbox implementation.
Name of contact: Prof. Adekunle Oloyede
Email of contact: k.oloyede@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 497265
CIA Name: Dr Benjamin Goss
Main RFCD: Orthopaedics
Admin Inst: Queensland University of Technology
Start Year: 2008
End Year: 2010
Total funding: $85,933
Grant Type: NHMRC Development Grants
Title of research award: The Next Generation of Biomaterials; In Vivo Assessment of Lumbar Spinal Fusion
Biodegradable Interbody Cages
Lay Description (from application):
Back pain represents one of the major health and economic problems facing the western world. Surgery is an
inevitable outcome for many sufferers and involves the implantation of metallic rods screws, plates or cages.
Biodegradable implants have theoretical advantages, but until now no material has existed that can sustain he
rigours of implantation into a load bearing site. We have developed such a material which will lead to
improvements in the treatment of many orthopaedic conditions.
Research achievements (from final report):
Back pain represents one of the major health and economic problems facing the western world. In Australia nearly
80% of adults will suffer with over $1.2 billion spent on medical intervention and losses in productivity of over $8
billion. A significant proportion of reported back pain will require surgery. Non-degradable implants are
commonly used to provide stability in spinal fusion. These materials a have major disadvantages including
implant stress shielding and long term problems associated with subsidence, migration and fracture.
Biodegradable spacers have been suggested as a potential solution to many of these problems, however the current
generation of biomaterials have unsatisfactory mechanical properties and degradation profiles for any load bearing
application.
In this project we examined a new class of biodegradable polymers in spinal fusion. Despite promising data in
some experiments, contamination of implants during the manufacture resulted in a variable response to the
implant. Despite being unable to show unequivocally that this material will make appropriate orthopaedic devices
we were able to show that the adverse reactions were unrelated to the biomaterial composition. We have since
successfully tested this material in applications where the implant is manufactured by different techniques.
Expected future outcomes:
This material is being tested in other applications including advanced drug delivery systems and bone graft
extenders
Name of contact: Ben Goss
Email of contact: b.goss@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 497266
CIA Name: Prof Zee Upton
Main RFCD: Clinical Sciences not elsewhere classified
Admin Inst: Queensland University of Technology
Start Year: 2008
End Year: 2010
Total funding: $125,041
Grant Type: NHMRC Development Grants
Title of research award: Development and pre-clinical evaluation of a novel wound dressing treatment for
chronic ulcers
Lay Description (from application):
Chronic leg ulcers are a common, painful and costly reality for many Australians, impacting on sufferers'
mobility, social interactions and overall quality of life. This research is directed at developing a novel costeffective wound dressing for treatment of this condition. This will be achieved through neutralising the ulcer's
toxic proteolytic environment through an interactive wound dressing. This then will allow the body's own cells to
promote wound healing.
Research achievements (from final report):
Chronic wounds, such as burns and venous leg ulcers, are well-known challenges in medical research. The cost
resulting from the treatment of these wounds is significant. This project proposed a novel, device-oriented
approach for the treatment of chronic wounds. The goal of this research is to inactive the proteases in the wound
fluid after the fluid is absorbed away from the actual wound bed. In this situation, the proteases required for
healing associated functions within the upper cellular layers of the wound bed remain active and available. In
order to achieve this, the project firstly conducted critical research on the development of a novel matrix
matalloproteinase (MMP) inhibitor, and then tethered this developed inhibitor to a carrier, a polymer hydrogel. It
is confirmed that the inhibitor itself demonstrated effective MMP inhibition in both standard active MMP
solutions and in chronic wound fluid extracted from patients who suffer from venous leg ulcers. When the
tethered inhibitors were tested against chronic wound fluid, we observed significant inhibition in proteolytic
activity suggesting our approach may prove useful in rebalancing MMPs within chronic wounds. The CIs have
protected this novel MMP inhibitor via a Provisional Patent application, which allows us to further conduct
critical product development and proof-of principle pre-clinical studies for the enhanced remediation of chronic
wounds.
Expected future outcomes:
We will conduct further product development and pre-clinical studies based on the outcomes from this project.
We expect that a novel, effective, reliable wound dressing product will be available in the near future to enhance
remediation of chronic wounds, thereby benefitting people suffering from chronic wound in Australia and worldwide.
Name of contact: Professor Zee Upton
Email of contact: z.upton@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 497267
Start Year: 2008
CIA Name: Prof Zee Upton
End Year: 2010
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $163,578
Admin Inst: Queensland University of Technology
Grant Type: NHMRC Development Grants
Title of research award: Development and Pre-Clinical Evaluation of a Silicone Dressing for Scar Remediation
Lay Description (from application):
This research is aimed at exploiting advanced polymers as a new therapy for patients with burn related scars, as
well as people who are genetically predisposed to scarring due to abnormal healing. In order to progress to clinical
trials, the technology needs to be tested on an animal scar model. Successful outcome of these tests will allow the
industry partner, Tissue Therapies, to proceed with a clinical trial, paving the way to a therapeutic product
available for scar treatment.
Research achievements (from final report):
Scarring is a unavoidable product of wound repair and can occur as a result of injury to the dermal layer of skin
from trauma (e.g. burns, cuts) and elective procedures. Each year over 100 million scars are acquired worldwide,
often causing significant pain to the patient as well as psychological damage in some cases. This project was
aimed at testing how lipid-like silicone oils can be used to treat severe scars known as hypertrophic scars which
are red and raised and can cause limited mobility and pain to the patient. What we have discovered is that these
silicones are mildy toxic to the cells found in skin and cause cell death in a controlled manner, similar to some of
the natural processes in the body involved in normal tissue turnover. When these silicones are applied in low
doses to cultured skin offcuts donated by patients undergoing abdominoplasty they can cause thinning of the skin
and at high doses can cause separation of the epidermis and the dermis. Thus, these silicones may be used as a
topical treatment for scars as an alternative to current treatments such as injections of the toxic drug, bleomycin.
We have also found that these silicones may be useful in the treatment of other skin disorders such as psoriasis
which is a condition characterised by hyperproliferative cells within the epidermis. Psoriasis affects approximately
2% of the population and can be managed but not cured using topical or systemic treatments or exposure to UV
light.
Expected future outcomes:
We currently own the intellectual property covering the use of amphiphilic silicone oils on scars and are
continuing to explore commercial opportunities using the results generated from this grant. We expect that if this
product is commercialised it will offer the many patients suffering severe scars an alternative and potentially more
effective treatment.
Name of contact: Prtofessor Zee Upton
Email of contact: z.upton@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 553028
CIA Name: Prof Zee Upton
Main RFCD: Surgery
Admin Inst: Queensland University of Technology
Start Year: 2009
End Year: 2012
Total funding: $275,203
Grant Type: NHMRC Project Grants
Title of research award: Improved ex-vivo culture of keratinocytes for clinical applications
Lay Description (from application):
Skin cells grown for clinical applications currently require animal-derived cells and/or non-defined products for
their expansion in the laboratory; these reagents can potentially infect patients who receive these therapies. This
project will identify the essential components provided by these reagents and develop a fully synthetic and defined
culture system. This improvement will provide safer, cost-effective grafts and cell-based therapies that will benefit
patients suffering burns and wounds.
Research achievements (from final report):
The culture of human skin cells in a laboratory requires the use of animal products (xenobiotics) to supplement the
media and as a compatible surface for the cells to grow on. The use of animal products brings a high risk of
disease transmission from animals to humans. This risk greatly limits the use of skin cells in a clinical setting for
skin regeneration treatments that are required following burn and scarring injuries. Therefore, this project aimed
to develop a way to grow human skin cells without the use of animal products. We utilised proteonomic based
techniques to examine the current culture system. We determined what products the animal cells produce that
enable the human cells to grow in the laboratory. We then utilised human or recombinant versions of these
supplements to develop a culture system which enabled the human skin cells to be grown without the use of
animal products. We were able to culture the human skin cells in this culture system for short periods without
compromising the health of the skin cells. The successful removal of all xenobiotic and non-defined materials
and their replacement with recombinant and synthetic reagents will allow the improved, safe manufacture of
keratinocyte-based cell therapies to treat burns, wounds and chronic ulcers. The outcomes from this project will
therefore facilitate delivery of safe regenerative and therapeutic keratinocyte-based treatments to the Australian
and global communities.
Expected future outcomes:
The techniques developed in this project will be expanded to enable safer, faster and longer culture of human skin
cells. Potential future applications include the treatment of burn and scarring victims.
Name of contact: Professor Zee Upton
Email of contact: z.upton@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 390102
CIA Name: Prof Helen Edwards
Main RFCD: Therapies and Therapeutic Technology
Admin Inst: Queensland University of Technology
Start Year: 2006
End Year: 2008
Total funding: $374,159
Grant Type: NHMRC Project Grants
Title of research award: Identifying the relationship between biochemical markers and healing in chronic leg
ulcers treated with compression
Lay Description (from application):
Chronic leg ulcers are a significant cause of pain, immobility and decreased quality of life for 1 - 3% of the over
60 years age group. The condition is difficult to heal and commonly becomes a long term problem, costing the
Australian health care system over $500 million / year. Additional costs to the community include loss of
productivity and social support systems necessary for people with limited mobility. As the number of people aged
over 65 years is expected to double in the next few decades, this problem will become increasingly significant.
Most chronic leg ulcers are caused by venous disease, and compression bandage therapy is the accepted standard
treatment. However, there is little information available on the cellular responses associated with compression
treatment and how they promote wound healing. The project proposed here will examine the cellular responses to
compression and investigate the relationships between these cellular responses and wound healing. Knowledge
gained from the study will provide valuable information for improved techniques to promote wound healing,
improved ulcer healing rates, informed decisions on wound care treatment, improved qualtiy of life and reduced
health care costs.
Research achievements (from final report):
Chronic leg ulcers are a significant cause of pain and immobility for older adults and care for chronic wounds
costs 1-2% of total health expenditure. The ulcers are difficult and slow to heal and knowledge of the biochemical
processes involved in wound healing is poor. Results from this study have provided new information on the
associations between biochemical changes at the wound site, progress in wound healing, and type of compression
therapy.
The discovery of relationships between uric acid levels and wound severity are likely to lead to development of
reliable, non-invasive point of care diagnostics to monitor the onset, prognosis and progress of chronic venous leg
ulcers. Importantly, this study has generated new evidence on the comparative effectiveness of two different types
of compression therapy for healing venous leg ulcers. Although compression therapy is the gold standard
treatment for venous leg ulcers, it is often associated with high costs and a need for specialised expertise to apply
correctly, which may inhibit commencement of treatment. Results from this study on the relative effectiveness of
two compression types provides health professionals and consumers with evidence on a greater range of effective
compression therapies. This together with the development of specific biochemical diagnostic tools would
transform current wound management by guiding clinical decisions and enabling treatments to be tailored to
differing needs and available resources. This information will promote increased use of compression treatment
and improved healing for those suffering with chronic leg ulcers.
Expected future outcomes:
New point of care diagnostics/therapies to promote healing in chronic wounds
Improved healing rates and quality of life for those who suffer with chronic leg ulcers
Reduced health care costs associated with improved healing rates
Name of contact: Prof. Helen Edwards
Prof. Helen Edwards
Email of contact: h.edwards@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 390100
CIA Name: Prof Zee Upton
Main RFCD: Medical Biotechnology
Admin Inst: Queensland University of Technology
Start Year: 2005
End Year: 2006
Total funding: $156,870
Grant Type: NHMRC Development Grants
Title of research award: Pre-clinical assessment of novel growth factor complexes as a topical agent in the
treatment of deep
Lay Description (from application):
Healing of deep burns, unlike that of superficial injuries, often resolves with scarring. Scarring is reduced with
rapid closure of burns. The CIs have discovered and patented novel growth factor complexes that stimulate the
growth and migration of keratinocytes, cells derived from skin. Hence these complexes hold therapeutic potential
for wounds that require rapid closure such as deep burns. This application will provide pre-clinical, proof-ofprinciple data to facilitate future patient trials.
Research achievements (from final report):
This preclinical study follows a trial completed in early 2005 which successfully demonstrated that VitroGro®
complexes significantly accelerate skin healing and appears to substantially reduce scar tissue formation,
providing confidence about the potential of VitroGro® as a wound treatment.
The most recent trial was conducted to prove 2 things. Firstly that recombinant VitroGro® works as efficiently as
the VitroGro® made from conventional purified proteins, and secondly to determine the optimal dosage in
preparation for clinical trials planned for 2007. Both objectives were successfully achieved and recombinant
VitroGro® performed as expected and the pre-clinical dose study found that there was no statistically significant
differences in the results obtained with the range of VitroGro® doses tested . Therefore the dosage of VitroGro®
used during both the first and this latest study will be employed in the upcoming human trials and is anticipated to
be effective.
In addition, the unexpected finding of the dosage study was the positive and statistically significant results for the
reduction of wound contraction when treated with VitroGro®. Wound contraction is a major problem in the
treatment and healing of wounds, particularly paediatric burns and is the most common reason for corrective
surgery required after burn injuries. In this regard, VitroGro® has been shown to significantly reduce wound
contraction in the pre-clinical study. Importantly, there are currently no approved treatments to minimize wound
contraction in adult or paediatric patients and more than half the operations performed on children by Associate
Professor Roy Kimble are due to contractures.
Expected future outcomes:
The industry partner, Tissue Therapies, intends to supplement this data with a further preclinical trial. This followup study will provide the final data required on a small number of endpoints and will complement the data
generated through the trial reported here. Together this will be used to prepare for the human studies planned for
2007.
Name of contact: Professor Zee Upton
Email of contact: z.upton@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 138711
CIA Name: Dr James Smeathers
Main RFCD: Biomechanical Engineering
Admin Inst: Queensland University of Technology
Start Year: 2001
End Year: 2003
Total funding: $185,665
Grant Type: NHMRC Project Grants
Title of research award: QUANTITATIVE ASSESSMENT OF LOOSENING IN HIP ARTHROPLASTIES
USING MECHANICAL VIBRATION DIAGNOSTICS
Lay Description (from application):
Recent advances and improvements made to the mechanical design of artificial joints have led to greater strength,
fatigue life and wear resistance. However, this extension to the working life of joint replacements has led to
patients becoming increasingly vulnerable to the problem of joint loosening. There are over 500 000 hip joint
replacements performed every year, on a worldwide basis. Of these 7 to 13% will require revision surgery because
of loosening at some stage of their working life. This is becoming a major concern to health services around the
world since revision surgery is associated with a higher risk to the patient and costs are far greater than for the
primary operation. Current diagnostic techniques using radiographic imaging are both invasive and lack diagnostic
accuracy. The ability to detect joint loosening and to discriminate between the various causes of joint loosening
following arthroplasty is of great importance to the success of subsequent care plans. This study will be the first in
the world to assess the validity of a new diagnostic test that uses low energy mechanical vibration to quantify the
degree of loosening in both components of the implanted hip joint. Once the technique has been proven it could
readily be extended to evaluate the degree of fixation of other implanted prostheses used to replace the knee, ankle
or joints of the upper limbs.
Research achievements (from final report):
This research program has significantly advanced the way that loosening of artificial hip joints is detected by
using low energy mechanical vibration to provide a safe additional means of evaluating the integrity of an implant
in the human body. The significance of this relates to the 500 000 hip joint replacements that are performed
worldwide annually. Unfortunately, up to 8% of these implants will suffer from aseptic loosening which, is
thought to be caused by tissue reaction to wear debris and resorption of the supporting bone. There is growing
concern over the increasing numbers of artificial joints that are failing by loosening due impart to the large
numbers in service and the trend to earlier implantation in younger more active patients. It is still difficult to
diagnose aseptic joint loosening with current clinical imaging techniques where loosening is confirmed by a
combination of invasive radiographic techniques, radio-opaque dyes injected into the joint space, pain provocation
tests and ultimately, physical assessment at the time of surgery. Hence this research evaluates a complimentary
diagnostic technique that is based on mechanical vibration to detect structural changes within the human body.
The principles of vibration based monitoring previously developed by engineering and aerospace industries to
detect failure in machinery is now being applied to the human body and the problem of loosening in artificial
joints. The potential of this novel application to the clinical problem of artificial joint loosening has been
examined by this research project under extensive laboratory tests and early clinical trials. In principle, this
additional diagnostic test will help improve the health of Australians through improved accuracy of diagnosis and
efficiency of surgical care by assisting the surgeon to make better informed decisions on whether or not to
reoperate on the joint and how to optimise the timing of revision procedures.
Expected future outcomes:
In the longer term knowledge gained from this research coupled with improvements in technology will enable a
clinical diagnostic device, for detecting loosening of artificial joints, to be manufactured in Australia and marketed
throughout the world. The diagnostic principles of this system will also have relevance to a wide range of other
structural problems and discipline areas.
Name of contact: James Smeathers
Email of contact: j.smeathers@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 390400
CIA Name: Prof R. Douglas McEvoy
Main RFCD: Respiratory Diseases
Admin Inst: Repatriation General Hospital, Daw Park
Start Year: 2006
End Year: 2008
Total funding: $466,765
Grant Type: NHMRC Project Grants
Title of research award: Experimental Investigation of Driving Impairment in Obstructive Sleep Apnea
Lay Description (from application):
Obstructive Sleep Apnea (OSA) affects 2-4% of the adult population. Repetitive throat obstructions at night lead
to sleep disturbance and oxygen deprivation which in turn lead to excessive daytime sleepiness and poor
concentration. Studies in severely affected OSA patients have demonstrated driving simulator performance
impairment and a 2-7 fold increased rate of motor vehicle accidents. Current data suggest that up to 50,000 MVAs
may be caused each year in Australia by OSA. While driving impairment and increased crash risk in severe OSA
seems clear it is not known whether patients with mild-moderate disease are also affected. This is an important
question since patients with mild-moderate disease make up the great majority of OSA sufferers and therefore
potentially pose the greatest concern for overall public safety. This study will determine whether mild-moderate,
as well as severe, OSA is associated with driving impairment. The study will also determine how partial sleep
deprivation and low dose alcohol impact on driving performance in OSA. These two behaviours are considered
part of the "norm" for modern societies, yet we recently showed that they act synergistically to markedly impair
driving in healthy subjects. We suspect that years of prior sleep disturbance and oxygen deprivation will render
OSA sufferers more vulnerable to the effects of these additional central nervous system insults. Finally, we will
determine how well driving impairment in severe OSA responds to nose mask CPAP treatment. We will find out
what minimum level of treatment adherence is needed to produce significant improvement and whether driving
impairment is ever truly reversed. The information obtained in this study will inform and significantly improve
patient care,"fitness to drive" guidelines and driver safety campaigns.
Research achievements (from final report):
This research award has aided in the development of knowledge of the effects of obstructive seep apnoea on
driving performance. The effects of additional sleep restriction and low-dose alcohol on OSA patients has been
explored with the finding that OSA patients are more vulnerabe to these additonal stressors. The effectiveness of
CPAP treatment in improving driving performance and reducing vulneraility to sleep loss and alcohol has been
assessed with the conclusion that treatment of OSA is partially effective in improvng driving performance and
alleviating OSA dependent vulnerability to sleep restriction and alcohol. These findings are of high clinical
relevance and provide clinicians with evidence supporting the need to warn patients of dangers of driving under
conditions of moderate sleep loss and low-dose alcohol, which occur commonly in society. These findings also
stengthen the case for prompt diagnosis and treatment of OSA patients in order to improve public health and
traffic safety.
Expected future outcomes:
Creating pulic awareness of these findings through media and journal publications which may lead to alterations
in clinical practice and public policy to improve patient healthcare and safety.
Name of contact: Professor Doug Mcevoy
Email of contact: doug.mcevoy@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 555429
CIA Name: Prof Marc Cohen
Main RFCD: Geriatrics and Gerontology
Admin Inst: RMIT University
Start Year: 2009
End Year: 2011
Total funding: $249,377
Grant Type: NHMRC Project Grants
Title of research award: Randomised controlled trial of yoga for improving sleep and quality of life in an
elderly population
Lay Description (from application):
Insomnia is very common in the elderly and is associated with increased morbidity and reduced quality of life.
Yoga is purported to assist with sleep and stress management but there is little rigorous research to confirm this
and no research to determine if yoga can be adapted to an elderly population in Australia. This study aims to
rigourously examine the effectiveness of yoga as an intervention for geriatric insomnia and to determine the
ability of yoga to enhance quality of life.
Research achievements (from final report):
This study aimed to determine if an integrated yoga intervention improves subjective and objective sleep measures
in elderly people with insomnia. The study demonstrated that it is indeed possible to design a double blind
controlled trial involving a yoga intervention however, due to an inability to recruit sufficent numbers, the
research question was not able to be answered definitively.
Expected future outcomes:
N/A
Name of contact: Prof Marc Cohen
Email of contact: marc.cohen@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 555427
CIA Name: Prof Marc Cohen
Main RFCD: Oriental Medicine and Treatments
Admin Inst: RMIT University
Start Year: 2009
End Year: 2011
Total funding: $416,301
Grant Type: NHMRC Project Grants
Title of research award: Randomised controlled trials of acupuncture vs. pharmacotherapy for acute pain relief
in emergency departments
Lay Description (from application):
The proposed study involves three separate randomised controlled trials comparing acupuncture alone and
acupuncture along with drug therapy, to drug therapy alone in providing pain relief for patients presenting to the
Northern Hospital and Epworth Hospital Emergency Departments with acute back pain, migraine and ankle
sprain. The research will help determine if acupuncture is safe, effective and acceptable to patients.
Research achievements (from final report):
This research involved three concurrent randomised controlled trials examing acupuncture alone, acupuncture
plus pharmacotherapy and pharmacotherapy alone in the provision of analgesia for patients presenting to
emergency departments with back pain, migraine and ankle sprain. More than 539 patients were recruited from
four separate hospital emergency departments including the Alfred Hospital, Northern Hospital, Epworth Hospital
and Cabrini Hospital. The research found that acupuncture was equivalent and not inferior to pharmacotherapy in
providing analgesia for patients presenting to emergency deprtments with back pain, migraine and anke sprain.
This study has demonstrated that acupuncture can be successfully provided to patients presenting with pain in an
acute emergency department setting and that the analgesia provided by acupuncture has similar efficacy as that
provided by drug therapy. This study suggests that acupuncture may provide an effective non pharmacological
option for emergency department patients and further suggests that training in acupuncture may be a useful
adjunct to emergency physician training.
Expected future outcomes:
Further analysis of the data will compare the adverse events, patient satisfaction and health resource utilization
between the three study groups and determine if acupuncture provides any benefit in terms of patient satisfaction,
safety and assocaited healthcare costs.
Name of contact: Prof Marc Cohen
Email of contact: marc.cohen@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 446201
CIA Name: Prof Annemarie Hennessy
Main RFCD: Medical Physiology not elsewhere classified
Admin Inst: Royal Prince Alfred Hospital
Start Year: 2007
End Year: 2012
Total funding: $632,700
Grant Type: NHMRC Enabling Grants
Title of research award: The National NHMRC Baboon Colony
Lay Description (from application):
The National NH&MRC Baboon colony provides access to large non-human primates to support Australia’s
research efforts in diverse scientific areas around the country. These include diabetes research (kidney
involvement and prevention of kidney damage, nerve damage and eye damage); treatment options inlcuding gene
therapy of blood/bone-marrow cancers; understandng pregnancy changes in blood pressure and the causes of
hypertension (high blood pressure) in pregnancy; identification of new techniques for analyis of brain function;
the effects of aging on liver function especially with regards to drug metabolism; new therapies for transplantation
which would allow more rational and lower/safer drug use for transplant patients; breaking down the barriers to
animal-to-human transplantation through assessment of safety and development of new techniques; behavioural
aspects of fertility management; vaccine development; development of oral vaccination; the nature of wound
healing.
There is diverse and wide access to the National NHMRC Baboon colony from research interests around
Australia. The use of the animals is at all times approved by the Animal welfare Committee governing the colony,
as well as that which governs the researchers involved. All approved projects have been given access to the
animals required. The need for non-human primate use as opposed to other animals or other techniques not
involving animals is justified to the relvant committees before any project proceeds. The use of the animals
therefore adds a dimension to Australian research due to animal similarity to humans physiology or size
comparisons.
Contributions made by the colony in the last 20 years are listed in the attached references, but understanding
physiology at a depth not possible with other animals has changed our thinking about the human condition as a
result of primate -based research.
Research achievements (from final report):
The provision of a colony of healthy, higher-order, non-human primates to the Australian biomedical research
community has allowed highly relevant research to be carried out in multiple national health priority areas.
Research into cardiovascular disease, diabetes, transplantation, pregnancy complications and other areas has been
facilitated by the provision of NHMRC funding. Research groups from 18 different institutions have been
supported by access to the NBC.
Expected future outcomes:
The ANBC will continue to meet its objectives of providing a healthy colony of non-human primates for
scientifically and ethically justified biomedical research in Australia. The maintenance of the highest standard of
animal welfare is a key priority.
Name of contact: The Director
Email of contact: RPAH.NBC@sswahs.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 343603
CIA Name: A/Pr Scott Wilson
Main RFCD: Quantitative Genetics
Admin Inst: Sir Charles Gairdner Hospital
Start Year: 2005
End Year: 2007
Total funding: $403,625
Grant Type: NHMRC Project Grants
Title of research award: Genetic regulation of hip geometry, structure and fracture
Lay Description (from application):
Osteoporotic hip fracture is common in the elderly and a major cause of hospitalization. Hip fracture may lead to
surgery, chronic reduced mobility, loss of function, institutionalization or death. The term osteoporosis covers a
heterogeneous syndrome including juvenile, secondary (e.g. corticosteroid induced) and postmenopausal
osteoporosis. This later broad grouping shows evidence of a strong familial association. Previous work has
shown that a family history of fracture increases the risk of fracture by more than four fold. Furthermore, studies
in twins have persistently shown that phenotypes such as bone mineral density (BMD), broadband ultrasound
attenuation of bone and hip structural indices are strongly inherited. This confirms a genetic basis for the disease
in some individuals. Community health in general has improved substantially in Australia in the past four decades
and this has resulted in increased longevity. In contrast, the incidence of hip fracture and the resulting drain on
public health funding continues to increase rapidly. Presently the cost of osteoporosis in Australia is $7.5 billion
per annum. Hip fracture accounts for the majority of these costs. Instituting effective prevention strategies is
essential. This project aims to contribute to one of Australia's National Research Pritoities by improving
understanding about the way in which inherited aspects of hip geometry and structure contribute to the hip
fracture susceptibility. We have successfully completed genome screen projects studying genetic linkage in the
families to localize genes regulating BMD in the past. However, BMD is only one of a number of relevant
phenotypes. In relation to hip fracture, geometry and structure are thought to be particularly important. In this
project we will make use of existing resources to advance studies of both genetic linkage and association to
examine fundamental issues related to hip facture.
Research achievements (from final report):
Osteoporotic hip fracture is common in the elderly and is a major cause of morbidity and mortality, the goal of
this project was to find genes that control hip structure, particularly those which are relevant to hip fracture. The
study used existing radiographs and dual x-ray absorptiometry (DXA) scans on a large cohort of women and
derived important new phenotypes on hip structure and geometry from these resources. That phenotype data was
then used in analyses with existing genetic data for these study subjects to identifying genes with a potential role
in the regulation of hip geometry and structure. We identified 13 discrete genomic regions that showed genetic
linkage to hip structure and geometry phenotypes. Furthermore, we identified 23 individual genes with replicated
evidence of statistically significant association with hip structure traits. These results assist in improving
knowledge and understanding of the genetic control of hip structure. The long-term goal of the research program
is to develop intervention strategies to reduce hip fracture incidence.
Expected future outcomes:
This data will enable targeted validation studies of the mechanisms involved in the genetic regulation of hip
structure and geometry. Although further replication and molecular biology studies are necessary to fully validate
the findings, some of the genes identified may be useful in the development of diagnositic and therapeutic
approaches for osteoporosis and osteopeania.
Name of contact: Lynell Belardo
Email of contact: Lynell.Belardo@health.wa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453624
CIA Name: Prof Donald Howie
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2007
End Year: 2009
Total funding: $411,517
Grant Type: NHMRC Project Grants
Title of research award: Determination of irradiation dose efficacy for use in impaction grafting at revision joint
replacement
Lay Description (from application):
Primary hip replacement is a successful intervention for hip disease, but 10-15% of hip prostheses fail and require
revision surgery within 10-15 years. At the time of revision, significant bone loss around the failed prosthesis is
not uncommon. A bone reconstruction procedure, called impaction grafting, where donor bone is minced and
placed in the areas of deficient bone before implanting the new prosthesis, has shown to give good results at more
than ten years in some centres. A high incidence of early complications of this procedure have included loss of
fixation within the bone. Fracture of the bone around prostheses has also reported in some centres. These events
require more surgery, putting the patient at higher risk greater complications and longer rehabilitations. Recent
improvements in surgical technique and donor bone preparation have improved results. A current debate questions
whether the dose of irradiation can be reduced from 25 kGy, while maintaining sterility of allografts. The risk of
bacterial contamination in allografts is low, and irradiation reduces the mechanical strength of the graft,
contributing to complications when irradiated bone is used. The benefits of decontaminating the bone may be
outweighed by the higher risk for failure due to poor bone quality and resulting prosthesis instability. We will use
ISO standards to test the validity of radiation dose for sterilising bone ex vivo. In the absence of controlled human
studies, our aim is also to compare the results of impaction grafting with non-irradiated bone versus bone
irradiated at current doses used by Australian bone banks, and lower doses indicated by ex vivo testing. We will
use a large animal model of revision hip replacement, with precise measures of prosthesis stability. The results of
this study will guide clinical decisions regarding the efficacy of current bone graft preparation procedures and the
use of irradiated bone in human hip replacement surgery.
Research achievements (from final report):
This project has led to the direct translation of research findings into clinical practice. Prior to this project the
irradiation dose required by the Queensland Bone Bank for the sterilisation of allograft bone was 25 kGy.
Following publication of the early results from this project, the Therapeutic Goods Administration (TGA)
approved the use of 15kGy for the sterilisation of allograft bone. Subsequent research led to validation of 11 kGy
which has now been adopted as the current standard irradiation dose for sterilisation at the Queensland Bone
Bank, settting a precedent for National Bone Bank Guidelines.
Expected future outcomes:
It is envisaged that the results of this important study may encourage more surgeons to use this important bone
restoring procedure.
Name of contact: Prof Donald Howie
Email of contact: donald.howie@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 565361
CIA Name: A/Pr David Haynes
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2009
End Year: 2012
Total funding: $403,639
Grant Type: NHMRC Project Grants
Title of research award: Regulation of key pathways causing peri-implant bone loss.
Lay Description (from application):
The failure of bone prostheses is becoming a major health problem in our aging population. Despite the
impressive success of joint replacement surgery, a significant number of arthroplasties fail. It is now apparent that
most implants fail due to bone loss around them which leads to loosening. This project aims to obtain a better
understanding of the causes of implant failure and find ways to extend the life of these implants .
Research achievements (from final report):
We have developed two new ways of understanding why implants fail. The first is an animal model of the
pathology that uses state of the art live animal CT scanning to assess bone loss. The second allows us to look at
the way cells respond to implant materials in a way that more closely resembles what happens in the patient. We
have used these techniques to understand what factors and cells are causing the bone loss. These findings have
nearly all been published and/or presented at international scientific meetings in the field. The findings influence
those deciding on the best type of materials to use in hip replacements and other joint implants.
Expected future outcomes:
The eventual failure of hip replacements results in high cost and morbidity. The results of the study will influence
surgeons and materials scientists as they show the vulnerability of traditional polyethylene implants to failure.
These findings will enhance the transition to newer, low wear, materials (eg. HXLPE) in the clinic.
Name of contact: David R Haynes
Email of contact: david.haynes@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 565176
Start Year: 2009
CIA Name: Prof Stan Gronthos
End Year: 2011
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $579,138
Admin Inst: University of Adelaide
Grant Type: NHMRC Project Grants
Title of research award: The Role of Eph-ephrin Interactions in Mediating Mesenchymal Stem Cell
Commitment, Migration and Bone Fracture Repair
Lay Description (from application):
In Australia, there is an increasing incidence of fractures that require surgical intervention and rehabilitation
therapy. Fracture healing is a complex process that involves the coordination of different bone and immune cells.
Our proposal will identify which cell-cell contact molecules mediate bone cell recruitment and development
during normal skeletal growth and bone fracture repair. This study will help advance therapies for fracture repair
and diseases of bone loss.
Research achievements (from final report):
1. We have identified several B class Eph and ephrin molecules as being highly expressed by mesenchymal stem
cells (MSC).
2. We have identified the role of B class EphB2 in human MSC migration, EphB4 and ephrinB1 in human MSC
bone formation, ephrinB1 and ephrinB2 in human MSC cell attachment/spreading.
3. We have characterised the Eph/ephrin gene and protein expression pattern during fracture repair.
4. We have completed the femoral fracture healing experiments using EphB4 overexpressing transgenic mice
driven by the collagen typeI promoter.
Collectively, these studies show that Eph/ephrin moleculaes are mediators of bone cell growth, migration and
function.
Expected future outcomes:
Knowledge gained from this study has increased our understanding of the factors that regulate bone progenitor
cell growth and differentiation. The study has provided potential molecular targets to enable the future
development of novel therapies that regulate endogenous MSC growth and differentiation to enhance bone
regeneration during fracture repair.
Name of contact: Prof. Stan Gronthos
Email of contact: stan.gronthos@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508097
CIA Name: A/Pr Stuart Pitson
Main RFCD: Cell Physiology
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2010
Total funding: $281,340
Grant Type: NHMRC Project Grants
Title of research award: The role of SKAM and sphingosine kinase in wound healing
Lay Description (from application):
Many aspects of wound healing are poorly understood. We have identified a novel cellular pathway that appears
critically involved in controlling wound contraction. This project aims to characterise this cellular pathway to
understand the exact mechanisms whereby it controls this critical aspect of wound healing. With this information
we will develop topical therapeutics to aid the wound healing process.
Research achievements (from final report):
Many aspects of wound healing are poorly understood. We have identified a novel cellular pathway that appears
critically involved in controlling wound contraction. This project aimed to characterise this cellular pathway to
understand the exact mechanisms whereby it controls this critical aspect of wound healing. To this end we have
demonstrated that the SKAM protein is elevated in tissues after wounding and enhances wound contraction by its
activation of the sphingosine kinase enzyme and subsequent formation of the bioactive lipid sphingosine
phosphate. We have used the fundamental knowledge gained to developed novel small molecule activators to
enhance the wound contraction process for potential development as a topical therapeutic to aid the wound healing
process.
Expected future outcomes:
The knowledge gained from these fundamental studies will be applied to further develop novel small molecule
activators and inhibitors to control the wound contraction process for potential development as a topical
therapeutics to aid the wound healing process and reduce scaring.
Name of contact: A/Prof Stuart Pitson
Email of contact: stuart.pitson@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 298900
CIA Name: A/Pr Allison Cowin
Main RFCD: Dermatology
Admin Inst: University of Adelaide
Start Year: 2004
End Year: 2006
Total funding: $472,750
Grant Type: NHMRC Project Grants
Title of research award: Function of the Flightless protein in wound repair and scar formation in skin
Lay Description (from application):
Understanding the factors that control T cell responses has been a major focus of immunology. Despite this effort
the factors that control T cell development, homeostasis and function are still only incompletely understood.
Accordingly we have been studying the TNF-family cytokine BAFF (B cell activation factor of the TNF-family)
in relation to T cell behaviour and function. Though BAFF was first described as being critical for B cell
development and maturation, a number of lines of evidence indicate that BAFF may be important in T cell
biology. Current studies suggest that BAFF exerts a pro-inflammatory effect upon T cell responses. Surprisingly
then, when we examined the role of BAFF upon T cell function in vivo in the context of the allo-immune
response, we found that ~60% of BAFF transgenic mice failed to reject a fully-mismatched allograft. Intriguingly,
BAFF transgenic mice exhibited an increased number of CD4+ CD25+ Foxp3+ cells in the periphery and in vivo
depletion of these CD25+ cells restored the ability of BAFF transgenic mice to reject an allograft. We
hypothesize that BAFF plays a potentially powerful anti-inflammatory role in regulating certain T cell dependent
immune responses. Our data suggests that BAFF can modulate T cell function by effecting T cell regulation.
Research achievements (from final report):
Our studies, investigating the function of the actin cytoskeleton in wound repair have revealed the potentially
important role of Flightless I, an actin-remodelling protein, in wound healing and scar formation. Using in vitro
and in vivo approaches our studies have revealed that FliI plays a key role in promoting cellular migration and
proliferation. We have further identified that changing FliI gene expression affects wound repair. Using mice with
different levels of FliI expression we found that FliI deficiency significantly improves healing. We have now
commenced the development of a novel antibody-based treatment aimed at reducing FliI expression in wounds.
Crucially, our in vitro and in vivo studies reveal that when this antibody is applied topically to wounds in vivo we
see improvements in wound healing. The benefit of a new therapy for improving wound repair and decreasing scar
formation is potentially of great importance particularly for children suffering from burn injuries.
Expected future outcomes:
Future outcomes include the development of new FliI-based therapies for treating wounds and reducing scar
formation. We will also continue studies aimed at understanding the mechanisms of FliI action in wound healing.
We hope to translate these findings into new clinical applications aimed at treating burn injuries which can lead to
devastating disabilities in children and adults.
Name of contact: Allison Cowin
Email of contact: allison.cowin@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508004
CIA Name: Prof Allison Cowin
Main RFCD: Clinical Sciences not elsewhere classified
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2011
Total funding: $339,766
Grant Type: Career Development Fellowships
Title of research award: Flightless I, a terget for new wound therapies
Lay Description (from application):
Wounds, burns and scalds are frequent injuries which can lead to deformity, disfigurement and loss of movement.
We have shown that the cytoskeletal protein, Flightless I (FliI), is an important regulator of wound repair. We
plan to further investigate FliI in wound and burn injuries using new cell-specific transgenic animal models and to
develop a new FliI-antibody based therapy to treat wound and burn injuries.
Research achievements (from final report):
Chronic wounds, diabetic ulcers, injuries in response to trauma, burns and scalds all form a medical need which is
expanding as the population ages and the diabetic epidemic grows. The overall goal of the research undertaken
during this fellowship was therefore to develop new therapies for improving wound healing and reducing scar
formation. My studies have identified a novel entry point to the study of wound repair and a new therapeutic target
which has been protected by international patents. I have subsequently developed monoclonal antibodies against
this protein which significantly improve healing when applied to wounds. Preclinical studies have comfirmed the
efficiacy of these antibodies for improving the rate of wound healing and in the quality of scar formation. To date
there are limited evidence-based treatments on the market for improving wound healing so these studies have the
potential to dramatically improve the health and well-being of a substantial number of the population.
Expected future outcomes:
Future outcomes include the development of a new antibody based topical therapy that can be applied directly to
wounds to improve their rate and quailty of healing. This new treatment has applications not only to burn injuries
and acute surgical wounds but also to chronic non-healing ulcers that affect the elderly and diabetic patients.
Name of contact: Allison Cowin
Email of contact: allison.cowin@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519211
Start Year: 2008
CIA Name: Dr Mark Gibson
End Year: 2012
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $690,876
Admin Inst: University of Adelaide
Grant Type: NHMRC Project Grants
Title of research award: Function of matrix proteins important for storage and activation of TGF and TGF induced tissue remodelling and repair
Lay Description (from application):
The growth factor TGF is important for tissue development and repair, and in diseases such as pulmonary
fibrosis, glomerulonephritis, liver cirrhosis, keloid formation and cancers. This project focuses on 2 important
matrix proteins first discovered by Dr Gibson, LTBP-2 and ig-h3, that modulate TGF storage and TGF -induced
tissue remodelling . We will use knock out mouse and cell culture models to determine the function of these
proteins in tissue development and repair, and in diseases.
Research achievements (from final report):
The grant has enabled my laboratory to define several molecular functions of extracellular matrix protein, LTBP2. Four heparan sulphate binding sites have been mapped on the LTBP-2 molecule and LTBP-2 was found to
inhibit the elastin precursor, tropoelastin in its interactions with fibulin-5 and heparan sulphate. These findings
increase our understanding the mechanism of elastic fibre assembly, a process important for the function of tissues
such as arteries, lung and skin. LTBP-2 was also found contain a single high-affinity binding site for FGF-2, a
potent growth factor implicated in fibrotic diseases. Moreover, addition of exogenous LTBP-2 to several cell lines
showed a marked stimulation of growth factor TGF-beta expression in the cells. The activity was mapped to a
small central region of LTBP-2. These findings prompted us to screen several fibrotic skin disorders for LTBP-2.
Using immunohistochemistry we showed increased staining in hypertrophic scar tissue particularly keloids,
suggesting a link between LTBP-2 levels and fibrosis.
Expected future outcomes:
The research has prompted a new grant application to investigate LTBP-2 in fibrotic diseases.
Name of contact: Mark Gibson
Email of contact: mark.gibson@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250344
CIA Name: Prof David Findlay
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2003
End Year: 2005
Total funding: $368,000
Grant Type: NHMRC Project Grants
Title of research award: Mechanisms of Periprosthetic Bone Loss
Lay Description (from application):
We will seek to address an important clinical problem in orthpaedics, namely the bone loss that commonly occurs
around joint replacement prostheses. Termed peri-prosthetic osteolysis (PO), this bone loss can result in the
loosening and ultimate failure and need for revision of the artificial joint components. PO is thought to be caused
by the body's reaction to wear particles generated from the articulating surface of the prosthesis. However, it has
not previously been possible to accurately explore the relationship between prothesis wear and PO, or the
progression of PO, because of a lack of techniques to image and measure the volume of PO around metal
prosthesis components. We have developed a means to accurately and reproducibly measure the volume of bone
loss, using CT, and will do so longitudinally in joint replacement patients to obtain the first information about the
progression of PO. New computer based methods will be used concurrently to relate prosthesis wear and
migration parameters to PO. Patients who come to surgery for replacement of failed prostheses will be
investigated further by analysis of the tissues involved in the bone loss around prostheses. Basic science
experiments will seek to understand the underlying causes of PO and the findings will be important in interpreting
the clinical results. An animal model will be used to seek approaches to inhibiting the pathological response to
wear particles. The significance of these studies is that they will lead to improved outcomes for joint replacement
patients, increasing the interval to revision surgery, which is both extremely costly and brings an attendant
morbidity and mortality.
Research achievements (from final report):
Peri-prosthetic osteolysis often limits the lifespan of total hip replacement implants. Therefore, the aim of this
project was to investigate peri-prosthetic bone loss, firstly by developing new imaging modalities and secondly by
identifying the molecular mechanisms responsible for this process. We made great progress towards these goals,
measuring in the same patient implant wear and migration and, for the first time, the progression of osteolysis. In
patients who required revision surgery, we analysed tissue taken from defined sites adjacent to osteolytic lesions
and found important relationships between particle accumulation in the tissues, the cell types present, and the
molecular species that are potentially causally involved in the pathological bone loss. These cytokines, such as
TNF and RANK ligand, were found in separate experiments to potentiate osteoclast formation and activity. This
work has therefore laid a strong basis for a new means of monitoring hip replacement patients and for
understanding (and therfore potentially treating) the cell and molecular basis for the bone loss that often occurs
around prostheses.
Expected future outcomes:
As stated, this work has therefore laid a strong basis for a new means of monitoring hip replacement patients,
which has been anabled by our development of a means to accurately quantitate osteolysis around medium to long
term hip replacements. The basic science part of the work may lead to new treatments for this bone loss.
Name of contact: David Findlay
Email of contact: david.findlay@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453497
CIA Name: A/Pr Stan Gronthos
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2007
End Year: 2009
Total funding: $485,928
Grant Type: NHMRC Project Grants
Title of research award: The role of TWIST family basic Helix-Loop-Helix transcription Factors in Bone Cell
Commitment, Function and Repair
Lay Description (from application):
In developed countries, projected estimates predict an alarming trend of a two to three fold increase in the number
of fractures that require surgical intervention and rehabilitation therapy in the coming decades as a consequence of
an aging population. Fracture healing is a complex physiological process that involves the coordinated
participation of different bone marrow cells, immune cells and skeletal progenitor cells. Multiple factors regulate
interactions between these cell types that influence the capacity of bone cell progenitors to develop into functional
bone forming cells known as osteoblasts. An understanding of the fracture healing is critical for the future
advancement of fracture treatment, and for identifying the mechanisms of skeletal growth and repair as well as the
causes of aging and disease. This proposal seeks to identify critical regulatory molecules that act to mediate bone
cell progenitor recruitment and development during bone fracture repair.
Research achievements (from final report):
1. The basic helix-helix-loop (bHLH) transcription factors, Twist-1 and Dermo-1 are known to be important in
normal mesodermal development during embryogenesis.
2. Our studies showed that Twist-1 and Dermo-1 are highly expressed by human mesenchymal stem cell (MSC) in
bone marrow aspirates but are quickly down regulated folloing ex vivo expansion.
3. Multiple human bone marrow derived MSC lines were successfully retrovirally transduced to overexpress
either Twist-1 or Dermo-1 in vitro. Functional studies were performed examining the effect of Twist-1 and
Dermo-1 on MSC proliferation, bone gene expression patterns and differentiation in vitro and in vivo following
implantation into NOD/SCID immunocompromised mice.
4. Enforced expression of Twist-1 and Derrmo-1 was found to maintain the MSC in an undifferentiated state and
greatly increase the growth and lifespan of MSC in vitro.
5. Interestingly, Twist-1 and Dermo-1 inhibited the capacity of MSC to differentiate into bone and cartilage
forming cells
6.
We have established a mouse femoral bone fracture model for the in vivo analysis of bHLH-transcription
factors during bone repair.
Expected future outcomes:
Characterising the role of Twist-1 and Dermo-1 in MSC growth, recruitment and development during fracture
healing may help identify genes that are regulated by Twist-1 and Dermo-1, which can then be used as therapeutic
targets for fracture repair.
Name of contact: Prof. Stan Gronthos
Email of contact: stan.gronthos@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 274307
CIA Name: Dr John Semmler
Main RFCD: Motor Control
Admin Inst: University of Adelaide
Start Year: 2004
End Year: 2006
Total funding: $198,500
Grant Type: NHMRC Project Grants
Title of research award: Motor unit synchronisation and neuromuscular performance
Lay Description (from application):
The fine control of force is important for many everyday tasks such as writing, grasping objects between index
finger and thumb, and fastening buttons. Factors that influence the ability to control force include the coordinated
activation of groups of muscle fibres called single motor units. This proposal focuses on the concept that the
coordinated activation of motor units is influenced by muscle activity and can impair the ability to produce finely
controlled muscle contractions. The goal of these studies is to explore the boudary conditions of the adaptive
nature of the nervous system to examine how coordinated motor unit activity influences these aspects of
neuromuscular performance. The outcomes of these experiments will identify if altering muscle activity
influences the control of movement by altering single motor unit activity. These results will have direct
application to the interpretation of abnormal movement control and tremor that is observed in certain neurological
diseases such as Parkinson's disease. Furthermore, new information will be gained on the adaptability of the
motor system and its role in the execution of fine motor tasks that may aid in the development of rehabilitation
strategies following stroke or spinal cord injury.
Research achievements (from final report):
The purpose of these studies were to determine whether changes in muscle strength influenced the control of force
by the nervous system. Experimental measures were performed at the level of the single motor unit, which is the
smallest element of neuromuscular control. We found that damaging the muscle with repetitive lengthening
contractions altered the correlated activity of human motor units and influenced the fine control of force.
However, a short period of strength training did not influence the neural control of force despite significant
increases in muscle strength. These studies demonstrate that alterations in strength of the muscle do not appear to
influence the correlated discharge of action potentials and do not impair fine motor control. Rather, we suggest
that correlated motor unit activity is an effective strategy to promote skilled and coordinated movements, but
could impair the ability to perform steady contractions under some circumstances. These results will have direct
application to the interpretation of abnormal correlated motor unit activity and pathological tremor that is
observed in certain neurological conditions such as Parkinson's disease.
Expected future outcomes:
The future direction of this work is twofold. First, we plan to explore the neural mechanisms that impair motor
performance following exercise-induced muscle damage. Second, we will examine the neural adjustments in the
central nervous system following skilled motor performance. These studies will have implications for
neuromuscular function and rehabilitation in athletes and patients.
Name of contact: John Semmler
Email of contact: john.semmler@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 298933
CIA Name: Prof Howard Morris
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2004
End Year: 2006
Total funding: $399,750
Grant Type: NHMRC Project Grants
Title of research award: Vitamin D Depletion and Femoral Bone Loss
Lay Description (from application):
An understanding of the way cells control their complex internal circuitry is relevant to diseases like cancer and
leukemia. The main focus of this project is a cellular regulator we identified several years ago called BORIS.
Normally dormant in all cells outside the male reproductive organs, BORIS is reactivated in many cancers. We
will study the network of factors perturbed when BORIS becomes inappropriately active in cancer cells.
Ultimately this project may lead to new treatments for cancer.
Research achievements (from final report):
A robust rodent model of vitamin D depletion has been developed. These animals have vitamin D levels that are
considered low but are the maximum achieved by some 50% or more of the community. Our studies demonstrated
that these rodents developed osteoporosis at early adulthood, that is just one quarter through their life span, which
was surprising. It was proposed that osteoporosis would not develop until they were older. Similar biochemical
markers were measured in the rodent model as have been measured in humans who have low vitamin D levels. A
very similar relationship was found suggesting that the findings with this model are likely to be useful for
estimating human vitamin D requirements. A minimum level of vitamin D for optimal bone striucture was
identified. As well the study identified the optimal form of vitamin D for skeletal health. The loss of bone that
occurred with low vitamin D levels was due to high bone resorption due to high levels of bone resorbing cells.
Evidence for the molecular mechanism of the increased number of bone resorbing cells was obtained. Evidence
has been obtained that a lower level of vitamin D is required to maintain optimal skeletal health as dietary calcium
levels increase.
Expected future outcomes:
The effects of age and dietary calcium intake on the level of vitamin D required for optimal skeletal health and
bone strength will be elucidated. It is expected that as we age we require higher levels of vitamin D to maintain
our health. Currently there is no understanding of the basis for such increased requirement and these studies will
provide the first indications.
Name of contact: Professor Howard Morris
Email of contact: howard.morris@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519248
CIA Name: Prof Robert Vink
Main RFCD: Central Nervous System
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2010
Total funding: $589,789
Grant Type: NHMRC Project Grants
Title of research award: Raised intracranial pressure after trauma: characterisation and development of
pharmacological interventions
Lay Description (from application):
Raised intracranial pressure (ICP) commonly occurs after traumatic brain injury (TBI) and is thought to be
responsible for up to 50% of all mortality, as well as significantly contributing to the persistent neurological
deficits in survivors. Few studies have examined the dynamics of raised ICP after TBI, or its effects on brain
oxygenation. This study will fully characterize changes in ICP and brain oxygen after TBI and develop novel
treatments to control such changes.
Research achievements (from final report):
Our goal was to determine whether small or large animal models are the most appropriate for the study of
intracranial pressure (ICP) changes after traumatic brain injury (TBI), and then to assess the effectiveness of
several current and potential drug therapies in the most appropriate model. Our results showed that rodent models
do not reliably replicate the human ICP condition after TBI and that a large animal model is a far superior model
of human TBI. We then demonstrated that current therapies such as mannitol and hypertonic saline are effective in
reducing ICP, but that they did not substantially increase brain tissue oxygenation. Magnesium and Progesterone
were ineffective with respect to both measured parameters. In contrast, substance P anatgonists were highly
effective in reducing elevated ICP and restoring brain oxygen levels to normal after TBI. We now have a complete
understanding of ICP/brain oxygenation dynamics after TBI and the ability to develop and assess novel
pharmacological interventions in a highly effective, large animal model of TBI. We also have developed one
novel pharmacological intervention that appears to be the first ever to effectively control ICP and improve brain
oxygenation after severe TBI.
Expected future outcomes:
We will now endeavour to obtain funding for studies that will establish the dose-response relationship and
therapeutic window for the substance P antagonists in our large animal model of TBI. This will greatly facilitate
translation to the clinical situation.
Name of contact: Professor Robert Vink
Email of contact: Robert.Vink@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508006
CIA Name: Prof Allison Cowin
Main RFCD: Clinical Sciences not elsewhere classified
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2010
Total funding: $194,071
Grant Type: NHMRC Development Grants
Title of research award: Development of Flightless antibody therapy for treating wounds
Lay Description (from application):
Chronic wounds, diabetic ulcers, injuries in response to trauma, burns and scalds form a medical need which will
only expand as the population ages and the diabetic epidemic grows. In our studies, we have shown that Flightless
I (FliI), an actin remodelling protein, is a negative regulator of incisional wound healing. We are now developing
a new antibody therapy to reduce FliI levels in wounds thereby leading to improved wound repair outcomes.
Research achievements (from final report):
Over the past 6 years, we have investigated the function of the actin-remodelling protein Flightless I (Flii) in the
wound repair process. Our group was the first to show that Flii is an important negative regulator of wound repair
and that attenuation of Flii leads to improved wound outcomes We found that if we reduced the level of this
protein using rabbit polyclonal neutralising antibodie we could significantly improve wound healing in mouse
models of wound repair. Over the last two years, with the support of this NHMRC development grant we have
now generated murine hybridomas against human Flii and have identified three monoclonal antibodies with
wound healing activity in vitro and also in a murine in vivo wound model. Being able to improve the wound repair
process is particularly important as the incidence of non-healing chronic wounds in our society increases. These
wounds are getting more prevalent in our society due to in the increasing numbers of aged, obese and diabetic
individuals who are all at risk of gettingnon-healing wounds. Additionally wounds caused due to trauma, burns
and scald injuries also lead to diffiult to heal wounds so there is a considerable potential for the development of
new therapies for treating wounds.
Expected future outcomes:
We expect to produce a new targeted therapy for treating wounds.
Name of contact: Allison Cowin
Email of contact: allison.cowin@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453510
CIA Name: Prof Howard Morris
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2007
End Year: 2009
Total funding: $543,302
Grant Type: NHMRC Project Grants
Title of research award: Maintenance of bone strength in aged rats: the Vitamin D requirement
Lay Description (from application):
Hip fracture remains the most devastating of the osteoporotic fractures particularly in women in whom the
incidence increases to about 3% per annum by the ninth decade. This incidence is bound to increase as the
population ages with increasing longevity. Supplementation of diets of elderly female nursing home residents with
vitamin D and calcium has been shown to reduce the risk of hip fracture by 30% in two years. However we do not
know how much vitamin D is necessary to maintain optimal bone strength. This project will determine the level
of vitamin D required to maintain optimal bone strength in aged rats using a simple blood test which could then be
used to screen the elderly and identify those at risk of hip fracture from low vitamin D levels. The project will also
investigate the effects of vitamin D on the bone cells that maintain optimal skeletal architecture. This information
is essential for comparison with the current knowledge of other biochemical bone markets in blood and vitamin D
status in the elderly, in order to develop nutritional recommendations to reduce the incidence of hip fracture.
Research achievements (from final report):
We have described for the first time that the effect of vitamin D depletion is to increase bone resorption and loss
of bone mineral content in this rat model. This study has identified that optimal bone mineral content is not
obtained unless the serum 25D level is greater than 80 nmol/L. Two feeding studies have been completed to
achieve levels above and below the critical values (25D 80 nmol/L) of vitamin D status for bone health as
determined from our first study. Dietary calcium levels have also been varied. Regression analyses demonstrated
significant positive relationships between serum vitamin D levels and bone mineral volume. Mechanical testing
demonstrated that resistance to fracture was positively correlated to vitamin D status. Furthermore the benefits of
high dietary calcium may at least partially be due to the maintenance of higher serum 25D levels.
SIGNIFCANCE: Long-term vitamin D deficiency causes bone loss in both the cortical bone as well as in
trabecular bone resulting in reduced bone strength. Importantly, while vitamin D status is a major determinant of
bone mineral content, both dietary vitamin D and dietary calcium are major determinats of serum 25D levels.
Thus the effect of dietary calcium to protect bone loss appears be due to improvement of serum 25D levels.
Expected future outcomes:
This dietary model is currently being used to further examine the effects on osteocyte density, apoptosis and
mechanical strength of long bones. Cellular activity in these trabecular and cortical bone regions are being
completed.
Name of contact: Howard Morris
Email of contact: howard.morris@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519223
CIA Name: Prof Donald Howie
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2010
Total funding: $192,187
Grant Type: NHMRC Project Grants
Title of research award: Radiostereometric analysis of the effect of a large articulation on prosthetic wear and
migration after hip replacement
Lay Description (from application):
At total hip replacement, there has been a recent trend to use prostheses with a larger ball and liner in the socket.
This may decrease the risk of post-operative dislocation, but may also increase the amount of wear, leading to
bone loss and loosening of prostheses, which may then require replacement. This project will use a special type of
x-ray to determine whether wear and movement of these new prostheses is clinically acceptable, so that they can
be used with confidence in patients.
Research achievements (from final report):
Large articulations in total hip replacement are increasingly being used. We have previously shown in an
NHMRC-funded randomised trial that a large articulation significantly reduces the risk of dislocation following
hip replacement. Although new polyethylene liners have made the use of larger articulations feasible, whether
larger articulations were associated with significant amounts of polyethylene wear was not known. Significant
polyethylene wear results in polyethylene particulate debris being deposited around the hip replacement prosthesis
which can then lead to localised bone loss, requiring costly revision of the total hip replacement with its associated
risks of both death and complications. We used a highly sophisticated radiographic technique, namely
radiostereometric analysis, to measure early polyethylene wear, which can not be seen on plain radiographs. Our
study has shown that the wear between one and two years of the large metal on highly cross-linked polyethylene
articulations now commonly used in total hip replacement are similar to those of the standard-sized articulations
and within the clinically acceptable range of wear. Therefore, these articulations can now be recommended for
more general use. However, continued monitoring of wear is required to ensure that there is no unexpected
increase in wear over time.
Expected future outcomes:
Wear of metal on highly cross-linked polyethylene articulations will continue to be examined to determine the
longer term wear associated with these hip replacements.
Name of contact: Dr Oksana Holubowycz
Email of contact: oksana.holubowycz@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453646
CIA Name: Dr John Semmler
Main RFCD: Central Nervous System
Admin Inst: University of Adelaide
Start Year: 2007
End Year: 2009
Total funding: $244,255
Grant Type: NHMRC Project Grants
Title of research award: Cortical Plasticity and Fine Motor Skills in Older Adults
Lay Description (from application):
Even in healthy individuals, the ageing process is usually associated with a progressive reduction in the
performance of various motor skills, such as writing, placing keys in keyholes and fastening buttons. These
deficits in manual performance may be due to an age-related decline in the ability of the brain to modify its
connections (plasticity) when learning new motor skills. This brain plasticity is a fundamental property of the
nervous system, where it is critical for learning and memory, but is also important for recovery from brain injury.
The goal of the proposed studies is to examine the extent of brain plasticity when performing fine motor skills in
older adults, and relate this to motor performance and learning in the elderly. We will use three complementary
approaches that will employ novel techniques of magnetic brain stimulation to achieve this goal. These studies
will be the first to ascertain a link between deficits in brain plasticity and impaired manual performance in older
adults. Furthermore, these studies will be the first to examine interventions designed to promote brain plasticity
and motor performance in older adults. Because the majority of patients requiring neurological rehabilitation are
in an older age group, it is important to understand the extent of brain plasticity in the elderly. This new
information may ultimately lead to innovative therapeutic or rehabilitation strategies to retain or improve fine
motor skills in the elderly and promote functional recovery from brain injury.
Research achievements (from final report):
The purpose of this project grant was to determine if the decline in fine motor skills commonly observed in older
adults was related to a reduced ability to modify brain connections (termed plasticity) with advancing age. To
achieve this goal, we used new advances in techniques of transcranial magnetic stimulation (TMS) to assess and
induce brain plasticity in young and old adults, and to determine how specific measures of brain function
influence the performance of fine motor skills. We found striking differences in the extent of brain plasticity and
motor performance in young and old adults, but the magnitude of brain plasticity did not relate to the motor
performance in young and old adults. This finding suggests that the deficit in fine motor skills in older adults was
not due to altered brain plasticity with advancing age. Furthermore, we found that older adults displayed similar
brain plasticity as their younger counterparts under some circumstances. We further explored some factors that
could contribute to the similar brain response in older adults, and showed that differences in physical activity
levels and muscle usage patterns related to hand preference could substantially influence the induction of brain
plasticity. By examining the boundary conditions of these effects, this new information may ultimately lead to
innovative therapeutic or rehabilitation strategies to retain or improve fine motor skills in the elderly and promote
functional recovery from brain injury.
Expected future outcomes:
We are now in the process of examining in more detail the boundary conditions that influence brain plasticity in
older adults, such as the contribution of physical exercise, genetics, and alterations in muscle usage patterns for
brain plasticity and motor function.
Name of contact: John Semmler
Email of contact: john.semmler@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508084
CIA Name: Prof Nicola (Nick) Fazzalari
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2010
Total funding: $434,498
Grant Type: NHMRC Project Grants
Title of research award: Vertebral body strength: Contribution of bone mass, bone structure and material
properties
Lay Description (from application):
This study will determine the contributions to vertebral body strength made by its structural and material
properties. Using state-of-the-art computed-tomography scanners, digitised representations of vertebral bodies in
three-dimensions will be produced, which enable measurement of bone structure. After strength testing of the
vertebral bodies, the structural and material properties, which combine to predict vertebral body strength, will be
identified in an aged population.
Research achievements (from final report):
We have successfully developed and implemented protocols for multi-modal and multi-scale imaging modalities
to achieve the project aims. The unique aspect of this study is that each of the complementary bone structure and
material parameters as well as a measure of whole vertebral body bone strength was obtained from the same
specimen. Using current clinically available DXA to meansure area BMD and pQCT to measure volumetric BMD
we validated these clinical data against high-resolution micro-CT imaging. We have developed and implemented a
sub-regional analysis protocol of bone mass at clinical resolution (DXA and pQCT imaging) against highresolution micro-CT imaging of whole vertebral bodies (Aims 1 and 4). This work was performed in conjunction
with our associate investigators at the University of Melbourne and is ongoing with the aim of making the analysis
clinically available for patient assessment of vertebral body fracture risk. We have also shown that a significant
proportion of the variability in bone strength can be explained by cancellous bone morphology and the validation
of these observations is about to be published in Osteoporosis International (Aims 2 and 3). To date the project
data has resulted in three peer-reviewed publications and thirteen conference presentations both nationally and
internationally. In additional, publications highlighting the clinical applicability of our findings are in preparation.
Finally, our unique regional analysis of data from the clinical imaging modalities will inform the clinical
guidelines for fracture risk assessment that will be necessary with new high resolution X-ray based imaging that is
currently being developed for clinical use.
Expected future outcomes:
This work is ongoing within our research program. We are continuing to correlate high-resolution morphometry
and biomechanics, with clinical imaging modalities, with the aim of implementing new improved clinical imaging
protocols to better predict vertebral body fracture risk.
Name of contact: Prof Nicola (Nick) Fazzalari
Email of contact: nick.fazzalari@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508085
CIA Name: Prof Sharad Kumar
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2010
Total funding: $656,396
Grant Type: NHMRC Project Grants
Title of research award: Roles of Ndfip1 and Ndfip2 as adaptors for the Nedd4 family of ubiquitin ligases
Lay Description (from application):
Part of this proposal is to understand how the body controls iron uptake through one of the iron transporters
(DMT1). We will also study how proteins called Ndfip1 and Ndfip2 that regulate DMT1, also control other
cellular processes, such as protection against brain damage following trauma. The results from this study should
ultimately contribute to the development of therapies for certain human pathologies.
Research achievements (from final report):
In ealier studies we had defined a novel mechanism for the regulation of DMT1, the primary non-heme iron
transporter. This regulation involves the members of the Nedd4 family of ubiquitin ligases and requires the
adaptors Ndfip1 and Ndfip2. In further experiments we used gene knockout in mice to show that Ndfip1-deficient
mice mice fed a normal iron diet have increased iron stores in the liver and spleen. We also found that in Ndfip1deficient mice fed a low iron diet, DMT1 expression and activity were significantly elevated compared to the
wild-type mice. However, despite the increased iron uptake, Ndfip1-deficient mice developed severe microcytic
anaemia due to a combined effect of iron deficiency and inflammatory disease in these animals. Ndfip1-deficient
mice are known to develop severe inflammatory disease, and our new observations suggest that iron deficiency
may accentuate this phenotype. Our results thus provide evidence that Ndfip1 is a key regulator of DMT1 and iron
homeostasis and this regulation may be critical under iron-limiting conditions. These findings have clear
implications in clinical medicine as the combination of iron deficiency and inflammation is a common clinical
problem. Most of the patients suffering with systemic illness such as systemic lupus erythematosus, inflammatory
bowel disease and malignancies frequently develop iron deficiency either due to low iron intake and/or blood loss.
Using Drosophila as a genetic model system we also found that Ndfip is a novel regulator of Notch signalling.
Notch signaling is frequently dysregulated in leukemia and other cancers. Thus our finding may be relevent to the
understanding of Notch signaling in human disease.
Expected future outcomes:
We expect to extend our understanding of the roles of Ndfip1 and Ndfip2 in iron homeostasis using mouse
models, focusing on iron recycling pathways and the two iron transporters. This will have direct implications in
understanding diseases of iron transport/metabolism and inflammation.
Name of contact: Sharad Kumar
Email of contact: sharad.kumar@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 207792
CIA Name: Prof Robert Vink
Main RFCD: Central Nervous System
Admin Inst: University of Adelaide
Start Year: 2002
End Year: 2004
Total funding: $241,650
Grant Type: NHMRC Project Grants
Title of research award: Characterisation of Substance P antagonists as a novel therapeutic intervention for use
in traumatic brain injury
Lay Description (from application):
Traumatic brain injury (TBI) is responsible for more deaths in Australians under 45 years of age than any other
cause. The economic and social cost of head injury to the community is enormous with billions of dollars spent
each year on the management and rehabilitation of trauma patients. Despite the enormity of this public health
problem, no effective treatment currently exists. A number of studies have demonstrated that much of the
morbidity following TBI is associated with the development of a secondary injury process that occurs between
hours to days after the insult. This delayed progression of injury suggests that appropriate pharmacologic
intervention can prevent, or at least attenuate, this secondary injury process with a resultant improvement in
outcome. Over the past 15 years, a number of groups, including ours, have been investigating the secondary
mechanisms associated with the development of functional deficits after TBI. Our previous studies have
demonstrated that decline in brain free magnesium is associated with functional deficits after experimental brain
injury, and that magnesium administration after injury can improve outcome. Magnesium is now on clinical trial
as a pharmacologic intervention. Recent studies have suggested that magnesium decline facilitates neurogenic
inflammation, which has been associated with oedema formation, oxidative damage and cell death. Although a
number of neuropeptides have been implicated in this process, it is thought that substance P release is closely
associated with these pathophysiological processes. Therefore, inhibiting neuropeptide release, or inhibiting
substance P binding, may offer a novel therapeutic approach for the attenuation of oedema and development of
neurologic deficits after TBI. This proposal will use a combined biochemical, pharmacologic and behavioural
approach to characterise the role of neuropeptides in brain trauma, and attempt to develop a novel therapy for use
in clinical trauma.
Research achievements (from final report):
We established that brain swelling (oedema) following traumatic brain injury followed a biphasic pattern, with an
early peak in brain water content occurring within 6 hours, followed by a second peak in brain water content at
three days after trauma that persisted for approximately 1-2 weeks. The early peak was associated with increased
vascular permeability, whereas the later phase was cellular oedema. The early oedema formation was initiated by
neuropeptide release, and in particular substance P, which increased blood brain barrier permeability and
facilitated the development of the early oedema. By inhibiting substance P release or binding, we were able to
prevent early onset oedema formation, and this subsequently led to an attenuation of the later oedema. We
concluded that the early oedema facilitated the subsequent cellular oedema. Administration of a substance P
antagonist not only attenuated oedema formation, but also improved motor and cognitive outcomes. Moreover,
the drug could be administered as late as 12 hours after the traumatic event and still result in a significant
reduction in brain swelling and an improvement in outcome. A more specific substance P antagonist with no
known side-effects was then donated by Roche pharmaceuticals and we were able to establish that this compound
was equally effective at preventing post-traumatic oedema formation and improving functional outcome. This
compound was subsequently patented and is expected to be entered into clinical trials in 2006/2007. If successful,
this drug has the potential to reduce mortality and morbidity after traumatic brain injury, and significantly reduce
the time victims of brain injury would spend in hospital.
Expected future outcomes:
The compound that was developed in this study will be entered into clinical trials in late 2006/early 2007. If
successful, it would revolutionise the management of brain swelling following traumatic brain injury.
Name of contact: Professor Robert Vink
Email of contact: Robert.Vink@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 250301
CIA Name: Prof Nicola (Nick) Fazzalari
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2003
End Year: 2005
Total funding: $423,625
Grant Type: NHMRC Project Grants
Title of research award: Interrelationships between the disc and bone of lumbar spinal segments
Lay Description (from application):
The cause of back pain due to osteoarthritis, osteoporotic vertebral crush fracture, and ageing is poorly
understood. Vertebral deformity, intervertebral disc disorganisation, and change to vertebral bone structure are
features associated with degeneration of the spine and with back pain. Degenerative disc disease is one of the
major causes of back symptoms and is believed to be associated with degeneration of the spine. Spinal
degeneration includes disc degeneration, facet joint osteoarthritis, compromised vertebral body bone quality,
muscle and ligament alterations. It is assumed that these changes result in increased or abnormal spine motion
and modified load distribution across the spinal joint. It has been found that with age, there is increased
disorganisation of the intervertebral disc and decreased quality of vertebral cancellous bone. However, bones with
the same density within the range of normal subjects, can show selective loss of bone structure and reduced loadbearing capacities of these vertebrae. An important concept here is that even for a given bone mass, fracture risk
increases with age, supporting the view that there is a component of bone fragility that is independent of mass.
Increased bone fragility may be associated with compromised cancellous bone structure. While the relationship
between disc degeneration and changes in vertebral bone is commonly invoked, the mechanisms of this
relationship have largely been overlooked, with age changes given more attention. However, it may be that
intervertebral disc disorganisation modulates age-related bone changes within the spine. Disc degeneration may
influence trabecular bone responses before changes with age put the patient at risk of vertebral crush fracture. We
propose that the mature disc cannot effectively regenerate after damage, and thus responses to disc damage will be
more readily observed in vertebral bone architecture than in the disc.
Research achievements (from final report):
We have developed and implemented a novel MRI protocol to measure the water content of the intervertebral
discs in the human spine. This protocol is breaking new ground in that it provides a new clinical tool to measure
the water content of the intervertebral disc of patients with back pain. We have been able to show that the MRI
scans are reliable and reprobucible. Until the development of this technique, assessing the amount of water in the
intervertebral disc has been based on the subjective interpretation of an MRI image by a radiologist. There are few
studies of this nature that have been reported and a patent application is pending.
In addition, this study has provided a novel perspective of the bone in the spine. The thickness of the bone wall
that surrounds the spongy bone structure in the vertebral body was thicker in the front of the vertebra than the
back of the vertebra, suggesting that the bone wall in the front of the vertebra has to support a greater load than the
back wall of the vertebra. Combined with the data we have on the deformation of the vertebral body bone wall
under load and how the load is transmitted through the spongy bone in the vertebral body we have a unique insight
into vertebral body mechanics. This places us at the forefront of understanding the mechanism of vertebral body
fracture where the patient has fragile bones. The study has enabled us to better understand the relationship
between the intervertebal disc and the vertebral body bone. These unique data from the human spine have not
been previously reported and hold significant potential to understand bone quality factors that ultimately
determine bone strength and what factors should be the target of treatment.
Expected future outcomes:
This was a pioneering study using a multidisciplinary approach and our unique experience to elucidate the
mechanisms of spinal degeneration. The MRI protocol to measure the water content of the disc will provide a new
clinical tool to identify the presence of disc degeneration, monitor progression of disc degeneration and monitor
the efficacy of treatment of disc degeneration in patients.
Name of contact: Nick Fazzalari
Email of contact: nick.fazzalari@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508081
CIA Name: Prof Robert Fraser
Main RFCD: Intensive Care
Admin Inst: University of Adelaide
Start Year: 2008
End Year: 2011
Total funding: $533,793
Grant Type: NHMRC Project Grants
Title of research award: Impact of gastrointestinal dysmotility on enteral nutrition in the critically ill
Lay Description (from application):
Critically ill patients require nutrition for optimum recovery. Ideally, this is provided via the gut, but oesophageal
reflux, slow gastric emptying and small intestinal dysfunction frequently prevent adequate delivery of nutrients to
these patients, exposing them to complications such as pneumonia and gastrointestinal bleeding. The work
performed by the applicants will improve the ability of doctors in the Intensive Care Unit to feed patients and
prevent the development of such complications.
Research achievements (from final report):
Upper gastrointestinal dysfunction, particularly slow gastric emptying, is common in critically ill patients, and has
been increasingly recognised to be a major contributor to poor outcomes. The work performed during this grant
provided the most definitive studies to date on the mechanisms underlying gastric stasis in these patients, the
contribution of various premorbid and treatment related factors to this condition and the most effective therapeutic
approaches to manage its occurrence. A component of this work included the development, validation and
application of novel measurement techniques in these patients. Additional experiments defined the role of
gastrointestinal dysfunction in glycaemic control, itself an independent risk factor for increased morbidity and
mortality in these patients. Building on this work, innovative studies initially in healthy humans, but subsequently
in patients, provided the first proof of concept studies for the use of incretin therapy, specifically Glucagon-LikePeptide (GLP-I), to provide safer treatment options for hyperglycemia in unconscious patients in the Intensive
Care Unit. A corollary to these latter studies was the demonstration that hormones such as GLP-I are likely to
have a major role in the normal physiological feedback regulation of gut motility after carbohydrate ingestion.
Further development of this concept will enhance the development and utilisation of novel agonists and
antagonists to manage abnormalities of glucose metabolism. As well as studies performed on gastric dysfunction,
additional studies demonstrated that disturbed small intestinal motility has a major impact on nutrient absorption
and is also likely to contribute to malnutrition in critical illness.
Expected future outcomes:
Future benefits derived from this grant will enhance nutritional support in critically illness by guiding the
development of novel therapeutic agents to address specific deficits in gastric motor function. In addition this
work will inform development of the novel methods to treat hyperglycamia more safely in these patients.
Name of contact: Assoc Prof Marianne Chapman
Email of contact: Marianne.Chapman@health.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299031
CIA Name: Dr Gerald Atkins
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2004
End Year: 2006
Total funding: $436,450
Grant Type: NHMRC Project Grants
Title of research award: Relationships Between Human Osteoblasts and Haemopoietic Cells in Bone
Remodelling
Lay Description (from application):
Bone diseases, such as osteoporosis and osteoarthritis, currently afflict more than 4 million Australians. These
diseases are characterised by abnormal bone remodelling, which can result in a net loss of bone (for example, in
osteoporosis) or abnormal bone structure (for example, in osteoarthritis). We are seeking to better understand the
factors that regulate bone remodelling, and particularly the cells involved in this process. Physiological bone
remodelling results from the intimate collaboration between osteoblasts and osteoclasts. Osteoblasts stimulate the
formation of osteoclasts and also produce new bone at resporption sites. However, the way that the same type of
cell can perform both these tasks, is not clear. Our studies are designed to increase our understanding of the
development of human osteoblasts and of the factors that cause them to be sequentially pro-osteoclastic and then
pro-osteogenic. We believe that an important factor in this process is vitamin D and we will test the hypothesis
that this molecule is produced in bone and acts locally to regulate bone turnover.
Research achievements (from final report):
The aims of this proposal were: 1. To further define the link between the osteoblast differentiation state and the
formation of osteoclasts in response to various factors that act on the skeleton;
2.
To further characterise the signals between, and the influences of, haemopoietic cells and osteoblasts
during both osteoclastogenesis and osteogenesis;
3.
To define the role of 1,25(OH)2vitamin D3 metabolism in human bone cell biology.
This has been a highly successful and productive period of research, resulting to date in 11 publications including
two book chapters. At least 6 further publications describing work encompassed in this project are in preparation.
We have succeeded in obtaining significant new insight into human osteoblast biology with respect to their
production of osteoclast activating factors, their response to osteoclast derived factors, and the way in which they
differentiate into mineral producing cells and further, into mature osteocytes. We have established that the
skeleton is an intracrine organ for vitamin D metabolism, effectively describing a paradigm shift in this field. This
has important implications for the interpretation of the diagnostic indicator of vitamin D status, namely, the serum
25-hydroxyvitamin D level. We have characterised a number of pathways whereby osteoblast differentiation is
modulated by proinflammatory signals deriving from both haemopoietic cells and from osteoblasts themselves,
which is likely to be important in bone repair and in diseases of bone inflammation, such as rheumatoid arthritis
and osteoporosis. We have also established an effective model, with which to examine the mechanism of action of
anabolic therapeutics for the treatment of osteoporosis. Our results have direct implications for the treatment of a
number of bone degenerative diseases.
Expected future outcomes:
This project has formed the basis of two further major projects, examining the role in bone of the inflammtory
cytokine TWEAK, and the effect on bone cells of wear particles derived from orthopaedic prostheses. We have
also established important collaborations with international companies to investigate the modes of action of
skeletal therapeutics on human bone cells in vitro.
Name of contact: Dr. Gerald Atkins
Email of contact: gerald.atkins@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 399305
CIA Name: Prof Nicola (Nick) Fazzalari
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2006
End Year: 2008
Total funding: $447,027
Grant Type: NHMRC Project Grants
Title of research award: Intrinsic bone qualities in fragility fracture patients: mass, microarchitecture,
mineralization and damage accumulation
Lay Description (from application):
Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients
receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures.
Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties.
Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no
detectable change to the structure of bone has been detected. It has also been shown that when bone renewal is
suppressed microdamage accumulates in bone tissue, leading to reduced bone toughness. The toughness of bone is
of primary importance in relation to fragility fractures, and it has been shown that the fatigue strength and fracture
toughness (work to fracture) reduce considerably with age. This proposed study would seek to elucidate the role
of bone tissue-level properties in determining bone quality for human subjects: patients with fragility hip fractures
on no osteoporosis drugs therapy, hip fracture patients on osteoporosis drugs therapies, and normal age- and sexmatched individuals. Our laboratory has extensive experience in the analysis of the structure of human bone
tissue. Recently, we have developed novel and unique techniques to assess bone quality, using micro-CT,
backscatter SEM imaging, confocal microscopy and immunohistochemistry. This multifaceted study will identify
at the bone tissue-level the structural mechanisms (micro-architecture, mineralisation, and microscopic cracking)
that are indicative of the efficacy of fragility fracture drugs. Better understanding of the mechanisms by which
bones are less likely to fracture will enable better targeting of osteoporosis drug therapy to individuals at risk of
fragility fracture.
Research achievements (from final report):
Fragility fracture risk is strongly dependent upon skeletal strength. Low bone mass is not the sole predictor of loss
of bone strength. Bone strength is determined by a number of inter-related structural and material components,
collectively constituting bone quality. We have undertaken complementary investigations of bone structure (how
bone is arranged in 3D space), bone mineralisation (how soft or brittle the bone is), and bone microdamage
accumulation (how many microscopic cracks are present in the bone) on bone specimens from the femur from
patients with fragility hip fractures that were not/were receiving osteoporosis drug therapy and skeletally normal
individuals (non-fracture controls). Measurements of trabecular bone volume (3D bone mass) and bone
microarchitecture do not discriminate hip fracture patients from controls. However, bone from hip fracture
patients is less mineralised and contains more unrepaired microdamage (damage is repaired/removed by bone
turnover) compared to control individuals. Hip fracture patients that were receiving osteoporosis drug therapies
prior to fracture, show a different bone mineralisation profile compared to the fracture patients not on therapy and
controls. Our data demonstrate that the effect on bone of osteoporosis drug therapies, and hence reduction of
secondary fragility fracture, may differ on an individual patient basis. Our finding of altered bone mineralisation
profiles for hip fracture patients that were not/were receiving osteoporosis drug therapies and non-fracture controls
implicates the involvement of bone turnover in determining bone material quality, and hence bone strength. This
project has delivered novel material property data for fragility hip fracture patients and non-fracture individuals
representative of the Australian population. These data together with other bone quality measures may be of
central importance in defining individualised fracture risk assessment and tailorised treatment efficacy.
Expected future outcomes:
Currently prescribed osteoporosis drug therapies only reduce the risk of fracture by approximately 50%. Novel
bone quality data obtained for fragility fracture patients arising from this project has identified individualised
responses to osteoporosis drug therapy. Future preventative treatment approaches for primary and secondary
fragility fracture must be considered on an individualised basis.
NHMRC Research Achievements - SUMMARY
Name of contact: Prof Nick Fazzalari
Email of contact: nick.fazzalari@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 207701
CIA Name: Prof Nicola (Nick) Fazzalari
Main RFCD: Orthopaedics
Admin Inst: University of Adelaide
Start Year: 2002
End Year: 2004
Total funding: $317,640
Grant Type: NHMRC Project Grants
Title of research award: Molecular determinants of bone remodelling in the bone microenvironment
Lay Description (from application):
There is little information regarding the expression of specific molecules in human bone tissue or their role in
skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our
understanding of the molecular signalling involved in activating bone remodelling is principally derived from
tissue culture and animal experiments. We will study human cancellous bone samples donated by patients
undergoing surgery, and with the consent of the next-of-kin, taken at autopsy. These molecular and
histomorphometric studies will determine whether the understanding derived from tissue culture and animal
experiments is consistent with associations demonstrable in the human cancellous bone microenvironment. The
elucidation of the molecular signalling in the human bone microenvironment is essential for the effective
diagnosis and treatment of bone disease. Recently reported studies have shown very persuasively that fatigue
microdamage accumulates in the skeleton and is targeted for repair by remodelling. Our preliminary data shows
that microcrack length is positively correlated with IL-11 mRNA gene expression. We will further investigate
mRNA gene expression of a number of cytokines involved in bone cell signalling and their association with the
level of microdamage in the bone. Using a animal model of controlled bone microdamage induction we will seek
to determine the bone remodelling causal relationship between microdamage and cytokine signalling.
Furthermore, the cellular and molecular mechanisms that lead to trabecular structures are not well understood.
These studies will provide new insight into the processes that determine trabecular structures. This project will
investigate these mechanisms and increase our understanding of bone cell function, essential for diagnosis and
design of rational treatment for bone diseases.
Research achievements (from final report):
In this project, we have investigated the expression of key regulatory molecules of bone renewal in the
microenvironment of trabecular bone samples from patients who have suffered osteoporotic fragility fractures and
osteoarthritis. We have combined investigation of gene expression in human bone with measurement of tissue
morphology (histomorphometry), to investigate links between molecules that participate in bone renewal. Bone
samples were taken from patients undergoing hip replacement for a fragility fracture of the femur and total hip
replacement for osteoarthritis. We have found that the expression of a number of key genes that control bone
renewal, RANK and IL-6 mRNA and RANKL/OPG mRNA ratio, was significantly elevated in the osteoporotic
fracture group compared to an age-matched control group. These data suggest a relative increase in the expression
of the molecular promoters of osteoclast formation (cells that remove bone) and activity in osteoporotic fragility
fracture bone, which may lead to the imbalance between bone formation and removal associated with fragility
fracture. When the same bone samples used for molecular analysis were examined by histomorphometry, bone
formation parameters were significantly reduced in the fracture patients compared to controls. These data are
important because they are among the first to draw attention to a reduction in bone formation, rather than
increased bone removal, in association with osteoporotic fragility fractures. In additional work, we have
performed microarray experiments, comparing gene expression in osteoporosis and osteoarthritis bone samples. A
number of different classes of genes have been identified as being up-regulated in osteoporosis compared to
osteoarthritis, which is consistent with the reduced bone mass seen in osteoporosis compared to osteoarthritis.
This project grant increased our understanding of the mechanisms of bone renewal and potentially identified new
tragets for novel drug development.
Expected future outcomes:
Our studies have shown that the disregulation of bone cell signals and their relationship to bone tissue properties is
a potential determinant of fragility fracture risk. The elucidation of the mechanism of bone renewal identifies
potential new tragets for novel drug development.
NHMRC Research Achievements - SUMMARY
Name of contact: Nick Fazzalari
Email of contact: nick.fazzalari@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284343
CIA Name: Prof Caroline Finch
Main RFCD: Epidemiology
Admin Inst: University of Ballarat
Start Year: 2004
End Year: 2008
Total funding: $646,540
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
My research into the prevention of injuries during sport has made a significant contribution to the health and
wellbeing of Australians. I have identified injury priorities and evidence-based strategies for their prevention that
have since been adopted by national/state/local sports bodies, government departments and health agencies. My
research has firmly established sports safety as a significant public health issue; quantified the magnitude of the
problem in Australia; developed and applied high quality epidemiological methods; placed sports injury
prevention within broader public health strategies to promote physical activity and ongoing sports medicine
development. My research has clearly demonstrated that sports bodies will not implement safety policies until
they are sure that safety measures actually prevent injuries, are acceptable to their participants, do not change the
essential nature/appeal of sport, and do not adversely affect participation/performance. Through investigation of
the sports implementation setting, my research has provided new understanding of the sports and individual
athlete behaviour contexts in which the interventions are to be implemented and has assessed potential factors
associated with the real-world introduction and application of safety measures and development of
implementation strategies to accompany the real world ''rollout'' of safety interventions. Underpinning all of the
above research is a need for high quality, reliable injury statistical data through surveillance activities. I have also
undertaken significant research into sports and falls injury surveillance and made methodological advances in the
design of injury surveillance systems, as well as contributing to international debate about how to code and
classify injuries.
Expected future outcomes:
My research will continue to make ongoing significant contributions to sports safety in Australia through
providing a strong evidence-base for developing sport safety measures and related policy initiatives. Most
importantly, they have focussed attention on better understanding of the sports context to enhance the adoption of
safety measures.
Name of contact: Prof Caroline Finch
Email of contact: c.finch@ballarat.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 502628
CIA Name: Dr Sheena Wee
Main RFCD: Medical Biochemistry: Proteins and Peptides
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2011
Total funding: $141,000
Grant Type: Early Career Fellowships (Australia)
Title of research award: Chemical aided phospoproteome sequencing with mass spectrometry
Lay Description (from application):
Essentially all of the body's functions from muscle contraction, energy expenditure through to appetite are
controlled by a complex molecular communications system. One of the key elements involves the modification of
proteins to alter their properties by adding and removing phosphate. By analysing this process in response to diet
and exercise we will obtain a greater understanding of their health benefits and understand how type 2 diabetes
and obesity develop at the molecular level.
Research achievements (from final report):
The sucess of an islet transplant may be more easily monitored now.
Expected future outcomes:
This may lead to higher survival rate for patients who receive this treatment.
Name of contact: Sheena Wee
Email of contact: swee@imcb.a-star.edu.sg
NHMRC Research Achievements - SUMMARY
Grant ID: 400388
CIA Name: A/Pr Paul McCrory
Main RFCD: Neurology and Neuromuscular Diseases
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2010
Total funding: $370,603
Grant Type: Career Development Fellowships
Title of research award: Concussive injury in children and adolescents.Novel imaging modalities in adult
concussive brain injury
Lay Description (from application):
Not Available
Research achievements (from final report):
My clinical research work has studied the clinical aspects of traumatic brain injury (TBI). This has been
especially important in the understanding of the effects of mild TBI in paediatric age groups where little is known
about the appropriate management of such injuries. In additon, the research has provided the basis of utilising
novel radiological techniques in adult TBI particularly in the setting of sports related TBI.
Expected future outcomes:
This research is critical in the development of clinical pathways for mild TBI management. The guidelines
developed for the management of sports concussion have already been utilised worldwide in all profession team
sports
Name of contact: N/A
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 382903
Start Year: 2006
CIA Name: Prof Stephen Jane
End Year: 2009
Main RFCD: Genetic Development (incl. Sex Determination)
Total funding: $623,065
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Title of research award: Defects in epidermal morphogenesis in mammalian Grainyhead-like gene deficient
mice
Lay Description (from application):
The cells of the skin play an essential role in development of the mammalian embryo. They are critical for closure
of the brain and spinal cord, for forming a protective barrier against infection and noxious stimuli, for preventing
excess fluid loss, for repair of defects and wounds, and for the generation of hair. Our laboratory has identified a
family of genes that are critical for all these processes. Loss of individual members of the family has different
consequences and the aim of this study is to determine the relationship between the genes to further our
understanding of the skin and its functions. These studies have direct and important relevance to human conditions
such as the congenital birth defects spina bifida and anencephaly, and infant prematurity where the skin is
underdeveloped and lacks barrier function. They also have relevance to wound healing and to conditions in which
hair growth is affected, such as alopecia. We believe that therapeutic interventions and prenatal diagnostic tests
could evolve from these studies.
Research achievements (from final report):
This grant identified and characterized a family of genes that are master regulators of the functions of the human
skin. They are essential for wound repair, formation and maintenance of the skin barrier, hair anchorage and
developmental events that require directional migration of the skin. Our findings have potential benefits in
premature infants, where the barrier fails to form, wound repair and a range of other skin defects.
Expected future outcomes:
We anticipate that this grant will form the basis of extensive further work on this gene family that will impact on
our understanding of diseases of the skin.
Name of contact: Stephen Jane
Email of contact: Stephen.Jane@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 435112
CIA Name: Prof Stephen Jane
Main RFCD: Foetal Development and Medicine
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2009
Total funding: $569,542
Grant Type: NHMRC Project Grants
Title of research award: The role of the mammalian Grainyhead-like gene family in neural tube closure
Lay Description (from application):
Failure of the skin to close over the brain and spinal cord during human development results in the devastating
congenital birth defects anencephaly and spina bifida, known collectively as the neural tube defects. These are the
second most common congenital birth defects affecting 1:1000 pregnancies. Anencephaly is not compatible with
life and affected babies die at birth. In contrast children with spina bifida survive, but suffer from limb paralysis,
bowel and bladder dysfunction, learning difficulties and psycho-social disturbances. Our laboratories have
identified a family of genes essential for the colsure of the neural tube in mammals. The aim of this proposal is to
understand the mechanisms of action with a view to developing new therapeutics that mey be used preventatively
in these conditions. We also hope that these studies may facilitate the development of a genetic test to screen
couples at risk.
Research achievements (from final report):
Defects in closure of the brain and spinal cord (neural tube defects) are the second commonest of all the
congenital birth defects. Our laboratory has made a substantial contribution in this area with the identification of
the Grainyhead-like gene family which plays critical roles in closure of the neural tube. By studying the
mechanism by which these genes work, we gain insights into potential screening and preventative measures that
could be developed for these devastating defects into the future.
Expected future outcomes:
We anticipate that our studies will lead to new preventative strategies for neural tube defects.
Name of contact: Professor Stephen Jane
Email of contact: Stephen.Jane@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 509146
CIA Name: A/Pr Heung-Chin Cheng
Main RFCD: Cellular Nervous System
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2011
Total funding: $519,715
Grant Type: NHMRC Project Grants
Title of research award: Deciphering how PTEN phosphatase mediates excitotoxic neuronal death
Lay Description (from application):
In stroke patients, oxygen deprivation indirectly induces massive nerve cell death by activating a cell deathpromoting enzyme called PTEN. We aim at unravelling (i) how PTEN is activated by oxygen deprivation, (ii)
where the activated PTEN is localised in cells, and (iii) how the activated and optimally localised PTEN induces
nerve cell death. The study will benefit development of therapeutic strategies to protect against brain damage in
stroke.
Research achievements (from final report):
We found that upon overstimulation of the cultured neurons by glutamate, PTEN and its down-stream substrate cSrc kinase, undergoes calpain-mediated limited proteolysis to generate a 50-kDa truncated PTEN and an 55-kDa
truncated c-Src. Further investigation reveals that the truncated c-Src is the key enzyme directing neuronal cell
death. Our finidngs indicate that inhibitors suppressing c-Src kinase activity and/or calpain-mediated truncation of
c-Src are potential neuroprotectants for prevention of neuronal death in patients suffering from ischaemic stroke.
Expected future outcomes:
development of c-Src kinase inhibitors as neurprotectants for treatment of stroke patients. As PTEN is an
endogenous inhibitor of c-Src kinase, studying how truncation of c-Src kinase allows it to escape regulation by
PTEN will shed light on the mechanism of neuronal death in stroke patients.
Name of contact: Heung-Chin Cheng
Email of contact: heung@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300054
CIA Name: A/Pr Jane Pirkis
Main RFCD: Mental Health
Admin Inst: University of Melbourne
Start Year: 2004
End Year: 2008
Total funding: $444,500
Grant Type: Career Development Fellowships
Title of research award: Preventing suicidal behaviours: Ecological studies of systemic protective factors
Lay Description (from application):
Not Available
Research achievements (from final report):
Most international research efforts in suicide prevention have focused on exploring the rates of and risk factors for
suicidal behaviour. My program of work considered some of the factors that might be protective against suicide at
a range of levels (individual, ecological, intervention/service-based, systemic). My work has influenced policy
and practice in a number of ways, including helping to shape national and international guidelines on media
reporting of suicide, and influencing the nature of several national mental health and suicide prevention initiatives.
Expected future outcomes:
I would anticipate that my work will continue to have an impact on policy and practice in a similar manner.
Name of contact: Jane Pirkis
Email of contact: j.pirkis@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508947
CIA Name: Prof John Furness
Main RFCD: Autonomic Nervous System
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2010
Total funding: $414,327
Grant Type: NHMRC Project Grants
Title of research award: Roles of the peptide hormone, ghrelin, in the spinal cord
Lay Description (from application):
This study investigates the control of internal organs of the body, the heart, blood vessels, intestine and bladder.
We have made the new and surprising discovery that ghrelin, previously known to be a hormone, is probably also
a neurotransmitter in the spinal cord. This raises the possibility that drugs that act on ghrelin receptors in the
spinal cord could be used to treat high blood pressure or other problems of internal organs.
Research achievements (from final report):
We have found that artificial compounds that mimic the action sof the naturally occurring hormone, ghrelin, have
actions in the spinal cord that influence bowel and bladder emptying and blood pressure. These are novel
discoveries. The stimulant effects on bowel emptying can be elicited in conscious animals which show no adverse
effects of the drug application. Thus the mechanism that we have discovered can be potentially used to treat
constipation, such as the constipation that occurs after spinal cord injury or in old age. In addition, the
observations imply that the ghrelin receptor is somehow involved in the maintenance of blood pressure. It is
possible that this sytem could be manipulated to reduce high blood pressure.
Expected future outcomes:
Suitable compounds to treat constipation have been developed and we anticipate that these will be used in human
trials.
Name of contact: Professor John Furness
Email of contact: j.furness@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251575
CIA Name: Prof Eleanor Mackie
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2003
End Year: 2003
Total funding: $120,775
Grant Type: NHMRC Project Grants
Title of research award: Cellular responses to thrombin in skeletal pathology
Lay Description (from application):
Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. The enzyme thrombin is involved in blood coagulation but also
causes bone cells to alter their behaviour. Thrombin stimulates proliferation of bone-forming cells and protects
them from premature death. Thrombin also stimulates the breakdown of bone. We will investigate how
thrombin's effects on bone cell behaviour influence the course of bone healing. We will also determine how
thrombin stimulates bone breakdown and increases survival of bone-forming cells. This study will contribute to
the understanding of how bone cells function in health and disease.
Research achievements (from final report):
Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. The enzyme thrombin is involved in blood coagulation but also
causes bone cells to alter their behaviour. In this project we have demonstrated that the early stages of bone
healing occur abnormally in the absence of the major thrombin receptor found in bone (PAR-1). We have found
that thrombin stimulates formation of osteoclasts (bone-resorbing cells). We have also identified a signalling
pathway through which thrombin prevents the death of osteoblasts (bone-forming cells). These observations add
substantiallyto our understanding of the biology of bone growth, maintenance and repair.
Expected future outcomes:
The observations made in this grant have led to ongoing studies on regulation of osteoclast function by proteases.
These and our future studies are likely to help in the development of improved therapeutic approaches to bone
disease.
Name of contact: Professor Eleanor Mackie
Email of contact: ejmackie@unimelb.edu.auYes
NHMRC Research Achievements - SUMMARY
Grant ID: 454686
Start Year: 2007
CIA Name: Prof Kim Bennell
End Year: 2008
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $271,503
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Title of research award: Reducing knee load and slowing disease progression with conservative interventions in
knee osteoarthritis
Lay Description (from application):
Knee arthritis is a painful, disabling, costly condition particularly affecting the elderly. As there is presently no
cure for arthritis, interventions that slow progression of the disease will reduce the personal and societal burden of
arthritis. Recently it has been postulated that specific exercise that targets how the muscles are controlled by the
nervous system may have greater disease-modifying effects than exercise aimed at strengthening the muscles.
Data are beginning to highlight the complexity of muscle strategies adopted by the nervous system to compensate
for joint derangement in knee arthritis. It is our contention that there may be specific strategies that provide more
optimal knee joint loading in relation to slowing disease progression. The first part of this project is to investigate
knee control in people with knee arthritis and to evaluate whether this influences disease progression. This will
provide the basis for refinement and optimisation of rehabilitation interventions for this patient group. The second
part of this project will investigate whether strengthening the hip muscles in patients with knee arthritis influences
knee load and hence disease progression. Hip muscle strengthening is currently not routinely included as part of
the management of knee arthritis. If the results of this project find it to be effective, then hip muscle strengthening
can be recommended for treating knee arthritis.
Research achievements (from final report):
This research investigated factors influencing knee load during walking and ways to reduce knee load in people
with knee osteoarthritis. This is important as knee load is a predictor of the risk of structural disease progression those who walk with higher knee load are more likely to progress to more serious disease. The research showed
that muscles around the hip are weaker in people with knee osteoathritis but that strengthening the hip muscles
does not change knee load although it leads to a significant reduction in knee pain and improvement in knee
function. This suggests that hip muscle strengthening is not a disease-modifying treatment as has been postulated
in the literature. The research also showed that neuroumuscular and biomechanical factors can influence knee load
and hence disease progression. This will impact upon the design of more effective rehabilitation programs for
knee osteoarthritis.
Expected future outcomes:
The research provides information that will influence rehabilitation programs for people with knee osteoarthritis
that will be of use to clinicians
Name of contact: Kim Bennell
Email of contact: k.bennell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208960
CIA Name: Prof Eleanor Mackie
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2003
Total funding: $216,100
Grant Type: NHMRC Project Grants
Title of research award: The role of protease-activated receptor-2 in regulation of bone metabolism
Lay Description (from application):
Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. We have recently demonstrated the presence of a receptor called
PAR-2 on bone-forming cells. We have also shown that activation of PAR-2 inhibits the development of boneresorbing cells (osteoclasts) in response to hormones. We plan to investigate the mechanism of this effect, as well
as to identify how PAR-2 activation modulates other responses of bone cells to hormones. Molecules that activate
PAR-2 are present in bone in certain disease situations, but it is not known what activates PAR-2 in bone under
normal conditions. We will identify physiological activators of PAR-2 within bone.
Research achievements (from final report):
Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. We have demonstrated that a receptor called PAR-2 on bone-forming
cells (osteoblasts) inhibits the development of bone-resorbing cells (osteoclasts) in response to hormones.
Furthermore, we have demonstrated that PAR-2 exerts this effect through inhibition of expression of a number of
factors produced by osteoblasts that are necessary for osteoclast formation. We have shown that a number of
tissue proteases that activate PAR-2 are not expressed in the bone environment, and that one putative activator of
PAR-2 is not capable of activating it. These observations add substantiallyto our understanding of osteoclast
biology, and therefore to bone biology in general.
Expected future outcomes:
The observations made in this grant have led to ongoing studies on regulation of osteoclast function by proteases.
These and our future studies are likely to help in the development of improved therapeutic approaches to bone
disease.
Name of contact: Professor Eleanor Mackie
Email of contact: ejmackie@unimelb.edu.auYes
NHMRC Research Achievements - SUMMARY
Grant ID: 454561
CIA Name: Prof Gordon Lynch
Main RFCD: Sports Medicine
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2009
Total funding: $288,210
Grant Type: NHMRC Project Grants
Title of research award: Improving muscle function after injury: Novel tissue engineering strategies for
exercise, surgery and sports medicine
Lay Description (from application):
Muscles can be injured by excessive strains when playing sports, in road and workplace accidents, and during
plastic and reconstructive surgery. Some surgeries require an unavoidable interruption to the muscle's normal
blood supply (called 'ischaemia'). Subsequent return of the muscle's blood supply (reperfusion) is problematic in
that a severe secondary muscle injury can ensue mediated by the influx of damaging free radicals when blood flow
is restored. Tissue-engineering provides a novel therapeutic approach to restore muscle structure and function to
damaged muscles after injury or disease. Our recent research using controlled release of growth factors from
biodegradable hydrogels has exciting application for muscle repairafter injury. We will utilize these cutting edge
tissue engineering strategies to deliver to damaged muscles a hydrogel containing controlled delivery (slow
release) microcapsules loaded with an anabolic agent (the beta-agonist, formoterol) and/or a growth factor (IL-15)
designed to enhance functional muscle repair after three distinct but clinically relevant models of muscle injury: a)
crush injury: A model for muscle injuries on the sports field, in the workplace, and those associated with road
trauma; b) ischaemia-reperfusion injury: a model for muscle damage associated with surgical interventions,
muscle transfers for functional restoration, and other injuries associated with plastic and reconstructive surgery;
and c) contraction-induced injury: a model for strain injuries such as hamstring muscle tears that can occur on the
sports field. After injury we will assess functional muscle repair using a comprehensive series of histological,
biochemical, molecular, immunochistochemical, and physiological techniques. The research has broad application
to exercise and clinical medicine; including sports, emergency and rehabilitation medicine, and plastic,
reconstructive, and orthopaedic surgery.
Research achievements (from final report):
Musculoskeletal injuries represent a major global public health problem and skeletal muscle damage and loss of
muscle function contributes significantly to the large burden of disability and suffering. Novel approaches that
can attenuate the severity of muscle trauma and/or hasten muscle repair to restore function would help to reduce
the economic burden of musculoskeletal injury and alleviate the personal suffering and financial hardship of
affected patients. Using novel tissue engineering approaches, we developed small spheres capable of being loaded
with the muscle growth promoting agent, formoterol. When injected into damaged muscles, the goal was that the
spheres slowly released the formoterol such that it prolonged the growth promoting effect beyond that achieved
normally from simply injecting muscle growth promoting agents directly into muscles. The work represent a
significant advance for the development of new therapeutics for muscle repair following injury.
Expected future outcomes:
The research will identify new ways of utilising tissue engineering to enhance the repair of skeletal muscle after
injury, with relevance to advancements in plastic and reconstructive surgery, sports medicine and rehabilitation.
Name of contact: Prof. Gordon S. Lynch
Email of contact: gsl@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508925
Start Year: 2008
CIA Name: Prof Mary Galea
End Year: 2012
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $382,320
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Title of research award: Pelvic Organ Prolapse Physiotherapy (POPPY)
Lay Description (from application):
Pelvic organ prolapse in women is associated with poor quality of life. The standard treatment currently available
for prolapse is surgery. The evidence for conservative management with physiotherapy is not clear. This
randomised controlled trial will examine the effect of physiotherapy treatment, including pelvic floor muscle
training, on prolapse symptoms and severity, compared with lifestyle advice only. Appropriate conservative
management may reduce the need for surgery and associated costs.
Research achievements (from final report):
Pelvic organ prolapse (POP) is highly prevalent in women over 40 years (40-50%) and is considered a major
epidemic. Symptoms of POP impact substantially on quality of life for women, affecting physical health and wellbeing, ability to exercise and personal relationships. Typical management involves surgery, which has a high
failure rate. This project has contributed to two independent but complementary randomised controlled trials, one
conducted in the UK and the other in Australia, investigating the effectiveness of conservative management of
POP using pelvic floor muscle training. Both studies showed that pelvic floor muscle training was effective and
cost-effective (UK) in minimizing the severity and bother of prolapse symptoms compared with lifestyle advice
about weight loss, constipation, and avoidance of heavy lifting, coughing and high impact exercise. This evidence
is sufficient for pelvic floor muscle training to be recommended as first-line management for prolapse.
Expected future outcomes:
The implementation of pelvic floor muscle training for women with prolapse may prevent the need for surgery,
prolong the time before a surgical procedure is required, and may improve the durability of the first surgical
procedure being undertaken, possibly avoiding the need for repeat surgery.
Name of contact: Helena Frawley
Email of contact: h.frawley@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568850
CIA Name: A/Pr James Brock
Main RFCD: Autonomic Nervous System
Admin Inst: University of Melbourne
Start Year: 2009
End Year: 2011
Total funding: $390,886
Grant Type: NHMRC Project Grants
Title of research award: Do postjunctional alterations explain the effects of diabetes on neurovascular
transmission?
Lay Description (from application):
Diabetes produces disordered skin blood flow that increases risk of skin ulcers and gangrene. The project
investigates nervous control of skin blood vessels in diabetes. It is assumed that all affects of diabetes on nerve
function are explained by loss of nerves. We hypothesize that some affects of diabetes are due to dysfunction of
blood vessels and not to nerve loss. The objective is to identify drug targets to improve blood flow in skin and
thereby reduce the risk of skin ulcers and gangrene.
Research achievements (from final report):
The primary achievement of this study is the establishment of an animal model for investigating the effects of
diabetes on the nerves (sympathetic nerves) that control blood vessels. Specifically the project has identified that
diabetes produces changes in the structure and chemistry of sympathetic nerve terminals in a small artery that
supplies blood to skin. While it is widely believed that diabetes can damage sympathetic nerves, to our knowledge
this is the first study to directly demonstrate that diabetes affects sympathetic nerves supplying arterial blood
vessels. Importantly, these changes were seen in an artey supplying blood to skin where diabetes is known to
impair nerve-mediated control of blood flow. The effects of diabetes on sympathetic nerves controlling arteries
that supply blood to the intestine were also investigated but these were not affected by diabetes. The new model
will provide opportunities to test drugs that prevent or reverse diabetes-induced nerve damage.
Expected future outcomes:
The viability of this model for testing neuroprotective agents needs to be further assessed. Ideally we would like to
do this with Industry support and will investigating this possibility in the near future.
Name of contact: James Brock
Email of contact: j.brock@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299840
Start Year: 2004
CIA Name: Prof Kim Bennell
End Year: 2006
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $384,675
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Title of research award: Efficacy and cost-effectiveness of physiotherapy for chronic rotator cuff pathology
Lay Description (from application):
Shoulder disorders are common, being third only to back and neck complaints as musculoskeletal reasons for
medical consultation and accounting for 10% of all physiotherapy referrals. The painful shoulder affects up to 25% of the general population, being more common in middle to older age. One of the most common shoulder
disorders is chronic rotator cuff pathology. This causes significant pain and disability that restricts activities of
daily living as well as work, sleep and leisure. Forty percent of sufferers will continue to have symptoms beyond
3 years and 15% will have persistent disability which may require surgical intervention. Because this disorder is
prevalent, it imposes a considerable burden on the Australian health care system. Physiotherapy is a common
conservative treatment option but its efficacy has not been well established. A recent Cochrane review of the
literature revealed several problems with many of the existing studies: (i) the populations have included a mix of
shoulder diagnostic categories; (ii) the research designs have major flaws and (iii) a single physiotherapy modality
has been evaluated rather than a combined program as is current clinical practice. Thus, this novel research project
involving 200 participants will answer important questions about the efficacy of a physiotherapy program for
chronic rotator cuff pathology and whether benefits can be maintained. In addition it will determine whether the
costs of physiotherapy represent good value for money which is important in today's economic climate. The
results of this project can be easily and immediately translated into clinical practice as recommendations can be
made about the usefulness of physiotherapy for this patient population. The results will be of major benefit not
just to the physiotherapy profession but to the medical profession who must justify patient referral to
physiotherapy and to funding and compensable bodies.
Research achievements (from final report):
This study was a clinical trial that investigated the efficacy and cost effectiveness of a 10 week physiotherapy
program for chronic rotator cuff pathology of the shoulder. One hundred and twenty people with the condition
were recruited from medical practices and from the general public by print and radio media. Participants were
randomised into a physiotherapy or a placebo group. Both groups attended a physiotherapist for 10 sessions over
10 weeks. The physiotherapy program was aimed at improving strength, range of motion, reducing pain and
improving shoulder function. The placebo group received inactive treatment. The groups were assessed at
baseline, after 10 weeks and at a 22 week followup with the main outcome measure being change in pain and
disability. This study provides information that assists in evidence based recommendations for the management of
this chronic shoulder condition. Specifically it provides evidence about the role of a physiotherapy program for
chronic rotator cuff pathology.
Expected future outcomes:
It is anticipated that this study will be used to inform clinical guidelines relating to the management of chronic
rotator cuff pathology. The results will also be used by physiotherapy clinicians to assist them to better manage
their patients with this shoulder condition. It will also be used by other practitioners who refer their patients for
physiotherapy.
Name of contact: Kim Bennell
Email of contact: k.bennell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566783
Start Year: 2009
CIA Name: A/Pr Paul McCrory
End Year: 2013
Main RFCD: Complementary-Alternative Medicine not elsewhere classified Total funding: $701,120
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Title of research award: Laser acupuncture in patients with chronic knee pain: a randomised placebo-controlled
trial
Lay Description (from application):
Chronic knee pain is a common and disabling musculoskeletal condition that causes a loss of functional
independence and results in significant health care costs. In the majority of patients the most common cause is
osteoarthritis. Acupuncture is a form of non-surgical treatment commonly sought by patients and often
recommended by GP's. The main outcomes from our project are to establish the role, clinical effectiveness and
cost benefit of laser and needle acupuncture in knee pain patients.
Research achievements (from final report):
Knee pain is a common, chronic musculoskeletal condition or which arthritis is the major cause in older adults.
'Arthritis' has been identified by the Government as one of its priority health areas. Acupuncture may be effective
in relieving knee pain, and laser acupuncture has the potential to be as effective or superior to needle acupuncture.
Our project compared the efficacy of needle acupuncture, laser acupuncture, and sham laser acupuncture to a
natural history cohort who did not receive acupuncture. We have completed a large Zelen-design randomised
controlled trial in order to answer this question. We have published the protocol for this clinical trial and are about
to commence analysing the data to determine the study findings. This work has potential to be published in the
highest impact literature in the field. The findings will contribute to the formulation of evidence-based clinical
guidelines for rehabilitation of knee OA and will impact the clinical practice of healthcare professionals
(particularly physiotherapists) who manage patients with knee pain.
Expected future outcomes:
We are about to analyse the data from our completed clinical trial. We expect to publish the findings in a major
medical journal, as well as present at multidisciplinary conferences. Our results will influence future clinical
guidelines and clinical practice.
Name of contact: A/Prof Paul Mccrory
Email of contact: paulmccrory@icloud.com
NHMRC Research Achievements - SUMMARY
Grant ID: 509215
CIA Name: Prof Stephen O'Leary
Main RFCD: Otorhinolaryngology
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2010
Total funding: $544,890
Grant Type: NHMRC Project Grants
Title of research award: Auditory nervous system function after treatment with trophic agents
Lay Description (from application):
Partial or complete deafness affects 11% of Australians and has great personal, social and economic cost .
Worldwide, over 60,000 deaf people can now understand spoken language because of the Bionic Ear. However,
after prolonged deafness, the nerves in the ear that the BIonic Ear stimulates die, reducing hearing quality. Our
research tests whether biological interventions with nerve growth factors and nerve stimulation can preserve nerve
function and improve hearing with the Bionic Ear.
Research achievements (from final report):
Neurotrophins are potent drugs that can protect against damage to the nerves of the inner ear in deafened
aniamals. However until now, we did not know what effect neurotrophins may have on hearing. We established a
model where we can deliver neurotrophins to the inner ear of guinea pig, through the round window membrane of
the cochlea, without perturbing the hearing. We found that after four weeks, BDNF resulted in improved hearing
so that guinea pigs could detect sounds at lower intesities than they could before neurotrophin treatment. We have
also found that neurotrophins applied to the inner ear after deafness can prevent degeneration that occurs in parts
of the brain involved in hearing. Neurotrophins prevented the shrinkage and damage to brain cells in the cochlear
nucleus of the brain, normally seen after deafness and also prevented the loss ions channels that are involved in
activating these brain cells. We aim now to further explorer these interesting findings to detemine if neurotrophins
may help prevent or restore gradual hearing loss, such as that which occurs with ageing.
Expected future outcomes:
Future planned studies in guinea pigs will determine the mechanism for the effect of neurotrophins on hearing, the
therapeutic dose and optimal duration of treatment. From here we hope to determine if promising effect of
neurotrophins at improving hearing will translate to patients who have progressive hearing loss.
Name of contact: Professor Stephen O'leary
Email of contact: sjoleary@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350297
Start Year: 2005
CIA Name: Prof Kim Bennell
End Year: 2008
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $480,850
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Title of research award: Effects of laterally wedged insoles on symptoms and disease progression in knee
osteoarthritis
Lay Description (from application):
Knee arthritis is a painful, disabling, costly condition particularly affecting the elderly. As there is presently no
cure for knee arthritis, strategies that slow progression of the disease will reduce the personal and societal burden
of arthritis. Most research has focussed on drug therapies, which are effective in reducing pain and disability but
have side effects and are expensive. Insoles worn inside the shoes are a simple, cheap, self-administered
intervention with the potential to slow disease progression in certain patients, in addition to managing symptoms.
However, to date there has been little quality research investigating the effectiveness of insoles in knee arthritis.
This study aims to see whether 12 months of wearing insoles can lead to improvements in knee pain and function
and slow disease progression in 200 people with knee arthritis. It will use state-of-the-art technology, magnetic
resonance imaging, to measure changes in the amount of knee cartilage. This research is timely and the findings
will be of major significance as there is increasing world-wide attention on slowing progression of knee arthritis.
Insoles are one of the few non-drug therapies with the potential to influence both symptoms and disease
progression. If the results show that insoles are beneficial, then this research will: 1. Better inform clinical
guidelines to firmly recommend insoles to manage knee arthritis 2. Provide the basis for developing education
strategies for health care practitioners and patients about the benefits of insoles 3. Provide the impetus to make
insoles more readily available directly to patients 4. Ultimately lead to better patient outcomes
Research achievements (from final report):
The majority of clinical guidelines recommend lateral wedge shoe insoles for medial knee osteoarthritis (OA),
despite limited and equivocal evidence of efficacy. The primary aim of this randomised controlled trial was to
assess the efficacy of lateral wedge insoles for improving symptoms and slowing structural disease progression
compared with control insoles in medial knee OA. 200 people with knee OA and aged 50 or more were recruited
from the community in Melbourne, Australia. Participants wore either full-length 5 degree lateral wedged insoles
or flat control insoles inside their shoes daily for 12 months. Measurements were taken at baseline and 12 months
later and included measures of pain, physical function, quality of life and knee joint structure (from magnetic
resonance imaging). Ninety percent of participants completed the study. The results showed that there were no
significant differences between the lateral wedge insole and the control insole groups for any of the measures.
This suggests that lateral wedge insoles worn for 12 months provide no symptomatic or structural benefits
compared to a flat control insole.
Expected future outcomes:
This study does not support the use of lateral wedge insoles in the management of people with medial knee
osteoarthritis. This is likely to alter future recommendations of clinical guidelines.
Name of contact: Kim Bennell
Email of contact: k.bennell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454693
Start Year: 2007
CIA Name: Dr Patrick Humbert
End Year: 2009
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $516,078
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Title of research award: Regulation of epithelial migration by Scribble in development and wound repair
Lay Description (from application):
The movement of epithelial cells within our body (the cells that form the thin protective layer on exposed bodily
surfaces such as skin and the lining of internal cavities, ducts, and organs) is essential for our normal embryonic
development as well as for healing of wounds following injury. Understanding how this movement is regulated is
therefore a fundamental area of medical biology. Although much is known about the mechanics of how a cell
moves, the signals used to coordinate this movement so as to ensure that each cell migrates to the right place
during embryonic development or in response to a wound is not well understood. A number of lines of evidence
suggest that proteins required for the correct orientation of cells within our body (a property of cells known as
polarity) may be essential for this process. Mutation of the polarity protein Scribble in the fly, zebrafish and
mouse causes a disorganization of epithelial tissues during embryonic development. We have now shown that
Scribble is required for cells to orientate correctly so as to be able to move in response to a wound in tissue culture
and also during embryonic development and wound healing in the mouse. It is currently unknown how Scribble
regulates migration. Here we propose to identify the molecules that Scribble regulates to coordinate cell
movement during development and tissue repair. These studies will provide new insights into the fundamental
process of how cell movement is coordinated and could lead to novel strategies for improved treatment of tissue
injuries.
Research achievements (from final report):
Control of cell migration is essential for normal development and in situations requiring tissue homeostasis such
as wound healing. Understanding the regulation of migration is therefore a fundamental area of medical biology.
Although much is known about the mechanics of migration itself, the signals used to coordinate migration during
development or in response to tissue injury are poorly understood. A number of lines of evidence suggest that
proteins required for the orientation ("polarization") of cells as they migrate may be essential for this process. We
have now shown that human Scribble is required for the polarity associated with directed migration in response to
a wound or chemokine gradient in vitro. Furthermore, this function appears relevant in vivo as mice mutant for
Scribble and other members of the Planar Cell Polarity pathway show defective wound healing of the epidermis.
Scribble is therefore a highly conserved positive regulator of migration in multiple cell types and organisms. We
have used a combination of cellular and in vivo studies to identify and characterize Scribble-dependent pathways
involved in migration.
Expected future outcomes:
Migration is a key process during embryonic development and tissue repair. We have identified Scribble and
associated proteins as a protein that is necessary for directed migration in vitro and in vivo. Our studies provide
new insights into these processes that could lead to novel strategies for improved treatment of tissue injuries.
Name of contact: Dr Patrick Humbert
Email of contact: patrick.humbert@petermac.org
NHMRC Research Achievements - SUMMARY
Grant ID: 454717
Start Year: 2007
CIA Name: Dr Linda Denehy
End Year: 2009
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $359,283
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Title of research award: Evaluation of exercise rehabilitation for survivors of intensive care
Lay Description (from application):
Intensive care medicine has improved survival in critically ill patients. However, international literature reports
poor quality of life and physical outcomes in ICU survivors compared to people of the same age. In addition,
patients who require a prolonged ICU stay consume a large amount of resources. This project is testing whether an
early ICU physiotherapist-directed exercise rehabilitation program continuing until after hospital discharge will
improve patient's quality of life, physical function and decrease the use of health resources compared with
patients' receiving standard care. Patients in the rehabilitation group will take part in a physiotherapy exercise
rehabilitation program including returning to out patient classes after discharge. The physiotherapist will treat
patients daily during hospital stay then twice weekly for 8 weeks after discharge. All patients will complete 2
quality of life questionnaires and physical function will be assessed using a new test developed for the acute ICU
stay the 6 minute walk test, which measures how far patients can walk quickly in 6 minutes. The timed up and go
test will also be used and it measures how quickly patients can get up from a chair and walk. An activity monitor,
worn on the wrist, for some of the time after discharge will measure how much exercise and moving about
patients are doing at home. Measurements will performed by a physiotherapist, blinded to the group to which
patients were randomly allocated, on admission to the ICU (quality of life only by proxy), on discharge from the
ICU, discharge from hospital and at 3, 6, 12 months after discharge. Economic evaluation will be performed to
examine overall use of resources using information from the questionnaires.
Research achievements (from final report):
Physical rehabilitation has been advocated for survivors of a critical illness to improve physical function and
health related quality of life. This is the first study to assess the impact of an intensive physical rehabilitation
program commenced in the intensive care unit and continued on the ward and as an outpatient program with
follow up for a 12 month period. It is also the first study to assess the economic impact of such a rehabilitation
program. The results of this trial have been submitted for publication and are currently under review by a highly
ranked international peer reviewed journal. In addition to this several publications have arisen from this study
regarding further development of a tool to measure physical function in the intensive care unit (ICU) and
measurement of physical activity levels in survivors of ICU. Preliminary trial results have been presented at a
number of national and international conferences and forums. International collaborations have been developed in
the USA and UKwith the view to developing future trials in the area. Measurement tools which were further
developed during the trial are now being used in international studies of ICU survivors.
Expected future outcomes:
Development of Australian guidelines for standard rehabilitation programs will lead to improved outcomes for
surviors of critical illness. Rehabilitation programs need to target specific groups within this population who will
benefit most from these services. In addition, factors which may affect participation along with the timing and
delivery mode of these services need to be assessed.
Name of contact: Associate Professor Linda Denehy
Email of contact: l.denehy@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251535
CIA Name: Dr Pritinder Kaur
Main RFCD: Dermatology
Admin Inst: University of Melbourne
Start Year: 2003
End Year: 2005
Total funding: $391,763
Grant Type: NHMRC Project Grants
Title of research award: Microenvironmental regulation of the tissue regenerative capacity of keratinocyte stem
cells and their progeny.
Lay Description (from application):
The protective outer layers of the skin known as the epidermis belongs to a group of tissues in the body that are
turning over at a rapid rate. The majority ofepidermal cells have a lifespan of just 2-3 weeks, and are shed as
mature cells from the skin's surface. These cells are replaced by continuous cell regeneration which is dependent
on growth factors and adhesive molecules (and other signals). It has recently come to light that the connective
tissue of the skin i.e. the dermis, which lies directly below the epidermal cells has a critical role in providing some
of these factors required for their growth and maturation. Indeed, it is becoming increasingly clear that the
epidermal and dermal cells co-operate to regulate epidermal proliferation and maturation. Recent work from our
laboratory has shown that a newly recognised adhesive protein laminin-10 may be produced as the result of such
co-operation and that it stimulates the growth of both normal and tumour epidermal cells. We have also recently
identified an interesting subset of dermal cells that may have a role in promoting the growth of the epidermal cells.
Thus, the aims of the proposed stuides are to investigate the role of laminin-10 and this specific dermal cell subset
in epidermal proliferation and maturation. These studies may also provide an insight into the role of these factors
in skin cancers.
Research achievements (from final report):
This work revealed that stem cells of the skin (particularly the outermost layer known as the epidermis) are
dependent on growth factors and proteins supplied by adjacent cells found in their environment i.e. dermal cells in
order to grow and repair skin tissue defects. Interestingly, the ability to repair wounds is not restricted to stem
cells alone as previously thought but can be conferred upon the maturing progeny of the stem cells when the
appropriate environmental signals are provided. Thus in laboratory models of skin tissue regeneration, skin repair
could be obtained by adding exogenous proteins normally found in the skin to non-stem cells. Particular subsets of
cells found in the dermis have also been identified as important populations in promoting tissue repair from nonstem cells. The significance of these findings is that it may be possible to use non-stem cells together with stem
cells to provide transplantable cells onto patients suffering from severe skin deficits such as burns. Specific skin
proteins may also be utilised to expand skin cells from patient's faster before transplantation avoiding delays in
getting skin grafts and reducing the risk of infection and thus survival of the patient.
Expected future outcomes:
The dermal cells identified in this study as being important for tissue repair need to be studied further to
understand the nature of signals (i.e. growth factors/proteins) they provide to stimulate skin repair. These
molecules could then be used to devise therapies for faster skin regeneration for patients.
Name of contact: Pritinder Kaur
Email of contact: pritinder.kaur@petermac.org
NHMRC Research Achievements - SUMMARY
Grant ID: 145634
CIA Name: A/Pr Colin Anderson
Main RFCD: Autonomic Nervous System
Admin Inst: University of Melbourne
Start Year: 2001
End Year: 2003
Total funding: $241,528
Grant Type: NHMRC Project Grants
Title of research award: Determination of sympathetic preganglionic neuronal phenotype
Lay Description (from application):
The nervous system is the single most complex part of our body. Its function depends on millions of connections
between neurons, all of which must form correctly during development. Furthermore, each neuron must select a
neurotransmitter with which to "talk" to its target neuron. A neurotransmitter is a chemical released from a neuron,
which passes a signal to a target cell. Some neurotransmitters cause excitation of the target cell, others inhibition.
Each neurotransmitter signals to the target cell via receptor molecule, matched to the neurotransmitter. Thus, a
neuron is faced not only with making choices about what connections to make within the developing brain, but
also it must select from a range of potential neurotransmitters and receptor molecules. We are interested in how
neurons select the appropriate neurotransmitter. There are a number of ways that a neuron might be guided to the
correct choice. It is possible that it could receive from the target cell a signal that guides the choice of
neurotransmitter. We wish to examine this hypothesis to see if it is applicable to the autonomic nervous system,
that part of the nervous system that controls functions like changes in blood pressure and heart rate. Our
laboratory is expert in identifying the chemistry of autonomic neurons. We will use this knowledge to see what
happens when we deliberately perturb the normal connections of autonomic neurons. Do they persist in expressing
the neurotransmitters they would have done prior to the perturbation? Alternatively, do they adapt to the change of
target via a signal received from the new target cell and express the appropriate phenotype? The results of these
experiments will give insights into how the brain develops. The results will be important for both our basic
understanding of biology and as a basis for the development of techniques for reversing neuronal damage.
Research achievements (from final report):
The nervous system contains many types of neurons. During development, each type of neuron must be generated
in the correct place and in the appropriate numbers. We focused on one aspect of how this may occur. When a
neuron extneds an axon to contact a target tissue, the target tissue can instruct the neuron as to which genes to
swtich on or switch off in order to generate the type of neuron appropriate for that target tissue. We have looked
for evidence that this process occurs in the peripheral nervous system by exposing neurons to novel targets to see
if the neuron can respond by changing its phenotype to match the new target. We have produced evidence that
sympathetic preganglionic neurons can respond to the presence of one of their normal target tissues when it is
chifted to a novel location. Preganglionic neurons that come to innervate the target in the new location adopt the
phenotype of neurons that would have innervated the adrenal chromaffin tissue in its normal location. We have
gone on to show that the same thing happens when a normal target of the postganglionic sympathetic neurons, the
pineal gland, is transplanted to a new location. Again, the innervating neuron adopt a phenotype appropriate for
the new target tissue.
Expected future outcomes:
This knowledge is important as much effort is currently being expended on generating new neurons from stem
cells for use in repairing human nervous systems damaged by trauma or disease. To succeed, it will be necessary
to generate specific types of neuron from the stem cells in a controlled way and the our study will contribute to an
understanding of the biological mechanisms involved.
Name of contact: Assoc Prof Colin Anderson
Email of contact: c.anderson@unimelb .edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350483
CIA Name: Dr Glenn McConell
Main RFCD: Exercise Physiology
Admin Inst: University of Melbourne
Start Year: 2005
End Year: 2007
Total funding: $340,750
Grant Type: NHMRC Project Grants
Title of research award: IS NITRIC OXIDE A CENTRAL REGULATOR OF EXERCISE-INDUCED
SKELETAL MUSCLE MITOCHONDRIAL BIOGENESIS?
Lay Description (from application):
Mitochondria are the energy producing parts of the cell and are the major controllers of metabolism. There is
now good evidence that reduced muscle mitochondrial size contributes to diabetes. Exercise is good for diabetics
due partly to increasing muscle mitochondrial production (mitochondrial biogenesis). Unfortunately, little is
known about the mechanisms involved in increased muscle mitochondrial biogenesis following exercise. It has
been shown recently that nitric oxide (NO), a gas made by muscle during exercise, plays a role in mitochondrial
biogenesis in fat cells. This project will determine whether NO is a central regulator of exercise-induced
mitochondrial biogenesis in skeletal muscle. If we find that NO increases mitochondrial biogenesis in muscle,
drugs designed to mimic these exercise effects may prevent or improve diabetes. We will firstly establish if
specific drug treatments that alter NO levels in muscle cells grown in culture alter mitochondrial biogenesis.
These results will help us to clarify the role of NO in mitochondrial biogenesis. However, it is difficult to directly
examine the effects of exercise in cultured cells. Therefore, further studies will then use real life models such as
rodents that have been exercised to examine the role of NO and exercise on mitochondrial biogenesis. We will
feed a drug to decrease NO levels in normal rats; and use mice, genetically altered to be lacking in NO to
determine if these treatments decrease mitochondrial biogenesis that is normally seen following endurance
exercise. Furthermore, since defects in mitochondrial biogenesis have such an important impact on diabetic
humans, we will use humans to examine if differences in NO levels in skeletal muscle among type 2 diabetics or
endurance-trained athletes correlate with mitochondrial biogenesis. Finally, we will infuse a drug into type 2
diabetics that increases NO in muscle to determine if it also increases mitochondrial biogenesis.
Research achievements (from final report):
Mitochondria are the energy procing oragns of the cell. Defective small skeletal muscle mitochondria are now
recognised as a major component of the metabolic abnormalities of diabetes. Exercise increases mitochondrial
volume and improves mitochondrial function (mitochondrial biogenesis). Many research groups are attempting to
determine how exercise increases mitochondrial biogenesis and thereby prevents or improves diabetes. There are
large gaps in our current knowledge. Prior to commencing our grant funding a paper presented convincing
evidence that nitric oxide (NO) regulates mitochondrial biogenesis in fat cells. As skeletal muscle NO production
increases during exercise, NO could provide an important link between exercise and its beneficial effects on
diabetes. In this project we examined whether NO plays an important role in the increase in mitochondrial
biogenesis in response to exercise. We provided clear evidence that NO plays an important role in resting (basal)
skeletal muscle mitochondrial biogenesis but not the increase in skeletal muscle mitochondrial biogenesis in
response to acute exercise or exercise training. Based on this we have begun investigations into other potential
regulators of skeletal muscle mitochondrial biogenesis in response to exercise.
Expected future outcomes:
We have begun investigations into other potential regulators of skeletal muscle mitochondrial biogenesis in
response to exercise, in particular free radicals. We have also obtained NHMRC funding to examine whether
exercise training can correct deficits in skeletal muscle mitochondrial biogenesis in adulthood when one is born
small.
Name of contact: Dr Glenn Mcconell
Email of contact: mcconell@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145654
CIA Name: Dr Pritinder Kaur
Main RFCD: Dermatology
Admin Inst: University of Melbourne
Start Year: 2001
End Year: 2003
Total funding: $212,037
Grant Type: NHMRC Project Grants
Title of research award: Developmental potential of murine keratinocyte stem cells
Lay Description (from application):
The stem cells of the epidermis or outer lining of the skin are an important group of cells with a role in normal
cell replenishment, in wound healing and in skin disorders such as psoriasis and cancer. These primitive cells
remain in the skin during the lifetime of an individual and are responsible for the production of mature, functional
cells that form a protective barrier against the environment and pathogens. We have recently developed a strategy
for the isolation of stem cells of the skin which places us in a unique position to further study these cells and
determine possible therapeutic approaches for the future. The aims of this project encompass testing the potency
of skin stem cells (i) to reform complex structures such as a mature epidermis, hair follicles and sebaceous
glands; and (ii) to give rise to cells from other tissues such as muscle and liver. A final aim of this project is to
dissect the complexity of the stem cell compartment further to gain insights into how normal skin growth is
regulated.
Research achievements (from final report):
The work we have performed has been aimed at gaining a greater understanding of the properties of stem cells of
the skin, particularly those stem cells that exist in the outer lining of the body (epidermis or epithelia) that
interfaces with the environment. Currently there are no experimental systems that are capable of measuring the
long-term activity of epithelial stem cells - many assays or techniques that are currently thought to show stem cell
behaviour are in fact too short-lived to allow us to sistinguish stem cells from other epithelial progenitor cells. Our
study has resulted in the development and optimisation of transplant models for analysing skin tissue regeneration
as a measure of stem cell activity. This study has also encompassed testing whether stem cells of the skin can be
isolated by staining with a Hoechst dye (Hoechst 33342) and simply collecting those cells that have an ability to
get rid of the dye (dye-effluxing cells identified as Hoechst dull cells). This work shows that although Hoechst
dull cells can be found in the epidermis, further work is required to determine if these cells are stem-cell like. We
have been able to optimise culture conditions to allow us to start analysing these cells both in culture and in
transplants to begin answering these questions.
Expected future outcomes:
A greater understanding of the biological properties of epidermal stem cells of the skin is needed to devise means
for their growth in the clinic for patients that have severe wounds (such as burns) and need skin replacement. Our
work will result in the development of techniques that facilitate stem cell isolation and cultivation
Name of contact: Pritinder Kaur
Email of contact: pritinder.kaur@petermac.org
NHMRC Research Achievements - SUMMARY
Grant ID: 209168
Start Year: 2002
CIA Name: Dr Kay Crossley
End Year: 2006
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $138,088
Admin Inst: University of Melbourne
Grant Type: Early Career Fellowships (Australia)
Title of research award: Factors affecting motor control and loading of the patellofemoral joint
Lay Description (from application):
Not Available
Research achievements (from final report):
Joint swelling and pain are hallmarks of many knee conditions, particularly knee osteoarthritis in adults and the
elderly and patellofemoral pain in adolescents or adults. Such conditions are also frequently associated with
altered thigh muscle function, including weakness, inhibition and altered activation, which occur in the absence of
damage to the muscle itself. It is not known whethe the pain or swelling directly influences this thigh muscle
function. This research was a series of studies, primarily conducted in healthy people. These studies involved the
injection of pain provoking substance into the knee and evaluating the effects of the resulting knee pain on thigh
muscle function. The results of this study demonstrated that the induced knee pain resulted in alterations in the
amount and timing of thigh muscle activity, and the way that people walk. The other study involved injecting fluid
into the knee to mimic knee swelling. Similar to the knee pain study, this artificial swelling resulted in alterations
in the amount and timing of thigh muscle activity in the during functional tasks. The results of these study provide
compelling evidence that knee pain and swelling have considerable effects on thigh muscle function and must be
addressed in order to attain successful rehabilitation of painful knee conditions
Expected future outcomes:
N/A
Name of contact: Kay Crossley
Email of contact: k.crossley@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509310
Start Year: 2008
CIA Name: Dr Kerrie Sanders
End Year: 2008
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $104,995
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Title of research award: Does An Annual High Dose Vitamin D Supplement Decrease Healthcare Utilisation in
Older Women?
Lay Description (from application):
The shorter bleaker days of winter can cause a vitamin D deficiency in Australian women, increasing their risk of
osteoporosis and broken bones including hip fracture. New research suggests that the low winter levels of the
vitamin may not be good for us in many ways and the NHMRC is funding a Geelong-based study to determine if
Austrlia's elderly can improve their overall health by taking a once-a-year dose of vitamin D tablets.
Research achievements (from final report):
Recent research suggests that higher levels of vitamin D in your blood may provide protection from many
disorders such as diabetes, osteoporosis, depression and certain types of cancer. This project represents the first
international study to investigate this hypothesis using a randomised, placebo-controlled clinical trial. The
hypothesis was that older women supplemented annually for 3 to 5 years with a high oral dose of vitamin D3
(500,000 IU) would use fewer healthcare services than those given placebo (dummy) tablets. The preliminary
analysis using data from Medicare Australia suggests there is no difference between the groups and that the
women randomised to vitamin D used the same number of Medicare services as women receiving placebo
(vitamin D group: 28.5 and placebo group: 28.0 Medicare services per person per year). The age of participants
did not differ between the groups (vitamin D: 76.8 years and placebo: 76.7 years). In the year prior to
commencing the study medication the women used an average of 18.5 services per person (vitamin D group: 18.6
and placebo group: 18.5). These results also suggest that women aged 70+ years had a 1.5 fold increase in the
average number of healthcare service/visits they used each year over a 2 to 3 year period and that this increase did
not differ between those given vitamin D and placebo.
Expected future outcomes:
Further analysis of the data will determine the cost of healthcare services between the vitamin D and placebo
groups to determine if there is a significant difference in the type of health services used and the total cost of
health service utilisation between the two groups. The data will be analysed by age group using 70-74; 75-79; and
80+ years and stratified by fracture (yes/no).
Name of contact: A/Prof Kerrie Sanders
Email of contact: kerrie@barwonhealth.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566621
CIA Name: Prof Seong-Seng Tan
Main RFCD: Cellular Nervous System
Admin Inst: University of Melbourne
Start Year: 2009
End Year: 2011
Total funding: $836,225
Grant Type: NHMRC Project Grants
Title of research award: Neuroprotection by Ndfip1 in brain injury - identifying targets and understanding
mechanisms
Lay Description (from application):
Brain injury from trauma and motor vehicle accidents is a serious health issue, affecting approximately 30,000
Australians per year. About 10% of the victims suffer serious long term consequences, including mental, physical
and behavioural impairment. We have discovered a new brain protein capable of preventing neurons from dying
following injury. This grant will improve our understanding of how this protein works, and provide a scientific
foundation for devising therapies.
Research achievements (from final report):
We discovered a natural protein in the brain that can be turned on to defend neurons against death after injury.
This new protein, called Ndfip1, is strongly switched on in brain cells after stroke or traumatic brain injury in
humans, and also in mice after brain injury. We found that if Ndfip1 is strongly switched on, then injured neurons
can survive the stress episode. A major aim of the grant was to understand how Ndfip1 is able to defend neurons
against death. This aim was successfully achieved by our studies identifying at least two mechanisms. (1) Ndfip1
is able to temporarily shut off entry of toxic metals into brain cells that can otherwise poison the neurons. We
identified that Ndfip1 is able to off the metal transporter DMT1 during brain injury, therefore limiting metal entry
into nerve cells. (2) Ndfip1 is able to hijack Pten, an anti-cancer protein in the cell, to defend brain cells. Ndfip1
achieves this by moving Pten into the cell nucleus, therefore quarantining the anti-survival effects of Pten.
Finally, we were also successful in manufacturing a drug that in principle, can increase Ndfip1 in nerve cells.
This drug is subjected to a patent application. All together, our studies provide real foundations for identifying
drugs that can increase Ndfip1 to increase brain cell survival after brain injury and stroke.
Expected future outcomes:
We expect to create more drugs that can increase Ndfip1 on demand in brain cells. This research will provide
strong foundations for therapeutic drug design. In addition, we are excited at the possibility that Ndfip1 might be
a key lever for controlling brain tumours by its ability to control the cancer protein PTEN.
Name of contact: Professor Seong-Seng Tan
Email of contact: sst@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508966
Start Year: 2008
CIA Name: A/Pr Kay Crossley
End Year: 2011
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $616,431
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Title of research award: Patellofemoral arthritis: Efficacy of physiotherapy and understanding the role of joint
stress
Lay Description (from application):
Arthritis of the kneecap leads to considerable pain and difficulty with daily activities. This project is testing
whether a physiotherapy treatment (8 sessions over 12 weeks) designed specifically for people with kneecap
arthritis is effective. In order to understand more about kneecap arthritis, this project will calculate the force on the
kneecap and its relationship to pain and other factors, including thigh and hip muscle strength, knee alignments
and knee movements.
Research achievements (from final report):
The patellofemoral joint (PFJ), or kneecap, is one compartment of the knee that is frequently affected by
osteoarthritis (OA) and is a potent source of symptoms. However, there are few treatments for PFJOA. Therefore,
this project aimed to evaluate whether a physiotherapy treatment, targeted to the PFJ, resulted in greater
improvements in pain and physical function than a physiotherapy education treatment.
We conducted a clinical trial in 92 people with PFJ OA. We observed that the targeted physiotherapy resulted in
greater improvements than the education group for perceived pain and function at 3 months.
We also determined the force in the PFJ, on a patient-specific basis using computer modelling. We observed that
people with PFJ walk up and down stairs with lower PFJ forces, muscle size and forces than people with no OA.
Significance:
Our physiotherapy treatment, targeted to the PFJ, resulted in superior outcomes than a physiotherapy-led
education treatment for PFJOA. Therefore, treatments for knee OA may be enhanced by targeting treatments to
the compartment most affected by the disease. The project's outcome will influence knee OA rehabilitation, thus
reducing the personal and societal burden of this increasing public health problem. Our findings also have the
potential to foster development of interventions that may prevent PFJ OA
.
Expected future outcomes:
The results of these studies should increase the awareness of the importance of PFJ OA. The results may lead to
improved treatment options for people with PFJ OA. We will also use the results of these studies to evaluate
treatments with potential to reduce development, or progression of PFJ OA.
Name of contact: Associate Professor Kay Crossley
Email of contact: k.crossley@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400139
CIA Name: Prof Ego Seeman
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2008
Total funding: $751,823
Grant Type: NHMRC Project Grants
Title of research award: Structural Basis of Femoral Neck Strength
Lay Description (from application):
Fractures, in particular femoral neck (FN) fractures, are a huge public health problem resulting in disabilities,
mortality and financial cost to the community. The prevention of these fractures is based on estimation of bone
strength. The decision whether someone needs treatment, or the effectiveness of a treatment can only be judged by
estimating bone strength. The bottom line is that currently we cannot correctly estimate bone strength. Present
methods such as bone mineral density (BMD) perform poorly. Most people who fracture are not detected by BMD
because their BMD is either normal or high, and many people with low BMD never fracture. The main aim of this
grant application is to develop new tools to allow doctors and scientists worldwide to better estimate FN strength.
To develop new methods to replace BMD, scientists need to make use of the 3D aspects of the bone such as size,
shape and internal architecture. Presently, these 3D aspects (structure) have not been adequately studied and
scientists incorrectly approximate them. As a result new methods are not any better. A good quantification of
structure is needed. Another reason for the failure to accurately estimate the strength of bones is that estimates
are based on a single parameter whereas the bone, like any architectural structure (e.g. building), comprises many
components acting together to maintain its strength. To determine the strength based on density alone is incorrect;
the size, the shape and things inside the structure need to be considered as a whole. After quantifying correctly
the structure and components of bone strength, we will determine how they can be used individually and together
to better estimate the strength of the FN in men and women. Tools generated will be used to better determine
people likely to fracture and needing treatment; to better tailor and monitor treatments. A better understanding of
the causes and epidemiology of fractures will ensue.
Research achievements (from final report):
Research in osteoporosis has focused in the role of trabecular bone (the spongy bone inside the cortical shell) loss
as the cause of osteoporosis because it was commonly believed that bone loss with advancing age is largely
trabecular. In this project we demonstrate that bone loss and fragility in old age originates not from the trabecular
compartment, but from the cortical compartment (outer shell of bone). This work received an award from the
American Society for Bone and Mineral Research.
Furthermore, we identified the mechanism through which the cortical bone becomes fragile - that is, by
enlargement and fusions of the holes inside the cortex, in particularly next to the marrow cavity. The end result of
this process is the transformation of a previously compact cortex in young age into a spongy-like structure in old
age leading to fragility.
We showed that this process is poorly detected by bone densitometry ( the currently used diagnosis tool) and this
may explain why most people with fragile bones are missed when the bone density test is used. Understanding of
the process has led us to develop a new diagnostic test. This test is currently subject to a patent application and its
ability to improve fracture prediction will be tested soon.
Insights into how bone size, shape and bone quality interact to make bone strong were have also being studied.
Expected future outcomes:
It is expected that quantification of porosity in clinical settings will allow better identification of individuals at risk
for fracture. Funds have been requested to test this hypothesis.
Name of contact: Ego Seemna
Email of contact: egos@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350227
CIA Name: A/Pr Ann Turnley
Main RFCD: Central Nervous System
Admin Inst: University of Melbourne
Start Year: 2005
End Year: 2007
Total funding: $486,000
Grant Type: NHMRC Project Grants
Title of research award: Signalling mechanisms regulating neurogenesis and neurite outgrowth
Lay Description (from application):
Injury and diseases of the central nervous system (CNS), such as traumatic injury, stroke, Parkinson's,
Huntington's and Alzheimer's disease, affect a substantial number of Australians each year and often have longterm consequences for sufferers and their families. This is primarily due to a lack of robust repair of the damage
and a paucity of therapeutic strategies available for treatment. However, although many hurdles are yet to be
faced, there is a substantial body of evidence that has emerged in recent years, that has led to the view that repair
of the central nervous system following injury of disease may indeed be a possibility. Effective neural repair is
likely to require a multi-factorial approach, including blockage of neuronal death, replacement of lost neurons by
neural stem cells, and regulation of appropriate subsequent neurite outgrowth and formation of correct
connections. We have shown that a regulator of cytokine signaling, SOCS2, promotes neuronal differentiation and
neurite outgrowth. This project aims to continue our investigations of the role of SOCS2 and interacting factors in
regulating neuronal differentiation as well as substantially expanding our investigations into the role of SOCS2 in
regulating neurite outgrowth, using both in vitro and in vivo models. An understanding of the mechanisms
involved in these processes may allow us to derive therapies for the repair of the nervous system after injury or
disease.
Research achievements (from final report):
We examined factors that have to potential to promote production of new neurons from neural stem cells and
enahnce their survival and integration into the nervous system. In culture We have found that both the
inflammatory regulators dexamethasone and IFN inhibited neural stem cell proliferation and enhanced neuronal
differentiation, while Growth Hormone accelerated neuronal differentiation and increased neural stem cell
proliferation. We also examined production of new nerve cells in the adult mouse brain following administration
of Erythropoietin (Epo) and in the presence of altered growth hormone signalling. Epo transiently enhanced
production of new neurons but did not promote long term survival. Epo also regualted growth of these neurons in
cell culture. Mice which expressed a regulator of growth hormone signalling, SOCS2 transgenic mice, showed
normal short term proliferation of neural precursor cells but enhanced long term survival of new neurons in the
brain. SOCS2 transgenic mice were also less anxious than normal mice and had enahnced memory. We have also
found that SOCS2 intereacts with other signalling pathways not related to growth hormone, in particular the
neurotrophin growth factor family, which may have important therapeutic consequences. Administration of Epo or
regualtion of SOCS2 or Growth Hormone may improve recovery following nervous system injury.
Expected future outcomes:
Further understanding of the role SOCS2 plays in regulating factors other than growth hormone. Future studies
will examine the role of SOCS2 and related factors in regulating recovery from nervous system injury.
Name of contact: Ann Turnley
Email of contact: turnley@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350426
CIA Name: A/Pr Paul Whitington
Main RFCD: Neurogenetics
Admin Inst: University of Melbourne
Start Year: 2005
End Year: 2007
Total funding: $251,325
Grant Type: NHMRC Project Grants
Title of research award: The molecular basis for target selection in the central nervous system by sensory axons
Lay Description (from application):
The normal function of the brain depends upon the specific connections that nerve cells make with each other.
These connections are set up in the developing embryo when nerve cells send out long processes - axons - which
grow towards their synaptic targets. How axons select their correct targets from amongst the millions of
alternatives in the developing brain is unknown. A better understanding of this problem will help us develop
therapies to assist regenerating axons re-establish correct connections following injury to the brain or spinal cord.
We propose to use a simple model system, the embryo of the fruitfly Drosophila, to find molecules that are
involved in this process of neuron target recognition - ' axon targeting' molecules - and to study how they work.
Drosophila can be genetically manipulated in ways not possible in higher animals. Furthermore the simplicity of
its nervous system means that we can determine the connections of individual nerve cells with a high degree of
precision. In the first part of our project, we will examine Drosophila embryos that carry mutations in genes
suspected to code for targeting molecules. We will stain individual sensory nerve cells in these embryos with dyes
to reveal the anatomy of their axons in the brain. If sensory axons terminate abnormally in the brain of a given
mutant, the affected gene is likely to code for an axon targeting molecule. In the second part of the study, we will
investigate the functions of candidate axon targeting molecules using two approaches. Firstly, we will seek to
determine whether the molecule acts in the sensory axons or in their target cells. Secondly, we will use time-lapse
microscopy to study how the homing behaviour of the sensory axons is affected in mutant embryos. The results of
these studies will lead us closer to an answer to the question: "How do axons recognise their specific target cells in
the brain?"
Research achievements (from final report):
The normal function of the brain depends upon the specific connections that nerve cells make with other nerve
cells. These connections are set up in the developing embryo when nerve cells send out long processes - axons which grow towards their targets. How axons select their correct targets from amongst the millions of alternatives
in the developing brain is largely unknown. A better understanding of this phenomenon of "axon targeting" will
help us develop therapies to assist regenerating axons re-establish correct connections following injury to the brain
or spinal cord. We are using a simple model system, the embryo of the vinegar fly Drosophila, to identify
molecules that are involved in axon targeting and to study how they work. We have discovered that a well-known
molecule, Epidermal Growth Factor Receptor (EGFR), is involved in this process. This protein plays a role in a
host of developmental processes in which cells are required to respond to signals in their environment, but was not
previously known to regulate axon growth. Our discovery will now enable us to work out how activation of this
molecule triggers changes in nerve cells that cause their axons to grow in the right direction. This knowledge
could be as relevant to cancer research as to neuroscience, because abnormal EGFR activity also leads to tumour
formation in ways that are as yet poorly understood.
Expected future outcomes:
The knowledge gained from this study will in the future help us find ways to promote recovery of function in parts
of the brain that are damaged by injury, disease or the aging process.
Name of contact: Dr Paul Whitington
Email of contact: p.whitington@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628701
CIA Name: Prof Ego Seeman
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2010
End Year: 2012
Total funding: $865,474
Grant Type: NHMRC Project Grants
Title of research award: Fragility Fractures: The Neglected Role of Cortical Porosity
Lay Description (from application):
We just discovered that bone lost with age occurs mostly from pores within the cortex (outer shell) of the bone;
These pores become larger (porosity) making bones fragile. This process is poorly detected by bone density
(currently used tool) so that most people with weak bones are missed. To address this issue, we have for the first
time, develop a technology to accurately quantify porosity in living peoples. With teams around the world, we
aim here to fill this gap in the diagnosis.
Research achievements (from final report):
Bone mineral density (BMD) the test commonly used in clinical and research settings to identify individuals at
risk for fracture. This test is neither sensitive nor specific; most people diagnosed by BMD as at risk for fracture
never sustain a sustain a fracture, and most (~70%) of all fracture occur in people with BMD higher than the range
defining osteoorosity. To prevent fractures the important challenge is to identify the majority of people with
normal BMD who sustain a fracture.
Our first study measureing porosity of bone was published in the Lancet. This identified porosity as a main
consequence of bone loss and weakness of bone. This now provides a test to identify people at risk for fractures
missed by BMD. The grant provided by the NHMRC helped us develop and validate a computer program that
automatically measures this porosity in clinical settings. This program called StrAx1.0 is now widely recognised
and we are collaborating with many investigators in Australia, Europe and USA applying this method. Several
studies are now published and the most recent identifies women at risk for forearm fractures not identified using
bone densitometry. this provides clinicians with useful information helping them decide who to treat and not treat
. This has been confirmed in two separates groups of women in Australia and USA. The work is in review at a top
medical journal at this time.
Expected future outcomes:
Measuring porosity will become a rountine test helping doctors identify patients needing therapy and will help to
determine if treatment is successful by reducing porosity.
Name of contact: Roger Zebaze
Email of contact: zebaze@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509317
CIA Name: A/Pr Paul Whitington
Main RFCD: Neurogenetics
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2010
Total funding: $426,006
Grant Type: NHMRC Project Grants
Title of research award: The role of cell adhesion molecules in regulation of axon advance
Lay Description (from application):
All cells contain on their surface a class of molecules, cell adhesion molecules, that enable them to adhere to
other cells in tissues. Cell adhesion molecules have long been known to be involved in the guidance of axons to
their targets during development. However the molecular mechanisms by which these molecules act are largely
unknown. We propose to use the powerful genetic tools available in the fruitfly to dissect the mechanisms by
which two cell adhesion molecules promote axon growth.
Research achievements (from final report):
As the embryo grows, nerve cells send out long extensions called axons, which make connections with specific
target cells, thereby wiring up the nervous system. The aim of this project was to enhance our understanding of
how axon growth is regulated at a molecular level. We have focussed on two proteins belonging to a class of
molecules called cell adhesion molecules (CAMs), which bind cells together in tissues. CAMs have long been
known to be important players in axon growth regulation, but how they act is poorly understood. Our research has
shed new light on this problem, information that may assist the development of therapies for repairing damaged
spinal cord axons following injury or disease. Our findings suggest that one of the CAM proteins under study
promotes the growth of axons by physically linking them to other axons within the nerve. The other CAM protein
acts in a different way. While, like the first protein, it promotes axon advance, it does so, not by linking the axon
to its neighbours, but by acting as a receptor on the surface of the axon for growth promoting signals. We have
identified at least one of the proteins inside the axon that cause it to grow forwards when this receptor protein
binds signalling molecules. While it has been previously suggested that this particular signalling pathway might be
involved in axon growth, our research has provided the first definitive evidence for this idea.
Expected future outcomes:
Our research has put us in a position to dissect in detail the molecular pathways involved in the function of these
two axon growth-promoting proteins. This knowledge will present us with possible molecular targets for
triggering the regrowth of axons in the damaged human spinal cord.
Name of contact: Assoc. Prof. Paul Whitington
Email of contact: p.whitington@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209014
CIA Name: Prof Ego Seeman
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2004
Total funding: $316,320
Grant Type: NHMRC Project Grants
Title of research award: Is periosteal bone formation responsible for sexual dimorphism in bone fragility
Lay Description (from application):
Men and women sustain fractures as they age because their bones become fragile. Women sustain fractures more
often than men. Bone thinning occurs in both sexes but it is usually believed that this thinning or loss of bone is
greater in women than men. We have evidence to suggest that this may not be correct. In fact, it is likely that
men and women lose a similar amount of bone, about half what they started with, but during ageing, men lay
down more bone on the outside surface of the bone than women compensating for the similar amount lost on the
inside of the bone. We also have evidence to suggest than men and women who get spine fractures do so because
the process of laying down bone may fail to occur normally. We will study these processes of bone loss inside the
bone and bone gain outside the bone to try to better understand why bones become weak. We will measure the
bone size and its density in healthy men and women and patients with fractures to determine how the increasing
size of the bone produced by laying down bone on its outside helps to keep it strong and to preserve the bone that
would otherwise be lost if it didn't occur or if a disease developed that might reduce the compensatory
Research achievements (from final report):
We studied 1013 healthy subjects (327 men, 686 women), 125 patients with spine fractures (36 men and 89
women), and 307 patients with hip fractures (127 men, 180 women). We made the following observations:
At the spine (i) reduced bone fromation on the outer surfaces (periosteum) of the verebral body during growth or
agening, may be in part responsible of verebral fragility and spinal fractures. (ii) The biomechanical index fracture risk indes (FRI) - is not a better predictor of spinal fractures than bone density. In addition, we found that
women, not men, with vertebral fractures may come from a population with short stature. The difference between
arm span and standing or sitting height cannot be sued to predict vertebral fracture risk.
At the hip, we reported that, differences in the geomentry between men and women were confined to further
displacement of the cortex (the wall of the bone) from neutral axis in young men compared to young women
explaining why men bones are stronger. Ageing amp;ified these differences shifting the cortex even further from
the neutral axis and maintaining the bending strength of the bone in men, but not in women. This at least partly
explained the lower fracture rate in men compared to women. Also, we observed that compared to their peers
women and men with hip have reduced cortical thickness. Women who fracture have larger bones. Where as
men who fracture have smaller bones.
Expected future outcomes:
target the periosteum as a very effective way of maintaining bone strength and reducing the burden of fracture.
It is likely that bone size, independently of bone density, could be used in the future to predict fracture. We plan
to test this hypothesis emanating from this grant.
Name of contact: Ego Seeman
Email of contact: egos@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209113
CIA Name: Prof Wayne Morrison
Main RFCD: Surgery
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2004
Total funding: $226,320
Grant Type: NHMRC Project Grants
Title of research award: THE ROLE OF RESIDENT MAST CELLS IN ISCHAEMIA-REPERFUSION
INJURY OF SKELETAL MUSCLE.
Lay Description (from application):
NHMRC 209113 LAY DESCRIPTION Ischaemia reperfusion injury occurs in skeletal muscle when the
blood/oxygen supply is cut off (ischaemia) and later restored (reperfusion). If the duration of ischaemia is short
some of the muscle survives. However, when blood flow and oxygen are restored the muscle is subjected to more
injury, which is thought to be caused by oxygen and/or white blood cells. This type of injury occurs in muscle
which has been crushed, limbs that have been broken or traumatized, in replantation of amputated parts, in
transplantation, after some surgical procedures and after microsurgical transfer of muscle. Once established there
is no effective treatment. Our experiments show that a particular cell, the mast cell, and a particular molecule,
nitric oxide, are involved in causing ischaemia reperfusion injury. However, the extent of their involvement is
unknown. In this proposal we will investigate the effect of replacing mast cells into muscles, in a unique variety of
mice which normally don t contain mast cells and are resistant to ischaemia reperfusion injury. In one group of
mice we will put back normal mast cells and in a second group of mice we will put back mast cells that cannot
produce the nitric oxide molecule. These experiments will determine, unambiguously, the extent of involvement
of mast cells and mast cell-derived nitric oxide. In the second part of this proposal will carry out a time course
study, using pharmacologically induced mast cell degranulation, to determine when the mast cells become
injurious to skeletal muscle. These experiments will identify the period during which mast cell behaviour can be
modulated in order to protect the muscle from ischaemia reperfusion injury. Determination of the role of mast
cells, and an understanding of the timing during which they become injurious would provide a logical basis for
optimizing drug therapy in clinical applications of these findings.
Research achievements (from final report):
Ischaemia reperfusion (IR) injury occurs in skeletal muscle when the blood/oxygen supply is cut off (ischaemia)
and later restored (reperfusion). If the duration of ischaemia is short some of the muscle survives. However,
when blood flow and oxygen are restored the muscle is subjected to further injury, which is thought to be cause by
oxygen and/or white blood cells. This type of injury occurs in muscle which has been crushed, limbs that have
been broken or traumatized, in replantation of amutated parts, after some surgical procedures and after
microsurgical transfer of muscle. Once established there is no effective treatment. Experiments from this study
show that a particular cell, the mast cell, plays a pivotal role in causing ischaemia reperfusion injury. By using
mice deplete in mast cells, we are able to reduce muscle death by more than 50%. Furthermore, by replacing the
mast cells back into the mast cell deplete mice (a technique known as re-engraftment), we were able to confirm
that mast cells contribute to the majority of muscle injury during IR. This work was presented at an international
conference in USA and a grant was awarded 1 of 4 scholarship, based on the quality of the research. The results
from this study have broader implications for the prevention/treatment of acute inflammatory reactions associated
with IR injury in other scenarios such as heart bypass, organ transplantation and heart disease.
Expected future outcomes:
Based on the results from this study, this has for the first time identified a clear target for drug therapy in IR injury
of skeletal muscle. It is likely to be relevant for prevention of injury in other ischaemic diseases, in particular
cardiac ischaemia (heart attacks).
Name of contact: Pfor Wayne Morrison
Email of contact: Wayne.Morrison@svhm.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400341
CIA Name: Dr Simon Murray
Main RFCD: Neurosciences not elsewhere classified
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2008
Total funding: $507,271
Grant Type: NHMRC Project Grants
Title of research award: Modulation of Neurotrophin Receptor Signaling: understanding the determinants and
phenotypic consequences.
Lay Description (from application):
Peripheral nerves are complex structures consisting of motor and sensory neurons, their axons, and the cells that
support them, Schwann cells. Peripheral neuropathy is a common neurological problem which covers many
disorders of the peripheral nervous system. There are predominately two types of neuropathies: those where there
is a primary loss or degeneration of neurons and/or their axons; and those where the Schwann cells are lost. These
degenerative pathologies have prompted interest in the potential of growth factors as a general therapy for
peripheral neuropathy. The neurotrophins are a family of neuronal growth factors that influence many key
aspects of neuronal development, as well as the maintenance of the mature peripheral nervous system. Work in
cells in vitro and in animal models provides solid support for the hypothesis that the neurotrophins prevent
neuronal death. However clinical trials testing the neurotrophins has led to variable results and side effects due to
their many effects. To make these therapies useful, it is crucial to expand our knowledge about how they actually
work and which of the many responses they induce actually produces their beneficial effect. This project aims to
achieve this goal. I have identified a mechanism where neurotrophin signaling is selectively modulated in vitro.
The aims of this project are to understand how this modulation of neurotrophin signaling is mediated, to identify
the cellular substrates that are selectively activated and to determine what the biological consequences of this
modulation are. Only through analyses such as these can we gain new insights into neurotrophin signaling and
develop an understanding of how the activities of neurotrophins can be more precisely harnessed to generate new
and more productive therapeutic approaches.
Research achievements (from final report):
The family of growth factors known as the neurotrophins exert profound influences on the devlopment, survival
and maintenace of the mature nervous system, as well as playing critical roles in higher order functions such as
learning and memory. This is achieved through their capacity to signal through an established cohort of receptors
that are primarily expressed on neurons. We have recently identfied a novel co-receptor for the neurotrophins,
called NRH2, and as a direct result of this grant have (i) identified that NRH2 is capable of forming interactions
with other neurotrophin receptors and established the basis of these interactions, (ii) found that co-expression of
NRH2 modifies neurotrophin signaling and identified the molecular basis underpinning this effect, and (iii)
investigated the impact this altered signaling has on neurotrophin signaling and its biological outcomes.
Collectively, these studies represent a substantial advance in our understanding of how neurotrophin signaling can
regulate such a divers array of biological effects, in identifying that through utilising distinct co-receptors, that the
nature and duration of neurotrophin signaling cascade can be dramatically altered. Taken in context, these
findings are significant as they move us closer to understanding the full complement of factors that regulate
neurotrophin signaling, which is important if their beneficial effects are to be harnessed in the future for
therapeutic benefit.
Expected future outcomes:
Now we have established that NRH2 influences neurotrophin signaling and identified the basis of this effect, our
future studies will be directed at investigating how we can utilise this knowledge in specifically regulating
neurotrophin signaling, to manipulate the signals that regulate neuronal survival and differentiation in a
therapeutically beneficial context.
Name of contact: Simon Murray
Email of contact: ssmurray@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566916
CIA Name: Prof Ego Seeman
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2009
End Year: 2011
Total funding: $620,381
Grant Type: NHMRC Project Grants
Title of research award: Bone Fragility: The Neglected Role of Cortical Porosity
Lay Description (from application):
Cortical (outer shell) or compact bone constitutes 80% of the skeleton. It is not solid as implied by its name but
made of inter-connected canals resembling a network of roads. We recently discovered that most of the bone loss
with age occurs from these canals, not from t rabecular bone as currently believed. This suggests to know why
and how bone breaks requires the study of the morphology of these canals and how they change with age. This is
what we propose to do. It has never been done.
Research achievements (from final report):
About 75% of all fractures in the community occur in women with bone density values above the osteoporosis
range. These individuals will not be offered treatment and so will go on to sustain fractures. There is therefore
an urgent need to develop tests that allow better identification of individuals at risk for fracture. Measurement of
porosity (i.e., holes in the bone) is a prime candidate because the higher the porosity, the more fragile the bone
independent of its density. The aim of this grant was to(i.) define the 3D morphology of pores (ii.) define changes
in tporosity associated with ageing . (iii.) Use the information obtained to build a software that measures this
porosity in clinical settings; and can be used a diagnosis test.
We reported that increase in porosity was responsible for 70% of the total bone loss during ageing and this was
poorly captured by the bone density test. This work was published in The Lancet. It is highly cited and has played
a key role in driving the bone medical community interested in cortical porosity.
Knowledge of the morphology network of pores has led to discovery of a method and system for quantification of
porosity in clinical settings. The method is patented and reached the national phase in key countries including the
USA, EU, Australia, Japan, China, and India. The software implementing the method has been developed and is
now used to quantify porosity in individuals worldwide including USA and Australia
.
Expected future outcomes:
We expect that the porosity measurement develop with the support of this grant will become a routine clinical test
for bone diseases; allowing to better identify individuals at risk for fracture in clinics, better monitor the effect of
diseases and treatment on bone. This will reduce disease burden with major social and economic benefits.
Name of contact: Roger Zebaze
Email of contact: zebaze @unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145820
CIA Name: Prof Ego Seeman
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2001
End Year: 2003
Total funding: $196,018
Grant Type: NHMRC Project Grants
Title of research award: Apportioning deficits in bone size and density in women with fractures to growth or
ageing by studies in their daughters
Lay Description (from application):
Women fracture their bones because the bones are small and break easily and because the bones are thin or low in
denseness (very porous like a honey comb). This study is aimed at identifying why women with fractures have
small bones and why the bones are so porous. They may have these problems because they lost a lot of bone as
they get older or because growth was abnormal so the size of the bone didn't reach its potential size or because the
denseness of the bones didn't develop properly. The study will be carried out in women with spine or hip fractures
and their daughters. All participants will have bone densitometry, provide a 24 hour urine sample and a fasting
blood sample of 20 ml whole blood. Informed consent will be obtained from all participants. The bone density
scan is associated with radiation exposure of about 4 mSv, about one tenth of a chest x ray, temporary bruising
may follow taking blood. If we can understand the different ways osteoporosis can occur we can then start to
devise specific treatments tailored to the individual. Also if we can identify the causes of small bones and bone
thinness during growth it may be possible to correct some of these causes before the reduced growth and reduced
building of bone occurs. We might also prevent the thinning of bone by identifying and removing causes of bone
thinning.
Research achievements (from final report):
The aim of this study is to determine if the deficits in bone mass and size in women with spine or hip fractures are
growth-related (reduced bone accrual during growth), age-related (excessive bone loss), or a combination of the
two.
Women with spine fractures have low bone density at the spine, which is likely due to reduced accrual during
growth, as the deficits in their daughters' bone density were about half that of their mother's. However, the lower
vertebral size in women with spine fractures is likely to occur during aging, as their daughters do not have deficits
in vertebral size.
Women with hip fractures have larger femoral neck bone size, lower bone density and a thinner bone. Daughter of
women with hip fractures also had larger femoral neck bone size, but normal bone density and normal bone
thickness. Therefore, we infer that the larger bone size in women with hip fractures is growth-related, but the
reduction in bone density and thinning of the bone occurs during aging. Fragility fractures at the spine and hip
have their origins in both growth and aging.
The results of this study should influence how osteoporosis is viewed and the approach taken to research, prevent
and treat osteoporosis. Approaches need to look beyond just factors influencing bone density during aging, to also
include factors that affect bone density during growth and influence bone size and structure. The major shift
appears to be from treatment in adulthood, to prevention and risk assessment during both growth and aging.
Expected future outcomes:
The results of this study open new approaches to research into the pathogenesis and prevention of bone fragility.
Drug therapy may need to be different in persons with deficits due to low peak accrual versus those with excessive
bone loss. Approaches to the whole of the population during growth and aging are needed just as cardiovascular
disease prevention is increasingly focussed at children.
Name of contact: Ego Seeman
Email of contact: egos@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299831
CIA Name: Prof Geoffrey Nicholson
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2004
End Year: 2006
Total funding: $432,645
Grant Type: NHMRC Project Grants
Title of research award: MALE OSTEOPOROSIS: A POPULATION-BASED STUDY IN GEELONG
Lay Description (from application):
Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone
fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily
activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture.
This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously
overshadowed by its effect in women, osteoporosis is increasingly being recognised in men. In Australia, 39% of
all fractures occur in men and prognosis for fracture in men is worse than in women. A consequence of increasing
male longevity is that osteoporosis will affect a growing number of Australian men. It is anticipated that between
1996 and 2051, the number of men with fracture will double, with a 4-fold increase in the number of male hip
fractures. Unless the problem of osteoporosis in men is addressed and effective interventions are implemented,
the substantial health burden imposed by age-related fractures will continue to escalate. In this case-control study
of fracture risk in men, men with fractures (cases) will be identified prospectively for 3 years from radiological
reports. Controls will be selected concurrently, at random from electoral rolls. Anticipated number of cases and
controls are 800 and 1400, respectively. Cases and controls will be characterised for risk factors for fracture: bone
density and bone geometry will be measured, serum samples collected, and diet, lifestyle and medical history
documented by questionnaire. The advantage of this type of data is that information from patients with fracture
will be used to tell us about the risk of fracture in healthy, unaffected men and about the characteristics of the
Australian male population at risk for fracture. The information can be used in decision making for the individual
and in policy making for the whole population.
Research achievements (from final report):
This large population-based epidemiological study enrolled 1,540 men (aged 20-97 years) to evaluate major
fracture risk factors. Assessments included bone mineral density (BMD), demographic, anthropometric and
clinical data; diet; osteoporosis risk factors; medical, falls and fracture history; drug exposures; muscle strength
and gait; and fasting blood samples for biochemical, hormonal and genetic analysis.
BMD reference ranges will be made available for use on all densitometers across Australia, once finalised. Using
bone densitometry, measurement of vertebral height identified alterations in vertebral dimensions that define
fracture. We have determined age distribution of newly recognised vertebral fractures for ambulatory men and
shown that these fractures remain largely undiagnosed, are associated with poor quality of life, compromised
mobility, balance and physical activity. Relatively few high trauma fractures occur among elderly men whereas
they predominate in younger men.
Among men with depression, BMD is reduced, suggesting that depression may be an osteoporosis risk factor.
Metabolic syndrome, a combination of features realted to obesity associated with increased risk cardiovascular
was identified in nearly 1/3 of middle-aged and elderly men. These men have increased BMD, possibly related to
skeletal loading. We have also reported that men with prostate cancer have reduced BMD. Magnetic resonance
imaging was explored as a promising technique for identifying structural parameters of bone associated with
ageing and bone fragility.
Expected future outcomes:
Development of a clinically useful fracture risk score incorporating multi-site bone mineral density, clinical risk
factors, biomarkers and structural parameters of bone, investigation of a common aetiology for osteoporosis and
depression based on predictive value of markers of inflammation and inflammatory cytokines, further evaluation
of the metabolic syndrome in men.
Name of contact: Assoc Prof Julie Pasco
Email of contact: juliep@barwonhealth.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350904
CIA Name: A/Pr James Brock
Main RFCD: Autonomic Nervous System
Admin Inst: University of Melbourne
Start Year: 2005
End Year: 2011
Total funding: $768,560
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The major focus of this fellowship has been investigation of the effects of nerve injuries on blood vessel function.
In particular, I have provided the first evidence that spinal cord injury (SCI) produces a widespread increase in the
effectiveness of nerves that constrict blood vessels. This change contributes to the development of dangerous
episodes of high blood pressure in SCI patients. These studies also identified potential drug treatments that reduce
the hyper-reactivity of blood vessels following SCI and that may be useful for preventing these episodes of high
blood pressure. We also investigated the use of drug treatments to stimulate defecation in SCI patients. These
studies have provided proof in principal that a chemical which mimics the actions of the hormone ghrelin
stimulates defecation and this is soon to be trialled in SCI patients. In new studies initiated during the fellowship I
investigated the blood pressure lowering effect of ghrelin. This action has been attributed to ghrelin dilating blood
vessels but our studies do not support this action. Instead, our studies indicate that ghrelin acts somewhere in the
brain to decrease the activity of nerves that constrict blood vessels. This finding is important because low blood
levels of ghrelin are associated with elevated blood pressure. Finally I continued my studies of mechanisms
whereby sensory stimuli activate nerves that generate painful sensations. The highlight of these studies has been
the development of a technique that allows the initiation of action potentials in these nerves to studied for the first
time.
Expected future outcomes:
The work on blood vessel function following spinal cord injury is ongoing and is focussing on identifying drug
treatments that prevent the episodes of high blood. I am also investgating whether the changes in blood vessel
function contribute to other complications associated with spinal cord injury such as bladder dysfunction.
Name of contact: James Brock
Email of contact: j.brock@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509328
CIA Name: Dr Helen MacLean
Main RFCD: Cell Physiology
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2010
Total funding: $703,665
Grant Type: NHMRC Project Grants
Title of research award: Role of non-classical actions of androgens in musculoskeletal physiology
Lay Description (from application):
Androgens (male sex hormones) are important for growth/maintenance of muscle and bone. The classical action
of androgens is to bind the androgen receptor (AR) and regulate target genes. They can also act via non-classical
AR mechanisms through other cellular pathways. To understand the role of non-classical actions in the
musculoskeletal system we will study mice in which androgens can only act via this pathway. This knowledge is
important for the treatment of osteoporosis and muscle wasting.
Research achievements (from final report):
This study investigated the mechanisms through which male sex hormones (androgens) act. Androgens normally
act through the androgen receptor, a key-lock mechanism required to make particular cells responsive to
androgens, which controls other genes to be switched on or off. Our study used a mouse line in which we created
a mutant version of the androgen receptor that cannot directly regulate other genes. We showed that mutant male
mice have alterations in body weight and weight of the kidney, spleen and muscle and decreased bone mass. In
contrast, mutant female mice had altered kidney, spleen and heart weight and reduced bone growth. This proves
that androgens act in males via the direct gene regulation pathway to control kidney, spleen, muscle and bone
development. This also shows that male sex hormones also play an important role in females to control kidney,
spleen, heart and bone development. We also showed that treatment of mutant male mice with male sex hormones
decreased their bone size, proving that male sex hormones also act through other mechanisms that do not involve
direct gene regulation, to modify bone development. This research has identified new pathways for male sex
hormone action in both males and females. Understanding these actions completely will open up new pathways
for drug design to target these actions. This may allow the development of more effective and specific therapies
for the treatment of osteoporosis, a highly prevalent disease of the aging population, and a number of conditions
associated with reduced muscle mass, including chronic disease and age-related frailty.
Expected future outcomes:
Results from continued research in this area will identify further actions of male sex hormones that occur via
novel mechanisms that do not involve direct gene regulation, including studying bone, muscle, fat and brain in
further detail. This knowledge may contribute to the development of novel treatments for osteoporosis, muscle
wasting and obesity.
Name of contact: Helen Maclean
Email of contact: hmaclean@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454536
CIA Name: Dr Mary Tolcos
Main RFCD: Central Nervous System
Admin Inst: University of Melbourne
Start Year: 2007
End Year: 2009
Total funding: $497,280
Grant Type: NHMRC Project Grants
Title of research award: Compromised fetal brain development: neurogenesis and the potential for therapeutic
intervention.
Lay Description (from application):
Lack of oxygen to the fetal brain during pregnancy is thought to be the main causes of brain injury in newborns.
Some of these infants will suffer developmental and behavioural problems including cerebral palsy, schizophrenia
and epilepsy. Currently, there is no effective treatment to redress these changes in brain development and this is
one of the major challenges in perinatal medicine today. We have previously shown in a guinea pig model of
chronic placental insufficiency (reduced oxygen and nutrient levels during pregnancy) that there is a reduction in
neurons and in the connections between them. This may result from a reduction in number of newly generated
neurons (neurogenesis), or an increase in neuronal death (apoptosis), or both. To develop therapeutic strategies to
improve brain growth and ultimately functional recovery, we must understand the mechanisms which lead to these
brain changes. In this project, we will use our guinea pig model to: 1) determine whether a suboptimal fetal
environment decreases neuronal numbers by influencing neurogenesis, apoptosis or both, 2) study changes in the
compromised brain environment which are likely to influence apoptosis and neurogenesis, 3) determine whether a
suboptimal fetal environment has long-term effects on adult neurogenesis and 4) determine whether treatment
with erythropoietin (Epo), a naturally occurring hormone, can resolve deficits in brain development and function.
Epo is an exciting candidate as it is, or is in the process of being used to treat stroke and newborn asphyxiation.
Epo has also been shown to prevent neuronal death and promote neurogenesis following brain injury.
Understanding the mechanisms and finding effective treatments for brain damage is a vital area of endeavour if
we are to help infants develop their maximum potential and reduce the enormous social, economic and
educational burden which must be borne by the individual and society in general when things go wrong during
pregnancy.
Research achievements (from final report):
Adverse prenatal development contributes to many neurological disorders which manifest postnatally including
cerebral palsy, cognitive and behavioural deficits and possibly schizophrenia. One factor thought to contribute to
these disorders is fetal hypoxia/ischemia (a reduction or loss of oxygen delivery to the fetus). A number of brain
alterations are associated with these disorders including a reduction in the volume of specific brain regions and
neuronal loss. It is likely that prenatal insults such as hypoxia/ischemia will occur during a time when neurons are
being developed therefore this important developmental process may be disrupted. Indeed, using a model of
prenatal compromise (placental insufficiency and fetal hypoxia) in the guinea pig, our group has previously
demonstrated a reduction in the number of neurons, inappropriate wiring of the brain and abnormal brain function.
The aim of this project was to understand the mechanisms underlying these brain alterations in order to develop a
novel approach to the effective treatment of such injury. Using our model of prenatal compromise we found that
there is an increase in neuronal proliferation in the brains of compromised fetuses and that this increase is
correlated with the severity of the insult. Although we know that ultimately there are fewer neurons, it appears that
the compromised brains may contain an intrinsic mechanism that regulates the production of neurons in an attempt
to "catch-up". It is unlikely that this increased production of neurons is sustained long-term, but understanding this
mechanism may be the key to developing novel therapies.
Expected future outcomes:
We hope to further investigate the mechanisms underlying the increase in neuronal proliferation in the prenatally
compromised brain. In addition, understanding the composition of the cerebral microenvironment, and which of
its components are altered by prenatal insults, may provide further insight into the development of appropriate and
more targeted therapies.
Name of contact: Dr Mary Tolcos
NHMRC Research Achievements - SUMMARY
Email of contact: m.tolcos@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251638
CIA Name: A/Pr Mark Kotowicz
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2003
End Year: 2005
Total funding: $428,225
Grant Type: NHMRC Project Grants
Title of research award: BONE SIZE AND BONE TURNOVER: RELATIONSHIP TO FRACTURE RISK
OVER TEN YEARS
Lay Description (from application):
The occurrence of fracture in the ageing population is a major public health problem because these fractures are
responsible for considerable morbidity and mortality. Of women reaching 90 years of age, one third will fracture
their hip and overall, one in every six women will sustain an osteoporotic fracture in her lifetime. The direct cost
to the community is unknown but estimated, conservatively, at 175 million dollars annually. Most of this is likely
to be the result of hip fractures which occupy an estimated 400,000 bed-days annually. This bed occupancy is
fourth next to mental illness, cardiac disease and cancer. The Geelong Osteoporosis Study is a large populationbased epidemiological study currently under way to evaluate the major risk factors for fracture in women . This
present study which will be an extension of the study to date, will provide in total, 8-10 years of data concerning
the processes that result in increased bone fragility and fracture.
Research achievements (from final report):
The present study is an extension of the Geelong Osteoporosis Study, a large population-based epidemiological
study designed to evaluate major fracture risk factors in women, and provides up to 10 years of data about the
development of bone fragility and fracture. We have shown that hip fracture patients have thinning of the outer
shell of the thigh bone that likely compromises bone strength and that there is a compensatory increase in the
diameter of the bone. Additional information about the biomechanical implications of these structural changes will
become available when Hip Structure Analysis of all bone densitometry scans is complete. We have developed a
clinically useful fracture risk (FRISK) score that predicts fracture by combining information from bone
densitometry, previous fracture and falls history. The FRISK score predicts 75% of fractures over a 2 year period.
Systemic inflammation, as assessed by measurement of high sensitive C-reactive protein (hsCRP), predicts
fracture risk over and above information provided by bone densitometry. The role of vitamin D, the influence of
drug exposures, the nervous system, genetic factors, oxidative stress and depression in bone fragility have been
reported. We have demonstrated that the population burden of fracture comes from the large number of
individuals with a modest reduction in bone mass rather than the relatively small number of high-risk individuals
with osteoporosis. Reference ranges for bone densitometry have been established, the health impact of fragility
fracture and cost benefit analyses of treating women with osteopenia and osteoporosis have been published.
Expected future outcomes:
Development of an updated FRISK score incorporating bone turnover markers and hsCRP, pursuit of a common
aetiology for osteoporosis and cardiovascular (CVD) disease based on predictive value of hsCRP in both disorders
and evidence of systemic inflammation in CVD, evaluation of osteoporosis in men using expertise gain from this
study (NHMRC Project 299831)
Name of contact: Assoc Prof Mark Kotowicz
Email of contact: markk@BarwonHealth.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400089
CIA Name: Prof John Wark
Main RFCD: Endocrinology
Admin Inst: University of Melbourne
Start Year: 2006
End Year: 2008
Total funding: $469,605
Grant Type: NHMRC Project Grants
Title of research award: The effect of antiepileptic medication on indices of bone health and risk factors for
falls and fractures
Lay Description (from application):
Epilepsy is a common brain disorder and most patients with epilepsy take anti-epileptic drugs (AEDs) for many
years. These patients have high rates of bone fractures, but the reasons are uncertain. Earlier studies identifying an
association between AED use and bone disease were performed on institutionalised patients, and more recent
studies on outpatient populations have been conflicting. A better understanding of this problem is critical for
designing potential preventive measures and treatments. One important additional mechanism by which AEDs
may increase fracture risk is impairment of gait and balance, leading to a high risk of falls. We have novel data
demonstrating the power of a Twin and Matched Sibling approach to study this important problem. This study
showed that chronic AED use was associated with significant deficits in bone mineral density (BMD), a key
predictor of the risk of fractures. The proposed project will ask the following questions: 1. Is BMD and estimated
bone strength lower in the bones most at risk for fracture in women and men chronically taking AEDs? 2. Is the
loss of bone in measurements over time greater in patients continuing to take AEDs? 3. Is the risk of bone loss
greater for certain types of AEDs, and is the risk influenced by length of exposure, age and menopausal status? 4.
How does AED treatment lead to reductions in BMD and bone strength? 5. Are measures of muscle strength, gait
and balance impaired in patients taking AEDs compared with matched people not taking AEDs? The proposed
study will utilise twins and pairs of siblings to investigate the effects of the long-term use of AEDs for epilepsy on
measures of bone mass and strength, indices of bone turnover, vitamin D status, calcium regulating hormones,
mineral levels, sex hormone levels, and measures of muscle strength, gait and balance function. In addition, a
group of patients newly commencing AED treatment for epilepsy will be studied over 2 years.
Research achievements (from final report):
Anti-epileptic drugs (AEDs) are required long-term for patients with epilepsy and several other disorders.
Fractures are a major adverse outcome in people taking AEDs.
This project explored the causes of AED-associated bone fractures using several approaches. One was the
powerful exposure-discordant twin/ sibling pair model, where one member of each pair used AEDs and the other
did not. We found significant deficits in bone mineral density (a key indicator of bone fragility) in people taking
AEDs; a person's age and duration of treatment added to their risk.
The second approach was a cohort study in newly-diagnosed epileptic patients and non-treated subjects, following
indices of bone health for 2 years. This study demonstrated accelerated bone loss (e.g., at the hip) in newly-treated
patients. Further observations may identify specific AEDs that cause bone loss and fractures.
We also conducted a comprehensive assessment of falls risk in AED-treated subjects and their non-treated twins
and siblings, identifying multiple balance impairments in the AED-treated subjects. Poor balance and bone
fragility are therefore key determinants of the increase in fractures associated with AED use. A survey of 150
epilepsy patients identified many with high falls risk, confirming the need for intervention in this population.
This research is unique and important, improving understanding of AED-associated fracture risk. We are now
launching the first specific treatment trial for AED-associated bone loss and plan a physcial activity intervention
trial seeking to reduce AED-associated falls. Our ultimate aim is to improved bone health in people taking AED
therapy.
Expected future outcomes:
Over the next ive years we expect to complete the first RCT of treatment for AED-induced bone loss, to conduct
the first physical activity RCT in prevention of falls during AED therapy and to have translated the findings into
improved clinical care and outcomes for AED-treated patients.
NHMRC Research Achievements - SUMMARY
Name of contact: Professor John D Wark
Email of contact: jdwark@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509217
CIA Name: Prof Philip Beart
Main RFCD: Cell Neurochemistry
Admin Inst: University of Melbourne
Start Year: 2008
End Year: 2011
Total funding: $747,928
Grant Type: NHMRC Project Grants
Title of research award: Mitochondria: molecular and cellular insights into their diverse contributions to
neuronal injury
Lay Description (from application):
Mitochondria are components of cells normally providing energy for essential functions and in the energy
demanding brain, under stress conditions, mitochondria acts as controllers of cellular decision-making processes
leading to neuronal death. Our goal is to understand mitochondrial mechanisms determining how neurones die
after various stresses and injury. Using pathological insults relevant to neurological conditions, we shall analyse
"death" molecules and how neurones adapt when threatened.
Research achievements (from final report):
Neurones die by various mechanisms in neurodegenerative conditions and understanding "death" is essential in
rescuing injured neurones. Our work was aimed at dissecting neuronal death mechanisms and studies were
undertaken in neurones isolated from animals and then maintained under physiological conditions. Herein it is
possible to "model" the cellular stresses to which brain cells are exposed in human neuropathologies. By
challenging cultured neurones with toxic stimuli (oxidative stress, excitotoxicity, growth factor deprivation)
known to operative in human neurodegeneration, we described for the first time the full cascade of death
signalling, including the mobilization of proteins from mitochondria (organelles for energy generation) that
initiate injurious events. Recruitment of four types of neuronal death identified (apoptosis, necrosis, programmed
necrosis & autophagy) was dependent on the type and effective magnitude of the toxic stimulus. Little is known
about one form of neuronal death, gene-programmed necrosis, and we identified endonuclease-G as contributing
intimately to the death signalling. This finding is totally novel, especially since blockade of its involvement was
neuroprotective, and suggested endonuclease-G is intimately linked to oxidative injury which is strongly
implicated as contributing to brain cell death in stroke. In some cases multiple death mechanisms were recruited interestingly autophagy (a cellular debris removal system) was found to contribute to neuronal death in concert
with oxidative stress-induced programmed necrosis. Since autophagy has protective ("good") and destructive
("bad") components, selective activation of the good component to remove damaged cellular components
represents a novel way to minimize the debilitating effects of neurodegenerative conditions.
Expected future outcomes:
Our findings need to be extended in vivo to determine if programmed necrosis and autophagy represent genuine
"targets" for rescuing injured brain. We need to delineate the interface between autophagy and the second debris
removal system, the ubiquitin-proteasome. These goals are being pursued in a mouse model of human stroke.
Name of contact: Professor Philip Beart
Email of contact: philip.beart@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208918
CIA Name: A/Pr Ann Turnley
Main RFCD: Cellular Nervous System
Admin Inst: University of Melbourne
Start Year: 2002
End Year: 2004
Total funding: $451,980
Grant Type: NHMRC Project Grants
Title of research award: Suppressor of Cytokine Signalling-2 (SOCS2) and its role in neuronal development and
function
Lay Description (from application):
Injury to the brain or spinal cord at present often results in permanent damage, such as paralysis, which is largely
due to a failure of neurons to regrow at the injury site. In order to overcome this, we are trying to find ways of
making new neurons grow, either from stem cells present in the nervous system or transplanted from cells grown
in tissue culture. However, little is known about how a neural stem cell decides to become a neuron or another cell
type, such as a glial cell and so we are examining factors which influence this process, which is called
differentiation. Growth factors are important mediators of this process and suppressor of cytokine signalling
(SOCS) proteins are important in determining how cells respond to growth factors. The overall aims of this project
are to determine the role that SOCS genes and in particular, SOCS2 play in neural stem cell differentiation into
neurons and glia, neuron process outgrowth and neuronal and glial injury responses in the nervous system. This
will be examined in normal cells and cells which over-express or do not express SOCS2 genes. Understanding the
biology of neural growth factor responsiveness may eventually allow us to devise therapeutic strategies for use
following brain/spinal injury or disease, including generation of neurons from stem cells.
Research achievements (from final report):
Our research has shown that a regulator of growth hormone (GH) signalling, Suppressor of Cytokine Signalling-2
(SOCS2), is also an important regulator of nerve cell growth. Neural stem cells grown from SOCS2 knockout
mice showed a 40-50% decrease in production of neurons while increased expression of SOCS2 promoted neuron
production. An important finding of these studies was that growth hormone (GH) is an important regulator of
neuronal differentiation and that SOCS2 is required to block GH signalling to allow neuronal production to
proceed. When the brains of SOCS2 knockout mice, which do not turn off GH signalling appropriately, were
examined, they showed a 30% decrease in neuronal numbers in their cortex. Conversely, analysis of brains of GH
receptor knockout mice, which are dwarf as they are unable to respond to GH, showed a 25% increase in neuronal
numbers. SOCS2 transgenic mice, which have decreased responsiveness to GH, showed little increase in total
neuron numbers, but showed marked increases in a subset of neurons called interneurons. While SOCS2 does not
appear to play a role in neuron survival, it is also a potent promoter of nerve process outgrowth, enhancing process
length and number in neurons. This appears to be a result of inducing activation of the epidermal growth factor
(EGF) receptor and appears to be independent of GH. SOCS2 and EGF stimulation induced similar effects on
cortical neuron process outgrowth, possibly through some of the same signalling pathways. Furthermore, analysis
of GH receptor knockout and SOCS2 knockout mice showed an apparent decrease in dendritic branching in
cortical neurons, while SOCS2 transgenic mice showed increased branching and an increased density of synapses.
Therefore, SOCS2 is involved in 2 important aspects of brain development and function: production of neurons
and regulation of how these neurons connect.
Expected future outcomes:
Regulation of how neurons are made and how they connect has implications for development of the brain and
regeneration after disease or injury. Understanding SOCS2 function in these processes may allow therapy
following neural damage and provide insight into development of mental health disorders that involve
abnormalities in brain wiring, such as Schizophrenia and mental retardation.
Name of contact: Ann Turnley
Email of contact: turnley@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251682
CIA Name: Prof Geoffrey Nicholson
Main RFCD: Primary Health Care
Admin Inst: University of Melbourne
Start Year: 2003
End Year: 2007
Total funding: $305,750
Grant Type: NHMRC Project Grants
Title of research award: Primary care prevention of falls and fractures in the elderly by annual vitamin D
supplementation
Lay Description (from application):
While Australia has one of the highest rates of skin cancer, many of us are not receiving enough sun exposure to
adequately maintain necessary blood levels of vitamin D. For years it was assumed that vitamin D deficiency was
rarely seen in Australia where sunlight abounds for most of the year. Although few foods are high in vitamin D, it
was thought that only certain cultural groups where women are always veiled in public, very dark-skinned people
and the housebound elderly, were at risk of vitamin D deficiency. Lower vitamin D levels following wintertime
have now been reported in many populations including those living near the Mediterranean and in Geelong,
Victoria. Vitamin D insufficiency is associated with an increased risk of falling through increased body sway and
muscle weakness. Low levels of the vitamin also encourage the removal of calcium from bones and will
predispose to bone fracture for two reasons - increased likelihood of falling and increased bone fragility and
osteoporosis. Osteoporotic fractures are amongst the most important causes of ill-health among elderly people,
causing an estimated 65,000 fractures in 2000-01. If nothing is done, fracture rates are estimated to increase from
one every 8.1 minutes in 2001, to one every 3.7 minutes in 2021. Falls among the elderly are also a major health
with about a third of people over 70years falling at least once every year. Almost 90% of all hip fractures result
from the impact of a fall. This project will trial an annual dose of vitamin D to the elderly at high risk of vitamin D
deficiency, falls and fractures. Fifteen hundred women will be supplemented with either vitamin D or a placebo
"dummy" pill at the beginning of winter for five years. The supplementation will take place through their local
doctor and researchers will expect to see fewer falls and bone fractures occurring in those receiving vitamin D
than in the group receiving the placebo.
Research achievements (from final report):
The Vital D study successfully recruited 2,317 women aged at least 70 years and who were assessed as at a higher
risk of fragility fracture or osteoporosis. Although the initial NHMRC 5-year grant funding has finished, the study
has been awarded further NHMRC funding to extend the project's outcomes. All participants will complete the
study during 2008. The findings have been extended to investigate not only the prevention of falls and fractures,
as originally planned but also to investigate if vitamin D supplementation improves mental health in the elderly
and if vitamin D supplementation over a number of years reduces the overall use and cost of medical and hospital
services. Since commencing this project in 2003 the many potential benefits of an adequate to high vitamin D
status has received much scientific attention. The project's pragmatic design continues to have much appeal. The
concept of a once-a-year dose of vitamin D tablets holds promise as several international studies on vitamin D
supplementation have reported low compliance of the study tablets when participants were required to take
calcium and vitamin D tablets on a daily basis. The results of these other studies generally show that vitamin D
prevents falls and fractures when targeted to participants likely to have a low vitamin D status. Not surprisingly
when the analysis of results includes both those participants who took the daily supplementation and those
participants who were asked to but didn't take the tablets on a regular basis, the evidence that vitamin D prevents
falls and fractures is weaker. The results of other studies has also shown that the dose of vitamin D needs to be
sufficiently large to increase the levels of the vitamin in the blood and to show benefits to bone health. Participants
in our study -Vital D randomised to vitamin D have been given an annual dose of 500,000 IU of vitamin D3
(cholecalciferol). This dose continues to be regarded as sufficiently high.
Expected future outcomes:
The main analysis comparing falls and fractures in participants taking the vitamin D tablets with those taking
placebo will commence later this year when all participants have finished the study and the research team are no
longer 'blinded' as to their active or placebo status.
NHMRC Research Achievements - SUMMARY
Name of contact: Dr Kerrie Sanders
Email of contact: kerrie@barwonhealth.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510314
CIA Name: Prof Shane Darke
Main RFCD: Central Nervous System
Admin Inst: University of New South Wales
Start Year: 2008
End Year: 2011
Total funding: $244,858
Grant Type: NHMRC Project Grants
Title of research award: Organic brain damage after non-fatal opioid overdose
Lay Description (from application):
The study will provide the first data on the level and nature of brain damage due to opioid overdose. The extent to
which overdose survivors suffer brain damage has important implications for clinical management, particularly in
relation to behavioural problems. It will also provide the first data on brain damage and drug treatment
performance. Screening of those with an overdose history may lead to specialised management of these
individuals with the potential for improved treatment outcome.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact: Professor Shane Darke
Email of contact: s.darke@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 113811
CIA Name: Dr Hala Zreiqat
Main RFCD: Biomaterials
Admin Inst: University of New South Wales
Start Year: 2000
End Year: 2002
Total funding: $273,429
Grant Type: NHMRC Project Grants
Title of research award: Peptides Bound to Commonly Used Orthopaedic and Dental Biomaterials:In Vitro and
in Vivo Effect on Osteogenesis.
Lay Description (from application):
In 1992, the orthopaedics industry fitted some 300,000 prosthetic devices, artificial hips, knees, giving this
industry a global market of $2.1 billion with a projected market growth exceeding 10% per annum. In (1994/5)
5,717 prosthetic hips and 4,593 knees were surgically implanted in NSW of which 14% of hips and 9.5% of knees
were revisions. Considerable health funding is allocated to joint replacement for the nation, although successful,
outcomes are finite. Importantly, and aside from costs, patients morbidity is high.
The major cause of longterm failure of these prosthetic replacements is aseptic loosening, the result of bone loss at the bone/device
interface. Novel approaches to development of more efficient implant materials would ultimately lead to major
contributions to the mobility and and quality of life for these patients. Considerable effort has been devoted to
alter surface characteristics of orthopaedic implants to improve the interlocking of device and skeleton. We were
the first to demonstrate that surface chemical modification of biomaterials using selected ions resulted in an
enhanced bone formation. This proposal is aimed at chemically modifying the surfaces of commonly used
orthopaedic and dental materials, to improve the biocompatibility of new devices and the surface coatings for
existing prostheses. Furthermore, this application will build on the in vitro data showing that particular peptides
specifically bind osteoblasts and therefore have the potential to provide a surface on a prosthesis that is conducive
to bone formation. To date, we have coupled these peptides to metallic surfaces and will proceed to study the
osteoblastic phenotype and subsequent osteogenesis. Development of these novel biocompatible surfaces is
anticipated to reduce patient morbidity and result in significant health care savings.
Research achievements (from final report):
N/A
Expected future outcomes:
The project has the potential to improve the binding qualities of prostheses, thus reducing the rate of revision
arthroplasty. This would lead to a significant reduction in the cost of health care in an aging population. National
benefits of this project include:
1.
Development of new implant material with improved bony integration.
2.
Improved quality of life for recipients of prosthetic devices.
3.
Provide guidelines for the design and/or surface modification of orthopaedic/dental biomaterials.
4.
Itemize strategies to improve long-term fixation of prostheses.
Knowledge and expertise gained will facilitate the optimization of various implant materials for orthopaedic and
implant dentistry, and thus will promote the technology transfer from academia to the relevant medical device
industry.
It is expected that some of the outcomes will generate IP, which would initiate negotiations towards improved
commercial devices.
Name of contact: Dr Hala Zreiqat
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 350823
Start Year: 2005
CIA Name: Prof Caroline Finch
End Year: 2009
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $2,351,750
Admin Inst: University of New South Wales
Grant Type: Capacity
Title of research award: Addressing injury in a population health framework: An integrated approach to
prevention, acute care and rehabilitation
Lay Description (from application):
In Australia, injury is the leading cause of death and disability in people aged under 55 years. It is also a major
cause of morbidity and mortality in older persons and, overall, accounts for a substantial proportion of acute
hospital services and long-term rehabilitation needs. This grant will build an internationally competitive research
team focused on reducing the public health burden of injury.
Research achievements (from final report):
This project supported the career development of 13 injury researchers whose collective research activity led to
>120 scientific publications/reports, >$7.4million in new research grants and >60 conference presentations.
Research findings were also instrumental in influencing injury prevention policy relating to roads, sport and falls
in older people.
Expected future outcomes:
The team Investigators have now established themselves as productive injury researchers. Several have their own
NHMRC Fellowship Support and others have moved on to research leadership positions of their own. They are
now placed to continue to conduct leading-edge injury research and to train the next generation of young
researchers.
Name of contact: Professor Caroline Finch
Email of contact: caroline.finch@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 350860
CIA Name: A/Pr Tony Butler
Main RFCD: Epidemiology
Admin Inst: University of New South Wales
Start Year: 2005
End Year: 2007
Total funding: $591,000
Grant Type: NHMRC Project Grants
Title of research award: A survey of the sexual behaviour and sexual health of Australian prisoners
Lay Description (from application):
The Australian Study of Health and Relationships telephone survey recently reported on the sexual attitudes,
knowledge, health and behaviour of over 19,000 Australians. One of the groups that was omitted from that survey
was prisoners. Yet prisoners are a high-risk group for sexual ill health. Prisoners are mostly drawn from the most
disadvantaged groups in society: they are more likely to be unemployed, they have less education and lower
incomes than other Australians, and many suffer from minor intellectual disabilities and/or mental illness. This
proposed survey of inmates in Australian prisons will fill in this missing data. Prisoners are the forgotten
population in many countries. Only a few surveys of prisoners' health have been performed. There are some
surveys of sexual behaviour in particular prisons overseas, though most of them concentrate on HIV risks and do
not explore the sexual lives of prisoners in the same way as the major national sex surveys in the US, the UK and
France did for people living outside prison. Prison is itself a dangerous place for people's sexual health. In prison,
much of the sex that occurs is not voluntary. Sexual assault in prisons can lead to serious physical injury as well as
risk of sexually transmitted diseases including HIV/AIDS. Although some of these injuries can be sufficiently
serious to require surgery, only a small proportion are reported to the authorities. Younger prisoners (aged 18-25)
and those who are small, slightly built or gay, are at higher risk of being assaulted. This study will explore the
factors surrounding sexual assault in prison and make recommendations for preventing it.
Research achievements (from final report):
- The study has been able to describe in detail for the first time the sexual health and behaviours of Australian
prisoners.
- It has helped to debunk the myth of high rates of prisoner rape in Australian correctional facilities.
- The study has also contributed to the public health debate on condom and dental dam provision in prisons. We
found that condom/dental dam provision does not promote increased sexual activity (consensual and nonconsensual) in prison.
Expected future outcomes:
- Possible development of interventions on sexual safety for prisoners.
- Input into evidence-based decision-making for prisoner welfare and services.
Name of contact: Tony Butler
Email of contact: t.butler@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455368
CIA Name: Prof Stephen Lord
Main RFCD: Geriatrics and Gerontology
Admin Inst: University of New South Wales
Start Year: 2007
End Year: 2010
Total funding: $530,741
Grant Type: NHMRC Strategic Awards
Title of research award: Identification and quantification of risk of falls in cognitively impaired older adults
Lay Description (from application):
This study represents the first systematic approach to understanding the complex interaction of factors that
contribute to risk of falling in cognitively impaired older people. The results will provide much needed
information on how to intervene to prevent falls and fractures in this high risk population. In the last decade, 25
randomised controlled trials have been published which show it is possible to prevent falls in older people.
However, a major disappointing outcome of research in this field is that trials that have included or specifically
focused on older people with cognitive impairment have been unsuccessful in preventing falls. Cognitive
impairment has long been known to be a major risk factor for falls and fractures but little research has been
undertaken to understand the underlying mechanisms as to why this is the case. It is likely that previous falls
prevention trials involving people with cognitive impairment were unsuccessful because they did not directly
assess mechanisms for falls in this group and simply translated intervention strategies from studies undertaken in
cognitively intact older people. This study aims to develop our understanding of the important factors that
contribute to risk of falling in older people with cognitive impairment and dementia. Participants will be recruited
from a number of sources including hospitals, out-patient clinics, retirement villages, hostels etc. Whilst some
participants will be able to consent to take part, all participants must have a nominated "person responsible".
Consenting participants will undergo a series of assessments, the majority of which can be undertaken in their own
home. These will include medical and medication history, measures of gait and balance and tests assessing
performance of different regions of the brain. An MRI scan will allow us to determine whether risk of falling
relates to any specific pathology in different parts of the brain. We anticipate that we will be able to identify which
risk factors and underlying mechanisms are most strongly associated with falling in cognitively impaired older
people. We then hope to use the information to design targeted and tailored intervention strategies to reduce falls
and fractures in this high risk population.
Research achievements (from final report):
This project has systematically assessed falls risk in older people with cognitive impairment. It has provided clear
evidence of marked physiological deficits in this population that are potentially amenable to intervention strength, balance and reaction time. It appears that the physical deficits play a greater role in risk of falls than any
of the neurocognitive measures. However, neurocognitive performance is relevant in terms of potential
interventions for the future.
Expected future outcomes:
The study finished in March 2011 and a pilot study for intervention has also been undertaken and has provided
additional information on how to shape an intervention for the future. The next step is to undertake an intervention
study and funding is currently being sought.
Name of contact: Jacqueline Close
Email of contact: j.close@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300420
CIA Name: Prof James Colebatch
Main RFCD: Central Nervous System
Admin Inst: University of New South Wales
Start Year: 2004
End Year: 2006
Total funding: $205,500
Grant Type: NHMRC Project Grants
Title of research award: Assessment of Vestibular Function and Balance in Humans
Lay Description (from application):
This proposal focuses upon the function of the vestibular apparatus and the related problem of impaired balance.
The vestibular apparatus contains receptors which help us to maintain balance. Their clinical assessment is
difficult because they are small and lie deep within the skull. With previous NH&MRC support, I have been able
to develop a series of new tests to assess the function of the vestibular apparatus and these are having significant
clincal impact. Amongst the findings has been a clear demonstration that vestibular function declines with age,
starting relatively early.
This proposal builds upon the findings of the previous application. Two main types of
investigations are planned. In one a new technique of activating the vestibular apparatus (localised skull
vibration) will be used to study the brain areas that receive its signals ("evoked potentials"). This will be the first
time that it has been possible to study the connections between the balance organs and the cortex of the brain in
intact humans. I will apply the technique to patients with disturbed vestibular function to improve our knowledge
of how the brain adapts to disease of these organs. In the second part of this study, a series of recordings will be
done measuring sway under a variety of conditions both in normal volunteers and in patients with some common
disease states affecting balance. This should reveal new information about both the factors that affect normal
balance function and why balance is disturbed in these diseases.
Research achievements (from final report):
This research project substantially increased our ability to measure the function of the vestibular apparatus
(balance organs) in normal humans and in disease states. Specifically the otolith component of the vestibular
apparatus was investigated, and this has been particularly difficult to assess in humans prior to the discovery of
our techniques. We have extended our earlier reports using clicks to other modalities. Many clinical diagnostic
laboratories both in Australia and overseas are now using these techniques to improve diagnosis and management
of a variety of vestibular (balance) disorders.
Expected future outcomes:
Further developments of these techniques is still occurring, including defining other pathways (to the eyes and
brain). These can be expected to further improve diagnosis and may also help to understand why some subjects
compensate in response to a vestibular (balance organ) disturbance while others do not.
Name of contact: Prof James Colebatch
Email of contact: j.colebatch@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157019
CIA Name: Prof David Tracey
Main RFCD: Sensory Systems
Admin Inst: University of New South Wales
Start Year: 2001
End Year: 2003
Total funding: $196,018
Grant Type: NHMRC Project Grants
Title of research award: Mechanisms of neuropathic pain
Lay Description (from application):
Disorders of pain sensation due to nerve damage are common, debilitating and difficult to treat. Nerve damage
often results in increased sensitivity to painful stimuli and the perception of innocuous stimuli as painful; it may
also result in spontaneous pain. Pain is one of the commonest clinical problems, and yet it is often accepted or
taken for granted. The outcome of this work will be an increased understanding of the way in which nerve injury
leads to spontaneous pain and increased sensitivity to painful stimuli. This will lead in turn to the development of
more effective treatments for neuropathic pain.
Research achievements (from final report):
Mast cells are part of the immune system often associated with asthma. There are resident mast cells in peripheral
nerves, and we showed that they play a key role in the chronic (neuropathic) pain which often results from injury
of peripheral nerves. We showed that stabilising mast cells with cromoglycate (an agent commonly used to treat
asthma) blocks the initiation of neuropathic pain in experimental animals. A role of histamine (which is released
by activated mast cells) was also demonstrated. These findings have potential significance for pre-empting the
development of neuropathic pain in patients where nerves are injured by surgery (for example in thoracotomy).
Expected future outcomes:
We plan to carry out further work on the subtypes of histamine receptor which contribute to neuropathic pain.
This could lead to pilot clinical trials.
Name of contact: David Tracey
Email of contact: d.tracey@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350889
CIA Name: Prof Vaughan Macefield
Main RFCD: Sensory Systems
Admin Inst: University of New South Wales
Start Year: 2005
End Year: 2007
Total funding: $375,750
Grant Type: NHMRC Project Grants
Title of research award: THE AUTONOMIC, SOMATIC AND CENTRAL NEURAL RESPONSES TO DEEP
AND SUPERFICIAL PAIN IN HUMAN SUBJECTS
Lay Description (from application):
Pain is a subjective experience, the intensity of which can be readily influenced by personal experience. Despite
this, pain originating from a particular part of the body will usually be described by all individuals as having
similar character. For example, pain arising from the skin is commonly described as being sharp or burning and is
usually easy to localise, whereas pain arising from muscle is commonly dull, throbbing and diffuse. In addition to
producing sensory changes, pain also evokes changes in blood pressure, heart rate and motor activity (often in an
attempt to remove the source of the pain). The proposed research aims to characterise the cardiovascular and
motor patterns associated with pain originating in skin and in muscle and to examine the brain regions that
produce these changes. More specifically, microelectrodes will be used to investigate changes in peripheral nerve
activity during transient painful skin and muscle events in awake human subjects. In a separate investigation
functional magnetic resonance imaging will be used to determine brain sites that are activated by skin or muscle
pain.
Research achievements (from final report):
This research has made significant contributions to knowledge on the effects of autonomic, somatic and central
responses to pain. We have used brain imaging to revela the differences in processing of pain originating in
muscle and skin, and uncovered a hitherto unknown gender difference in pain processing. Moreover, we have
documented for the first time differences in how the sympathetic nervous system, important in the regulation of
blood pressure and blood flow, responds to acute pain. Finally, our work has provided detailed evidence that
refutes the 'vicious-cycle' theory of muscle pain - an hypothesis based on animal experiments and which underpins
many pain management strategies.
Expected future outcomes:
While this project examined the effects of acute pain, induced by bolus injections of hyeprtonic saline into muscle
or skin of awake human subjects, in 2009 we shall be submitting a Project Grant that extends this work by
examining the effects of tonic muscle pain, induced by intramuscular infusion of hypertonic saline. This more
closely approximates the onging pain associated with chronic pain.
Name of contact: Prof Vaughan Macefield
Email of contact: v.macefield@uws.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455215
CIA Name: Prof Simon Gandevia
Main RFCD: Central Nervous System
Admin Inst: University of New South Wales
Start Year: 2007
End Year: 2009
Total funding: $365,105
Grant Type: NHMRC Project Grants
Title of research award: Novel assessments of the central and peripheral control of the human hand
Lay Description (from application):
This is a study of how the human hand works. The hand is supremely adapted for manual skills ranging from
writing and playing a musical instrument to non-verbal communications via gesture and pointing. How is the
range of hand skills achieved? We are motivated to study this because the ability of the hand to recovery from
some neurological disorders, particularly stroke, is very poor. One important element in virtually all activities of
the hand is precise movement of the thumb. The tip of the thumb is flexed by a single muscle, a muscle only
present in humans. We want to determine how this muscle works, and how the force it produces affects the whole
hand. We will use specialised neurophysiological techniques to do this in human volunteers. There is no
comparable animal model for this type of work due to significant differences at both the level of the brain and the
level of the muscle. Second, we want to understand better how the cells in the spinal cord which control the hand
(and other) muscles work. We have two new ways to do this, including a novel technique which can activate
these cells with a form of stimulation that may help us improve functional electrical stimulation. Finally, with 27
bones and more than 25 muscles which operate it, the hand is not simple to control. We will use a new apparatus
to measure how well it is controlled, and we will directly stimulate the motor areas of the brain to evaluate the
control. From this, we will come up with new understanding, as well as new stimulus and measurement
techniques that can be applied to patients with impaired hand function, as occurs all too often after stroke.
Research achievements (from final report):
This project aimed to reveal key principles involved in the central and peripheral control of the human hand at the
level of the muscles, the spinal motoneurone pools, and the motor cortex. W tried to find out (1) why the control
of the human thumb is special, (ii) how the various hand muscles are coordinated to produce strong hand forces,
and (iii) how the brain controls the muscles which extend the fingers to lift them from grasped objects. We
developed a new method for testing voluntary drive to the hand and examined novel ways that muscle can produce
force when stimulated electrically. This work will contribute to understanding hand function and how it can be
affected by disease.
Expected future outcomes:
N/A
Name of contact: Professor Simon Gandevia
Email of contact: s.gandevia@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300437
CIA Name: A/Pr Lynne Bilston
Main RFCD: Biomechanical Engineering
Admin Inst: University of New South Wales
Start Year: 2004
End Year: 2008
Total funding: $527,500
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
This fellowship has underpinned my research program, and allowed me to make significant research discoveries
and translate these into public policy. Key research findings from the fellowship period include: (a) definition of
the key factors underpinning injuries to children travelling in cars, and input into legislative changes to require
size-appropriate restraints for children in cars, and improvements in safety standards for child restraints; (b)
development of models of paediatric spinal cord injury that are able to reproduce the key differences between
paediatric and adult spinal cord injury, (c) development of novel imaging techniques to measure soft tissue
biomechanical properties, particularly for brain and muscle tissue.
Expected future outcomes:
The research conducted during this fellowship is expected to lead to new information on the mechanisms of injury
to children and other occupants of the rear seat of cars (currently being conducted), and preclinical studies
possibly leading to new diagnostic techniques bases on imaging of tissue stiffness.
Name of contact: Lynne Bilston
Email of contact: L.Bilston@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351000
Start Year: 2005
CIA Name: Dr Shauna Sherker
End Year: 2009
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $290,298
Admin Inst: University of New South Wales
Grant Type: Early Career Fellowships (Australia)
Title of research award: A program of evidence-based sports injury prevention injuries.
Lay Description (from application):
Not Available
Research achievements (from final report):
There were many achievements in the research program of evidence-based sports injury prevention initiatives.
Research projects undertaken included:
- A review of NSW sports injury hospitalisation and deaths
- Establishing a framework for review of motorsports injury in NSW
- Identifying risk and protective factors for mild traumatic brain injury
- The role of alcohol, drugs and fatigue towards injury risk attitudes and perceptions among high-risk sports
participants
- Evaluating risk management training to improve the safety activities of community sport
- Review of guidelines for prevention of heat illness in sport
- Encouraging compliance with safety standards in local government playgrounds
- Evaluation of a national campaign to reduce the risk of beach drowning
Expected future outcomes:
It is anticipated that this research will contribute to future evidence-based sports injury prevention initiatives.
Name of contact: Shauna Sherker
Email of contact: shaunasherker@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 350855
CIA Name: Prof Stephen Lord
Main RFCD: Optometry not elsewhere classified
Admin Inst: University of New South Wales
Start Year: 2005
End Year: 2007
Total funding: $493,000
Grant Type: NHMRC Project Grants
Title of research award: A randomised controlled falls prevention trial of long distance glasses in elderly
multifocal wearers
Lay Description (from application):
Each year, one-third to a half of people over 65 years old will fall at least once. The consequences of falls are
immense in terms of suffering, loss of independence, fear of future falls, carer burden, mortality, residential care
admissions and other health care resource usage. Clearly, effective and affordable falls prevention strategies are
needed to address this major health care problem. Over 50% of people over 65 years old use bi-, tri- or multifocal glasses. The lower part of these glasses are useful for reading and seeing at close range only and there is now
evidence that the use of these glasses is associated with an increased risk of falls due to the blurring of vision
when looking through the lower lenses at ground level obstacles. This is particularly relevant in unfamiliar
outdoor situations. This study will determine whether providing plain distance glasses (with extensive counselling
and recommendations for use in standing and walking activities) will prevent falls and their consequences over a
one year period in older persons who wear bi-, tri- or multi-focal glasses. Pilot studies suggest that most elderly
bi-, tri-, or multi-focal wearers at risk for falls are willing to purchase and use a second pair of glasses if the
benefit of new plain distance glasses for their vision is demonstrated. We expect that the results of the study will
be incorporated into all relevant areas of clinical practice and public health strategies.
Research achievements (from final report):
There are over 2.4million people aged over 65years of age in Australia, one third of whom fall annually at least
once. As age advances, visual condition called presbyopia in which the crystalline lens of the eye losses its
flexibility makes focusing on close objects difficult. To correct this people are prescribed separate single lens
glasses for distant and near vision or for convenience bi/tri/progressive lens glasses for conducting daily tasks for
e.g. driving, shopping and cooking. Consequences of falls are immense in terms of suffering, loss of
independence, suffering, fear of future falls, carer burden, mortality, residential care admission and other health
care resource usage. Previous research shows that most falls occur outside due to "trips". Our trial attempts to
minimize the potential harm associated with the use of multifocal glasses.
Expected future outcomes:
Reduction in falls rate and related morbidity, resulting in reduced demand for acute, subacute and non-acute health
services, with low-cost, accessible intervention.
Name of contact: Professor Stephen Lord
Email of contact: s.lord@powmri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350903
CIA Name: A/Pr James Brock
Main RFCD: Peripheral Nervous System
Admin Inst: University of New South Wales
Start Year: 2005
End Year: 2007
Total funding: $408,000
Grant Type: NHMRC Project Grants
Title of research award: Mechanisms underlying disordered skin blood flow following nerve injury
Lay Description (from application):
Many people who recover from traumatic injury or who have chronic conditions such as diabetes or neuropathy
from exposure to a toxic chemical suffer from peripheral vascular disorders leading to poor circulation in the
extremities. These conditions are characterised by impaired wound healing, cold hands and feet and ongoing pain.
These people must face a long life with progressively increasing disability. Even normal ageing can lead to similar
problems. This project is directed at understanding the role of the nerve supply to blood vessels in the skin in
these disorders. The experiments will be conducted in skin blood vessels of rats with various forms of nerve
lesion that will mimic these conditions in patients. We will use our knowledge of the structure and behaviour of
nerve/blood vessel connections to analyse the changes in the properties of vascular smooth muscle and relate it to
the state of the innervation. Skin arteries normally receive two types of nerve - sympathetic (which release
noradrenaline) and afferent ( which release peptides) - that have opposing actions on the vessel (constriction and
dilation respectively). We hypothesize that removal of part or all of the innervation changes the contractile
mechanism of the smooth muscle in the wall of the vessel so that it becomes much more sensitive to calcium ions
and produces larger and more prolonged contractions. We will combine electrophysiology and contraction
studies with immunohistochemistry and biochemical analysis to define the relation between the nerve deficit and
the vascular responses. The aim is to identify appropriate drug targets for which local application in the affected
region can alleviate the symptoms without causing widespread side effects.
Research achievements (from final report):
Nerve injuries and neuropathies that cause loss of vascular innervation produce disordered regulation of skin
blood flow and are associated with altered skin function, including sensory disturbances and persistent skin ulcers
that are difficult to treat. In this project we have characterised the effects of surgically induced injuries to the
nerves that supply of blood vessels in skin. The findings demonstrate adaptions of nerves, rather than changes in
behavour of muscle within the artery wall, maintain neural control of blood vessels. This is surprising because
clinical assessments have used changes in responsiveness of the artery muscle to indicate denervation in dieases
such as diabetes. Deficits in the neural control of arteries only occur when greater than 50 % on the nerves are
lost. The findings should change the clinical assessment of sympathetic nerve damage is diseases such as diabetes.
Expected future outcomes:
The completed experimental work provides the groundwork for future studies investigating the changes that
underlie diabetes- and inflammation-induced changes in neural control of skin blood flow
Name of contact: James Brock
Email of contact: j.brock@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401189
CIA Name: Prof Nigel Lovell
Main RFCD: Instruments and Techniques
Admin Inst: University of New South Wales
Start Year: 2006
End Year: 2006
Total funding: $199,105
Grant Type: NHMRC Development Grants
Title of research award: Development of a wearable triaxial accelerometer with embedded algorithms to detect
and prevent falls in frail older adu
Lay Description (from application):
Not Available
Research achievements (from final report):
We developed a wireless ambulatory monitor called a 'PreventaFall' to assist in the detection, management and
assessment of falls risk in the elderly. The falls monitoring system is based on a sensor known as a triaxial
accelerometer. It can also be used to assess activity level and postural orientation. The device has an in-built
algorithm that can be used to automatically detect a fall or stumble and create a voice connection with a call
monitoring centre - thus performing the task of an advanced personal alarm system. Currently there are more than
30,000 pendant alarm systems in use in Australia and approximately eight times this number in the UK. Such
systems are simple passive devices which need to be activated by the user for an alarm to be registered. They can
play no role either in preventing falls or in assessing the likely risk of an imminent fall, or to generate an alarm
automatically should a fall occur and the user is unconscious. In contrast, this PreventaFall device has these
capabilities.
Expected future outcomes:
We are currently working to allow the PreventaFall to prompt the wearer to perform a routine set of movements.
From these movements we hope to derive indicators of stability and ambulation and thus have a device that can be
used to assess and manage falls risk, with the end aim of creating a system that effectively prevents falls.
Name of contact: Prof Nigel Lovell
Email of contact: N.Lovell@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350852
CIA Name: A/Pr Janet Taylor
Main RFCD: Motor Control
Admin Inst: University of New South Wales
Start Year: 2005
End Year: 2007
Total funding: $311,250
Grant Type: NHMRC Project Grants
Title of research award: How Changes in the Motor Cortex and Spinal Cord with Exercise Contribute to
Fatigue in Humans
Lay Description (from application):
Fatigue with exercise is a common experience in healthy people and can be a problem in many illnesses. With
fatigue people are less able to produce force with their muscles. Much of this weakness occurs because of events
in the muscles but some results from changes in the nervous system. The size of the contribution of the nervous
system to fatigue is not known for the kinds of exercise that cause fatigue in everyday life e.g. prolonged weak
contractions like holding the shopping or a plate of food, rhythmic contractions like walking or painting a wall,
and more vigorous exercise that causes changes in breathing and body temperature. The behaviour of nerve cells
in the brain and spinal cord is altered in fatigue but how and why many of these changes occur, and how they
affect the control of movements, is poorly understood. Three approaches are planned. In the first set of studies, we
will use brain and nerve stimulation to measure the impact of sustained low-level activities on people's ability to
drive their muscles fully. We will identify whether such activities, as well as increased demands on other body
systems, can cause fatigue in the nervous system. In the second set of studies, we will investigate whether changes
in the motor areas of the brain can alter peoples' performance of fatiguing motor tasks or their perception of how
much effort the tasks take. Finally, we will use stimulation of the spinal cord to work out why motor nerve cells in
the spinal cord fire more slowly with fatigue.Fatigue is an important symptom which is not confined to diseases of
any one system in the body. For example, it is a major complaint in multiple sclerosis, cardiac failure, chronic
obstructive airway disease, depression and cancer, as well as after chemotherapy, surgery, and viral illness. The
implications of better understanding of the contribution of the nervous system to fatigue range from targeting
treatments in patients to improving the performance of athletes.
Research achievements (from final report):
Fatigue with exercise is common in healthy people and is magnified in many illnesses. Some of the loss of force
in muscle fatigue is due to changes in the nervous system. We have demonstrated for the first time that processes
in the nervous system are important during the development of fatigue in submaximal contractions. In particular,
in weak sustained efforts, supraspinal fatigue can account for a half to two-thirds of the force loss. Supraspinal
fatigue develops during rhythmic arm movements as well as in static contractions and so is likely to be a factor in
all kinds of exercise. Investigation of the influence of some of the systemic effects of exercise showed that
supraspinal fatigue is exacerbated by hyperthermia with some of this due to changed muscle properties. However,
high rates of breathing had no effect on performance of fatiguing arm contractions.
In conjunction with these studies on fatigue in the nervous system, we also developed a new technique for
measuring changes in muscle behaviour during voluntary contractions.
Expected future outcomes:
Our methods allow simultaneous measurement of supraspinal fatigue, cortical behaviour and muscle fatigue to be
measured simultaneously. We expect these methods to be useful in investigating the contributors fatigue in
different patient groups.
Name of contact: Janet Taylor
Email of contact: j.taylor@powmri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568769
CIA Name: Dr Nicole Jones
Main RFCD: Pharmacology not elsewhere classified
Admin Inst: University of New South Wales
Start Year: 2009
End Year: 2012
Total funding: $293,230
Grant Type: NHMRC Project Grants
Title of research award: Hypoxia-inducible factor-1 (HIF-1): Pharmacological and molecular insights into its
role in brain protection
Lay Description (from application):
At present, there are no effective therapies for reducing brain damage which can occur after acute brain insults
including birth asphyxia. This project aims to study whether increasing a naturally occurring protective protein
(HIF) in the brain can minimize brain damage in a model of perinatal brain injury. We plan to validate HIF as a
novel therapeutic target for reduce brain injury and promote brain repair processes.
Research achievements (from final report):
Hypoxia is an important feature of many neurological conditions. While severe hypoxia causes brain cell death, it
is known that exposure to mild hypoxia can induce tolerance and protect the brain against a subsequent injury.
Key events in this protective phenomenon are regulated by the transcription factor hypoxia-inducible factor-1
(HIF-1), its regulatory enzymes (HIF-1 prolyl hydroxylases (PHDs)) and its many target genes.
- We showed that two of the PHD inhibitors tested ((DFX), and EDHB)) can protect astrocytes, via increasing
HIF-1 and VEGF and this work resulted in 1 publication (Chu et al, 2010).
- We also found that a number of PHD inhibitors tested in vivo (EDHB, DFX, CoCl2) can reduce brain tissue loss
at 5 days after HI injury .
- Studies have also determined that expression of PHD enzymes are differentially altered in response to HI injury,
and PHD3 appears to be involved with cellular injury process.
- Post injury treatment with EDHB (200mg/kg) can improve long term functional impairment up to 5 weeks after
HI injury and may also affect cell proliferation.
Expected future outcomes:
We have 1 published manuscript and a book chapter based on work generated by this grant and we have 3
additional manuscripts in preparation.
Name of contact: Nicole Jones
Email of contact: n.jones@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350825
CIA Name: Prof Simon Gandevia
Main RFCD: Sensory Systems
Admin Inst: University of New South Wales
Start Year: 2005
End Year: 2007
Total funding: $507,378
Grant Type: NHMRC Project Grants
Title of research award: Neural Mechanisms underlying Human Proprioception
Lay Description (from application):
This is a study of the senses which arise from our muscles and which tell us where our different body parts are, at
any point in time. These senses, collectively called proprioception, are also involved in the automatic, unconscious
control of our muscles. So, ultimately, they allow us to stand and to move freely with precision and confidence,
even in the dark. One of these senses, the sense of effort or of heaviness, is believed to be generated within the
brain. It intensifies when we become fatigued. These experiments will be concerned with finding out more about
how this works. We have a method that uses magnetic stimulation of the brain to change its control of our
muscles. Using it we will learn how this sense is generated. When we close our eyes and move our limbs we
realise that we know exactly where they are at any point in time. It remains uncertain exactly how this information
is generated within the nervous system. One idea, arising from some recent experiments which we want to test, is
that as we move the limb, the skin over the moving parts is stretched and stretch-sensitive nerve endings in the
skin provide us with information about the movement. Alternatively, perhaps it is the effort we exert to maintain
limb position against the force of gravity which tells us where the limb is. In another recent study we have found
that when a muscle has become painful from excessive exercise or from some local strain injury, our ability to
control the muscle and so move the limb is no longer as effective. We want to study the underlying nervous
mechanisms responsible for the changes in movement control. Are they designed to spare the muscle while it
recovers from injury? How are they brought about? All of this work is important for a better understanding of
ourselves, for a better clinical diagnosis when something goes wrong and for improved treatment of diseased or
injured muscles.
Research achievements (from final report):
Adequate proprioception is critical for the performance of all voluntary movements and postures. This grant has
revealed new aspects of this important but somewhat neglected group of sensations. A key study used paralysis
and anaesthesia of the arm and this has provided novel definitive evidence for signals related to motor commands
being used in judgement of human joint position. Evidence was provided that conditioning elbow muscles could
lead to systematic errors in position sense in the vertical plane. Loading arm muscles led to reduction in
conditioning-dependent errors. However, loading the arm did not produce extra errors for position matching in the
horizontal plane, as predicted by the motor command hypothesis. Our new view is that a forward 'internal model'
operates which compares observed and anticipated feedback signals.
In addition, cutaneous stretch receptors were shown to contribute for the first time to movement sense at the elbow
and knee. But, Pacinian receptors selectively impaired movement detection. Further work showed that pain
inputs impaired the detection of movement. These three findings reveal new avenues for study.
Expected future outcomes:
Further publications will evolve from research conducted during the grant. These will focus on novel impairments
of proprioception produced by muscle pain and muscle damage in humans.
Name of contact: Professor Simon Gandevia
Email of contact: s.gandevia@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455316
CIA Name: A/Pr Janet Taylor
Main RFCD: Central Nervous System
Admin Inst: University of New South Wales
Start Year: 2007
End Year: 2009
Total funding: $393,201
Grant Type: NHMRC Project Grants
Title of research award: Corticospinal transmission in human subjects
Lay Description (from application):
The corticospinal pathway is the major route from the brain to the spinal cord for the control of voluntary
movement in people. Little is known about how transmission through this pathway might alter with activity. It is
known that, elsewhere in the brain, connections between nerve cells can be made stronger or weaker by specific
patterns of activity and it is thought that such changes underlie learning and memory. We propose that similar
changes might happen in the spinal cord at the connection between the nerve cells which carry signals from the
brain and the nerve cells which carry the signals out to the muscle. This project will demonstrate that the
connections in the pathway from the brain to the muscle can be strengthened or weakened in a controlled way by
imposed patterns of activity. In addition, we know that after voluntary contractions, there are dramatic changes in
the way signals in this pathway are transmitted to muscles. After brief strong voluntary contractions, muscle
responses are immediately reduced. After longer contractions in which the muscles become fatigued, the reduction
is followed by an increase in responses which can last many minutes. Thus, this project will also study changes in
the pathway from the brain to the muscle after natural activity. The effects of changes induced by artificial or
natural activity on the control of voluntary movement will also be investigated. Understanding how activity
drives changes in the pathway that controls voluntary movement is important for all situations that involve
learning motor tasks. These include normal development and learning of motor skills, as well as rehabilitation
after all kinds of nerve or muscle injury. It is also important in understanding motor changes that occur when
activity is altered by disorders like spinal cord injury or stroke. Improved understanding of the processes occuring
should allow improvement in rehabilitation therapies.
Research achievements (from final report):
To deliberately move our limbs and bodies we send signals from the brain to activate nerve cells in the spinal
cord. In turn, these nerve cells signal the muscles. Our research concentrated on the connection between the
corticospinal tract, the main pathway which conveys movement signals from the brain, and the nerve cells that
convey the signal to the muscle. Our studies found that this connection is not a simple relay but can be changed
both by a person's voluntary activity and by artificial stimulation. The findings related to voluntary activity
suggest that changes at a spinal cord level influence our control of our muscles in the short-term, and in the
longer-term, the connections in the pathway from the brain to the muscles may adapt their strength and behaviour
to the way we use each of our muscles. We also developed a method which uses nerve stimulation in a precisely
timed way to modulate the strength of the connections. This demonstration of plasticity in the spinal cord in the
path that controls movement may lead to a rehabilitation technique to help strengthen connections between the
brain and the muscle when these have been reduced by injury.
Expected future outcomes:
Our work will help understand the role of the spinal cord in learning motor tasks. Further research will determine
whether our method to increase the strength of synaptic connections in the pathway between the brain and muscles
can help improve strength in patients who have incomplete spinal cord injury.
Name of contact: Dr Janet Taylor
Email of contact: j.taylor@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 571178
CIA Name: Dr Wei Du
Main RFCD: Epidemiology
Admin Inst: University of New South Wales
Start Year: 2009
End Year: 2012
Total funding: $349,407
Grant Type: International Exchange Early Career
Fellowships
Title of research award: Translation of effective interventions in injury prevention and trauma care to a Chinese
setting
Lay Description (from application):
Evidence informed injury policy is not currently well developed in China. This research project will provide
measures of the effectiveness of both a trauma care protocol in a hospital setting, and an intervention program for
novice driver education/training in China, and will therefore contribute to the building of an evidence based injury
prevention capacity in China.
Research achievements (from final report):
The project aims to address a major and growing public health problem in China, road trauma, by a partnership
between Australian experts with internationally recognized track records in road safety research and key Chinese
agencies and Chinese researchers. Road trauma is emerging as a leading cause of death, disability, and injury in
China, and this is forecast to increase, as China is under rapid motorization. Reducing road trauma, by translating
effective interventions in road trauma prevention into the current Chinese setting, where proper knowledge,
legislation, and practice are missing, is thus a high priority for global health. Specifically, this project has two key
components, i.e., 1) developing and implementing a cost-effective kindergarten based parental educational
intervention to encouraging the correct use of age appropriate child restraints for young children while travelling
in cars; and 2) developing and evaluating an on-road driver education and training program to reduce novice
driver crashes. Both programs were trialed in Beijing of China, and if successful, they could be straightforwardly
extended to other similar settings across China.
Expected future outcomes:
The compulsory use of child restraint for young child car passengers is expected to be trialed in Shanghai soon,
and nation wide legislative change as to the introduction of compulsory child restraint use is currently under
review.
Name of contact: Wei Du
Email of contact: kelvindu@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 510110
CIA Name: Prof Stephen Lord
Main RFCD: Preventive Medicine
Admin Inst: University of New South Wales
Start Year: 2008
End Year: 2010
Total funding: $564,727
Grant Type: NHMRC Project Grants
Title of research award: Impaired stepping as a risk factor for falls in older people
Lay Description (from application):
Stepping is often the last protective option to prevent a fall. This study will investigate stepping responses as a
risk factor for falls. Complementary studies of physiological and psychological contributions to stepping will also
be conducted. A path model will be used to examine the relative importance of physiological, psychological and
behvioural factors. An exercise program to imrpove stepping responses will be trialed. Findings will inform future
interventions for preventing falls.
Research achievements (from final report):
This study examined physiological and neurophyschological contributions to appropriate and impaired responses
to postural perturbations and determined the role that impaired stepping plays in predicting future falls in a large
cohort of older adults. We found older adults stepped earlier and with reduced force, compared to young adults.
Force thresholds for stepping were related to balance, strength and reaction time performance and were predictive
of future falls in older adults. Those who responded with multiple steps almost twice as likely to fall in the future
12 months than those who responded with a single step. A secondary study was performed to investigate the role
of a cognitive dual-task on balance responses. Participants whose stepping thresholds were reduced in the dualtask condition were over 4 times more likely to have an injurious fall in the following 12 months than those who
were unaffected. These studies have provided insight into how older adults respond to unexpected balance
responses, as well as the relationships with physiological and cognitive functioning and future falls. Findings will
inform future intervention studies to prevent falls in older people.
Expected future outcomes:
Findings highlight important physiological and psychological factors that underpin protective stepping
performance, which will directly inform exercise programs to facilitate appropriate stepping in prevent falls in
older people. Findings also indicate that a simple unexpected backward perturbation assessment may prove useful
in clinical practice to enhance falls risk assessment.
Name of contact: Professor Stephen Lord
Email of contact: s.lord@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1000674
CIA Name: A/Pr Leslie Foster
Main RFCD: Medical Devices
Admin Inst: University of New South Wales
Start Year: 2010
End Year: 2011
Total funding: $213,125
Grant Type: NHMRC Development Grants
Title of research award: Application of Sutureless Technology 'SurgiLux' for Dura Mater Repair: A Proof of
Concept Study
Lay Description (from application):
A unique technology that combines biomaterials and lasers to effectively close and seal wounds could replace
sutures in delicate surgery close to the brain. Wound closure in the cranium is still reliant upon sutures or 'stitches'
and these have complications; a major one being leakage of cerebro spinal fluid (CSF). The application of
'SurgiLux' technology will both close and seal these wounds quickly and easily, with significant health and
economic benefits.
Research achievements (from final report):
Current procedures for the closure of the dura mater remain reliant upon sutures. Leakage of cerebrospinal fluid
(CSF) is a common and expensive complication of certain operations that often requires inclusion of prophylactic
preoperative lumbar drains. CSF leakage is associated with high additional costs while research has shown that a
significant reduction of these costs can be achieved through the use of sealants. However, despite considerable
research in the area, commercial adhesives and sealants are inappropriate and unused. Thus, there is an identified
health requirement for a surgical device to effectively close and seal the dura mater after surgery. Thin films of
'SurgiLux' were found to readily seal incisions in the dura mater and prevent leakage. Irradiation of the SurgiLux
with a near-infrared laser effectively bound the film to the tissue while showing no thermal damage. The
procedure of cutting SurgiLux to size and its irradiation were found to be up to seven times faster than the current
procedure using sutures. However, feedback from surgeons and research results have highlighted the requirement
for the development of a pulse laser system to reproduce these results using current surgical procedures.
Expected future outcomes:
results have highlighted the requirement for the development of a pulse laser system to reproduce these results
using current surgical procedures.
Name of contact: A/Prof. L.J.R. Foster
Email of contact: J.Foster@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510201
CIA Name: Prof James Colebatch
Main RFCD: Central Nervous System
Admin Inst: University of New South Wales
Start Year: 2008
End Year: 2011
Total funding: $225,357
Grant Type: NHMRC Project Grants
Title of research award: Vestibular reflexes evoked by brief lateral head acclerations: a new measure of
utricular function
Lay Description (from application):
The vestibular (balance) organs are difficult to investigate as they lie deep within bone. Disease of these organs
may cause severe vertigo, imbalance and difficulty with vision. This project attempts to build on earlier
developments in my laboratory and thereby improve understanding and diagnosis of these disorders. This grant
relates to a new form of stimulation which may allow simple assessment of an important part of the vestibular
apapratus, the utricle.
Research achievements (from final report):
This series of experiments has extended our knowledge of the function of the vestibular apparatus (inner ear
balance organs), particularly the otolith organs, in both normal subjects and in disease. Achievements include
defining the properties of short latency vestibular reflexes to the eyes and neck evoked by brief lateral
accelerations and the evidence provided that these are likely to be mediated by the utricle (one of two otolith
organs). In addition, evidence has been found for differing resonant frequencies of the two otolith organs through
the tuning properties shown for neck reflexes (cVEMPs) and eye reflexes (oVEMPs). This proposal, if
substantiated, would be an important new finding for human vestibular physiology. We have shown the changes
occurring in short latency VEMPs in three diseases: superior canal dehiscence (in which VEMPs are a particularly
useful diagnostic technique), internuclear ophthalmoplegia (often seen in Multiple Sclerosis) and vestibular
neuritis (inflammation). These techniques have become internationally recognised as an important new type of
vestibular investigation and our current results extend these applications and provide important new insights into
vestibular otolith function in normal humans.
Expected future outcomes:
We expect these findings will prompt further application of VEMPs in diagnosis and in understanding a variety of
diseases affecting the labyrinth (inner ear) and its central pathways.
Name of contact: Prof Jg Colebatch
Email of contact: j.colebatch@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350840
Start Year: 2005
CIA Name: Prof Ann Williamson
End Year: 2009
Main RFCD: Environmental and Occupational Health and Safety
Total funding: $670,500
Admin Inst: University of New South Wales
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The overall aim of my research is to improve our understanding of the causes and effects of fatigue on
performance and safety and to develop better ways of overcoming the effects of fatigue especially in transport.
Over the past five years my research has clarified the relative effects of sleep deprivation and time of day on
performance. This research showed that night work can be performed safely and without error if the person is
properly rested whereas long work hours that extend into the midnight to dawn, circadian trough period should be
avoided as this combination of factors has clear adverse effects on performance. My research on fatigue and the
road transport industry showed that short haul light trucking produced as much fatigue for drivers as long haul
heavy trucking even though the causes were very different. Short haul drivers do shorter, daytime shifts, but work
under very high pressure, but long haul drivers do extremely long hours and work at any time across the 24 hour
clock. My research on long haul trucking also showed that drivers who are paid on a productivity-based payment
system were twice as likely to experience fatigue and three times more likely to resort to stimulant drugs as
drivers paid a salary or by the hour.
Expected future outcomes:
This research has clear policy impact and I am working with regulators and industry in the transport industry on
changing work practices with respect to fatigue risk management.
Name of contact: Ann Williamson
Email of contact: a.williamson@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209633
CIA Name: Prof Stephen Lord
Main RFCD: Geriatrics and Gerontology
Admin Inst: University of New South Wales
Start Year: 2002
End Year: 2006
Total funding: $610,500
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Reseach Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
My Fellowship ran in concert with the POPI Prevention of Injuries in Older People Partnership Grant
(www.powmri.edu.au/POPI) of which I was the Director. This major grant provided the foundation for my
research into falls injuries in older people. Major outcomes from this research include:
o
Two studies that elucidated the mechanisms underlying impaired voluntary stepping in older people.
o
A large RCT (n= 3,995) that examined interventions for preventing falls in older people when in hospital.
o Six RCTs that examined strategies for preventing falls in at-risk groups.
o
Three studies which provided objective findings about shoe features that maximise balance.
o The development of both simple and sophisticated fall risk assessment tools.
o
A large prospective study that identified cognitive and physiological risk factors for unsafe driving.
Falls and fall related injury in older people continue to challenge health and social care systems on a worldwide
basis. The approaching impact of fall related injury in Australia has been characterized as a potential future
"epidemic" creating resource demands that will be difficult to meet. The research undertaken enhances our
understanding of strategies to prevent falls, so as to address this important issue.
Expected future outcomes:
As a SPRF I am continuing research in the areas of falls risk factor identification and falls prevention strategies.
Work underway is examining falls risk factors in people with cognitive impairments and Parkinson's disease; the
development of fall risk screening tools and interventions for preventing falls in at-risk groups.
Name of contact: Stephen Lord
Email of contact: s.lord@powmri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157063
CIA Name: Prof Marcus Stoodley
Main RFCD: Neurology and Neuromuscular Diseases
Admin Inst: University of New South Wales
Start Year: 2001
End Year: 2003
Total funding: $344,442
Grant Type: NHMRC Project Grants
Title of research award: Investigations of cerebrospinal fluid flow in extracanalicular syringomyelia.
Lay Description (from application):
Cysts in the spinal cord (syringomyelia) develop in children and young adults with congenital spinal cord
abnormalities such as spina bifida, and in people of all ages after spinal cord injury or meningitis. Syringomyelia
causes pain and paralysis that usually does not improve even with treatment. The current lack of knowledge about
the mechanism of spinal cord cyst formation and enlargement is preventing the development of effective therapy.
We have previously shown that some types of spinal cord cysts enlarge by the normal fluid surrounding the spinal
cord being pumped around small arteries into the centre of the spinal cord. The mechanism of enlargement of
post-traumatic spinal cord cysts remains unknown, and this debilitating type of syringomyelia remains difficult to
treat. Our hypothesis is that post-traumatic spinal cord cysts also enlarge by fluid being pumped into them around
small arteries. A further hypothesis is that reductions of arterial pulsations and of the pressure in the fluid
surrounding the spinal cord will prevent or inhibit cyst enlargement. These hypotheses will be tested by
examining fluid flow in models of post-traumatic syringomyelia in rats and sheep. We have established a model
of post-traumatic syringomyelia in rats and the first phase of the project will be to refine and characterize this
model and to reproduce it in sheep. The second phase will be to determine whether these cysts enlarge by a flow
of fluid around small arteries that is driven by arterial pulsations, as they do in other types of syringomyelia. The
final phase will be to determine whether reducing the pressure in the fluid around the spinal cord prevents cyst
enlargement. Confirmation that these techniques prevent cyst enlargement would open up new possibilities for
the treatment of human syringomyelia.
Research achievements (from final report):
This project investigating aspects of fluid flow in extracanalicular syringomyelia was completed in 2003. The
first phase involved refining the rodent model of post-traumatic syringomyelia and this was successfully
completed, with a technique developed that produces syrinxes in 100% of animals. Development of the sheep
model proved more complex, but a success rate of syrinx production of over 75% was achieved. Fluid flow
studies demonstrated that CSF enters extracanalicular syringes via perivascular spaces and also (to a lesser extent)
by a direct transparenchymal route. Flow into perivascular spaces is greater at levels adjacent to the arachnoiditis
than at other levels in the cord. Shunting CSF from the spinal subarachnoid space to the peritoneum decreases
perivascular flow in the brain, but does not affect the increased flow at the level of the syrinx. Dr Andrew
Brodbelt (a British neurosurgical trainee who interrupted his clinical training specifically to work on this project)
was awarded the prestigious Tow Prize at the Prince of Wales Hospital for the presentation of this research work,
and his PhD will be awarded in May 2004. This research has contributed to our understanding of post-traumatic
syringomyelia, which will lead to improvements in management of the condition.
Expected future outcomes:
This research has contributed to our understanding of post-traumatic syringomyelia, which will lead to
improvements in management of the condition. We are continuing our research, focussing on the forces that drive
fluid from the subarachnoid space into the spinal cord.
Name of contact: Marcus Stoodley
Email of contact: m.stoodley@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400918
CIA Name: Prof Elspeth McLachlan
Main RFCD: Neurosciences not elsewhere classified
Admin Inst: University of New South Wales
Start Year: 2006
End Year: 2008
Total funding: $457,268
Grant Type: NHMRC Project Grants
Title of research award: Delayed neuronal death after peripheral nerve and spinal cord injury
Lay Description (from application):
After injury to the nervous system, even under optimal conditions for regeneration of broken nerve processes
(axons), there is little chance of normal function being restored because few regrowing axons will find appropriate
cells to connect with. The time taken for many regrowing axons to reach their targets can be so long that both the
axons and their targets lose the ability to recognize each other. Equally importantly, some damaged nerve cells die
over the months that follow an injury. This slow loss of nerve cells can lead to progressive and ongoing
deterioration. Given recent advances in our understanding of how to improve axon regeneration, the degree of
functional recovery could be disappointing unless we know more about how to prevent these neurones from
dying. This project will use rats as experimental animals to try to understand which types of nerve cells are likely
to die or survive after injury to peripheral nerve trunks or to the spinal cord. We will investigate two regions of
the nervous system that are commonly involved in injuries in people. After injuries to limb nerves, people lose
sensation and movement and can unpredictably develop chronic conditions such as neuropathic pain (unrelated to
the damage and often occurring spontaneously) as well as poor blood flow and wound healing in the hands/feet.
After most injuries to the spinal cord, the lower part of the cord beyond the injury (in particular the lumbosacral
cord controlling hindlimb movement and sensation and the function of bladder, bowel and sexual organs) is often
disconnected from the brain leading to paralysis and disrupted control of pelvic organ function. We will identify
and study specific populations of nerve cells with sensory (mainly pain-sensing) functions and four identified
groups of nerve cells in the lumbosacral cord that project to the brain. Once we know which nerve cells do not
survive, we will search for the likely causes of their death and ways to prevent it.
Research achievements (from final report):
We have identified in experimental animals that at least half of the nerve cells in the spinal cord below a spinal
cord injury that normally project to the brain and upper parts of the spinal cord die within 2 months after their long
ascending processes are broken. Our analysis suggests that particular pathways are more vulnerable than others.
We have some evidence suggesting that the late influx of T-lymphocytes into the cord may be involved in this
type of cell death.
Studies on animals with peripheral nerve injuries have indicated that the small sensory nerve cells that innervate
the skin are particularly vulnerable and die over the months that follow the lesion. These nerve cells are
responsible for sensing painful stimuli. To try to identify the factors responsible for the death of the injured nerve
cells, we have labelled them at the time of injury and have followed their survival over time. By analysing the
effects of a series of distinct types of lesion, we plan to find out whether or not the invasion of immune cells
around the cell bodies of these cells is protective or destructive. We have found increasing numbers of Tlymphocytes around the sensory nerve cells over the period of their death. We hope to determine the nature of
this relationship between the immune system and damaged nerve pathways.
Expected future outcomes:
If these findings apply in humans, they imply that the outcome of regenerative strategies after spinal cord injury
may not be successful if the time to reach the lower parts of the cord is prolonged. The loss of sensory nerve cells
that normally detect damaging stimuli may underlie neuropathic pain. Ways to protect against degeneration of
specific groups of nerve cells will need to be developed.
Name of contact: Elspeth McLachlan
Email of contact: e.mclachlan@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400947
CIA Name: Prof David Tracey
Main RFCD: Sensory Systems
Admin Inst: University of New South Wales
Start Year: 2006
End Year: 2008
Total funding: $262,959
Grant Type: NHMRC Project Grants
Title of research award: Does the complement system contribute to neuropathic pain?
Lay Description (from application):
Nerve injury often results in increased sensitivity to painful stimuli and the perception of innocuous stimuli as
painful; it may also result in spontaneous pain. These disorders of pain sensation due to nerve injury are common,
debilitating and difficult to treat. They are symptoms of neuropathic pain. Pain is normally signalled to the brain
by sensory nerve cells called nociceptors. Following nerve injury, nociceptors are sensitised by chemicals released
by inflammatory cells. This contributes to neuropathic pain. We have evidence that inflammatory responses
play a key role in initiating neuropathic pain. Other evidence suggests that the immune system contributes to
neurological diseases and accompanying pain (e.g. Guillain-Barr syndrome and multiple sclerosis). We plan to
test the idea that a component of the immune system known as the complement pathway contributes to the
development of neuropathic pain following peripheral nerve injury. The outcome of this work will be a better
understanding of the way in which nerve injury leads to chronic disorders of pain, including increased sensitivity
to painful stimuli. This will lead in turn to the development of more effective treatments for neuropathic pain.
Research achievements (from final report):
Neuropathic pain is a persistent pain often caused by nerve injury. Such pain is a debilitating condition that lacks
effective treatment and represents a significant health problem because it interferes with daily activities leading to
reduction in quality of life, reduced productivity and significant health care costs. Recently it has become clear
that interactions between the nervous system and the immune system play an important role in neuropathic pain.
In this project, we demonstrated that peripheral nerve injury induces C3 deposition and activates the complement
system. This contributes in turn to leukocyte recruitment and neuropathic pain. Complement inhibition markedly
suppresses C3 deposition and lymphocyte and macrophage recruitment to the injured nerve and produces
significant alleviation of neuropathic pain. This research benefits the scientific community and the general
population. This study significantly enhances our understanding of the immune mechanisms underlying
neuropathic pain and offers a new approach to therapeutic intervention by means of complement inhibition.
Findings have already been reported in international peer-reviewed journals and at professional meetings in
Australia and overseas, and are expected to attract considerable international attention and thereby raise the profile
of Australian science in the field of neuroscience.
Expected future outcomes:
Complement inhibitors including soluble complement receptor 1 (sCR1) have shown efficacy in controlling the
pathologic consequences of several disorders (e.g. reperfusion injury, rheumatoid arthritis, multiple sclerosis,
Alzheimer's disease and stroke) and our data support complement inhibition as a potential therapeutic approach
for neuropathic pain.
Name of contact: Gila Moalem-Taylor
Email of contact: gila@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209583
CIA Name: Prof Phil Waite
Main RFCD: Central Nervous System
Admin Inst: University of New South Wales
Start Year: 2002
End Year: 2004
Total funding: $255,990
Grant Type: NHMRC Project Grants
Title of research award: Repairing the injured spinal cord: potential for human olfactory ensheathing cells
Lay Description (from application):
Spinal cord injury is a major cause of morbidity, particularly among young people involved in road accidents and
sports injuries. Finding ways to treat paraplegia is a major goal of neuroscience research. Recently, there has been
considerable interest in a special cell found in the olfactory system, the ensheathing cell, which has been found to
support regeneration in the spinal cord. Our laboratory has shown that injection of these ensheathing cells into the
completely cut spinal cord of adult rats can lead to limited functional recovery of hindlimb movement. We used
peripheral ensheathing cells because, in humans, such cells can be obtained relatively easily and they reduce
problems of tissue rejection. We found that peripheral cells are as effective as previous reports using central
ensheathing cells. Our overall aim now is to advance towards the use of olfactory cells in human spinal cord
injury, by trialing 3 procedures of clinical relevance: a) to test whether human olfactory cells can also support
functional recovery in rats. Human cells can be obtained from the nose by a simple biopsy procedure. If they able
to support regeneration, this will open the way for their use in autografts in human paraplegia. b) to delay the time
when the olfactory cells are applied to the injured cord. At present, neurosurgeons are not be willing to treat the
cord immediately after the injury, because of the risk of causing further damage. This trial is designed to test
whether delayed treatment is still effective. c) to test the effectiveness of the cells after bruising, rather than
cutting, the cord. Bruising is a more common type of injury in people, hence it is necessary to know how these
cells respond to this type of damage. These procedures have been chosen to move our basic research closer to
clinical application. Although treatment in humans is still a long way off, these basic studies are essential if
conditions like paraplegia are eventually to become treatable.
Research achievements (from final report):
Spinal cord injury continues to be a major cause of morbidity, particularly among young people involved in road
accidents and sports injuries. Finding ways to treat paraplegia and quadriplegia is a major goal of neuroscience
research. Studies around the world have reported encouraging improvements in function in animals models of
spinal cord injury after transplants of a special support cell, the olfactory ensheathing cell (OECs). Most of these
studies have used OECs from rats and reported improvements in locomotion when transplanted into injured rat
spinal cord.
We have extended the basic data on the potential of OECs for clinical application in patients by:
an OECs in different types of spinal
cord injuries (transections, contusions, dislocations) and different functional problems (locomotion and
cardiovascular dysfunction).
a similar manner to that
seen with rat OECs. They also cease proliferating, hence eliminating complications from abnormal growths.
These outcomes are significant in that they provide essential baseline data on the properties and survival of human
OECs. Such baseline data is a critical preliminary for the use of OECs in patients after spinal cord injuries.
Expected future outcomes:
A safety and feasibility trial of human OECs in 3 spinal patients is already underway with one of our CIs (A, M-S)
in Brisbane. Once long term safety and feasibility of these transplants can be assured, the way will be open for
clinical trials to test efficacy in spinal patients.
Name of contact: Prof Phil Waite
Email of contact: P.Waite@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568702
CIA Name: A/Pr Janet Taylor
Main RFCD: Motor Control
Admin Inst: University of New South Wales
Start Year: 2009
End Year: 2011
Total funding: $331,390
Grant Type: NHMRC Project Grants
Title of research award: Neural aspects of human muscle fatigue
Lay Description (from application):
Muscle fatigue is common after exercise in healthy people. In many tasks, some muscles become more fatigued
than others. Thus, the nervous system must often coordinate fatigued muscles (which produce less force) with
unfatigued muscles. We will investigate how fatigue of one muscle alters the way the brain controls other muscles
that are engaged in the same task or in unrelated tasks. This will aid understanding of the failures of coordination
that lead to poor performance and injury.
Research achievements (from final report):
Fatigue produced by exercise involves changes in muscle itself but also in the nervous system at spinal and
cortical levels. The "central" contribution to fatigue is substantial and is particularly prominent during sustained
weak contractions. Studies in this project developed a new way to examine the behaviour of the motor nerve cells
in the human spinal cord while participants perform fatiguing muscle contractions. This technique showed that the
motor nerve cells become harder to activate with fatigue and that this likely depends on repetitive activity of the
cells. This suggests that mechanisms at a spinal level contribute to fatigue with exercise, whereas testing of the
brain region that controls movement did not show changes that would lead to reduced output. Other studies
examined the contribution of sensory feedback from the muscle on people's ability to drive the muscles
maximally. Contrary to expectations, muscle pain produced experimentally was found to have surprisingly little
effect on the ability of people to produce muscle force. However, sensory feedback related to fatigue did reduce
drive to the muscle, and this occurred whether the feedback came from the tested muscle or a different muscle in
the limb. These results suggest that sensory feedback related to metabolites produced by muscle work contributes
more generally to central fatigue and that the pathway conveying muscle pain may differ from that conveying
fatigue sensations.
Expected future outcomes:
Understanding the specific mechanisms which lead to fatigue with exercise is important in directing interventions
for patients who suffer excessive fatigue in performing the tasks of daily life (e.g. after stroke or cancer), as well
as directing exercise for fitness in the general population and maximising athletic performance.
Name of contact: Janet Taylor
Email of contact: j.taylor@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401102
CIA Name: Prof George Paxinos
Main RFCD: Central Nervous System
Admin Inst: University of New South Wales
Start Year: 2006
End Year: 2008
Total funding: $441,750
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Studies of the brain have the allure of discovering the cause and treatment of disorders such as schizophrenia,
depression and Alzheimer's disease. The aim of the fellowship was to provide the basic maps of the normal
human brain and spinal chord, and to establish the homologies, correspondencies, between the brains of humans
and experimental animals.
The Atlas of the Human Brain, 3rd Edition, was published in 2008 (Mai, Paxinos and Voss). This work is the
most accurate atlas of the human brain available and is now used by stereotaxic neurosurgeons when they want to
accurately target small structures deep in the brain. The atlas is also used to interpret the images in the clinic, and
to identify areas activated in functional MRI experimental studies.
Under the present fellowship, I completed work started earlier: on the atlas of the avian brain (The Chick Brain in
Stereotaxic Coordinates) and the atlas of the developing mouse brain (Atlas of the Developing Mouse Brain). In
the Chick Brain Atlas we identified 180 areas that were either unknown to science or were not known to be
present in the bird (but were known to be present in mammals). I also did most of the work on our spinal cord
atlas.
The above atlases permit scientists to navigate seamlessly between the brains of humans and experimental
animals, to test hypotheses inspired by human considerations. I also published studies on the human
hypothalamus and autonomic control areas, as well as the echidna brain.
Expected future outcomes:
The maps that have been constructed in my laboratory are used internationally to map the brain and its functions.
Most scientists studying the relationship between brain and disease either in humans or experimental animal
models use these maps.
Name of contact: George Paxinos
Email of contact: g.paxinos@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568700
CIA Name: Prof Simon Gandevia
Main RFCD: Neurosciences not elsewhere classified
Admin Inst: University of New South Wales
Start Year: 2009
End Year: 2011
Total funding: $475,152
Grant Type: NHMRC Project Grants
Title of research award: NOVEL CENTRAL MECHANISMS IN HUMAN PROPRIOCEPTION
Lay Description (from application):
Proprioception is how we sense the position of our joints, the movements of our joints, and the forces generated
by our muscles. Disturbances of proprioception can cause major disruption of all movements and postures. We
will undertake novel studies of how signals generated in the brain which command our movements contribute to
all key aspects of proprioception. Finally we will unravel how the brain builds up the overall 'scheme' of our body
which we need to make any accurate movement.
Research achievements (from final report):
The proprioceptive senses are critical for the performance of volitional tasks. These sensations must function
properly to allow normal control of movements and postures. Overall we aimed to determine novel neural
mechanisms underlying proprioception as this will provide insight into movement execution and its clinical
disturbances. A key feature of the first two aims of the grant was to assess the role of centrally generated
command signals in specific component sensations of human proprioception. Such signals are known to
contribute to force sensation but their role in other components in controversial.
We have shown using local paralysis with curare-like compound that motor command signals bias the sense of
joint position when the usual afferent proprioceptive signals are intact. This proprioceptive effect was graded with
the level of motor command. Other data also supported this view. We have determined that signals of command
also generate sensations of movement using ischaemic anaesthesia and paralysis to produce a phantom hand.
We examined the illusory overestimation of force that occurs when it is generated passively on the skin compared
with when it is generated actively. Our work suggests that this force overestimation may have an alternative
explanation to the conventional one (based on a simple 'cancellation' model).
To understand the body image, we studied experimental 'phantoms' produced by ischaemia. We have shown that
there is not a default position of a phantom arm. Further studies are underway.
Expected future outcomes:
This project has opened the way for new work on the lilnk between the 'body image' and proprioception. The link
is crucial for all our voluntary movements.
Name of contact:
Professor Simon Gandevia
Email of contact: s.gandevia@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510326
CIA Name: Prof Skye McDonald
Main RFCD: Central Nervous System
Admin Inst: University of New South Wales
Start Year: 2008
End Year: 2011
Total funding: $338,422
Grant Type: NHMRC Project Grants
Title of research award: Reinstating emotion perception after brain damage: An experimental approach
Lay Description (from application):
Many people with traumatic brain injury (TBI) cannot recognise emotions in others. This disrupts social
behaviour leading to isolation and unemployment. In this project we determine whether: (1) selectively attending
to a person's expression improves empathy and emotion recognition; (2) whether mimicking an expression
improves recognition of the emotion and; (3) whether poor recognition of emotional tone of voice (prosody) and
audiovisual displays is improved by focusing on voice or face alone.
Research achievements (from final report):
Being able to understand emotional expressions is critical to social competence. We read the emotions of others
in order to respond to them and to monitor their reactions to us. For many people with severe traumatic brain
injuries (TBI) this capacity is lost. The aim of this project was to examine several theoretically motivated
strategies to improve emotion perception deficits after TBI. We looked at whether poor recognition of emotional
expression is related to a failure to mimic that expression and conversely, whether mimicking can improve
accuracy. We found that people with TBI do fail to mimic but curiously, this is not related to emotional accuracy
although it is related to low self-report lowered empathy. Clearly mimicry does play a communicative role that is
lost post TBI although its exact role remains uncertain. We also examined whether focusing on emotion in voice
(and not the words) increases accuracy. We found that it did not - suggesting that people with TBI are mainly
having trouble recognising tone of voice per se so that is where remediation needs to focus. These results provide
important information to guide remediation efforts for emotion perception deficits. The finding of impaired
mimicry was dramatic. It suggests a basic deficit in affective responses that might underpin, not only social
responsiveness, but also emotion regulation. Emotion regulation is also commonly disordered after TBI but, to
date, very difficult to quantify. Our findings are thus relevant to both emotiion perception and emotion regulation.
Expected future outcomes:
The results of this research will be used to guide the development of better remediation for emotion perception
and emotion regulation after TBI. This will greatly improve their social skills and psychosocial function and lead
to greater opportunities and quality of life
Name of contact: Skye Mcdonald
Email of contact: s.mcdonald@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510222
Start Year: 2008
CIA Name: Prof Skye McDonald
End Year: 2011
Main RFCD: Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)
Total funding: $500,938
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Title of research award: Which treatment works? New approaches to treating emotion perception deficits after
brain injury
Lay Description (from application):
Many people with traumatic brain injury (TBI) cannot recognise emotions in others. This makes appropriate
social behaviour impossible and leads to isolation and unemployment. In this project we compare training that
minimises errors (errorless learning) versus training that provides strategies for recognising emotions while
allowing errors to occur. Adults with severe TBI will be allocated to one of the two treatments, a social nontherapeutic group or to deferred treatment (waitlist control).
Research achievements (from final report):
Being able to understand emotional expressions is critical to social competence. We read the emotions of others
in order to respond to them and to monitor their reactions to us. For many people with severe traumatic brain
injuries (TBI) this capacity is lost. This project evaluated treatment approaches to improving emotion processes in
people with TBI, focusing on emotion perception and decision making. In this study we had several major
acheivements:
We compared the efficacy of "errorless learning" where participants are prevented from making mistakes to "selfinstructional" training wherein participants are encouraged to develop strategies for themselves in several
treatment studies.
We developed a professional quality emotion remediation kit distributed through ASSBI Resources
We examined whether alexithymia (poor self awareness of emotions), disorders of emotion regulation, poor social
decision making and insensitivity to ostracism were also related to poor emotion perception. This helps us better
understand what causes poor emotion perception to refine targets for remediation. We experimentally manipulated
attention as another potential remediation technique . We also examined emotion perception in both normal
adolescents and those with TBI .
The outcomes for people with TBI will be practical and far-reaching, including:
- Improving their ability to read and respond to the mood of others;
- Increase their social skills and social opportunities; and
- Lead to a better quality of life for them, their families and the broader community.
Expected future outcomes:
It is expected that the results of this research will lead to significant improvements in the quality of life for people
with TBI. Specifically, improvements in their ability to read and respond to the moods of others and their social
skills and opportunities.
Name of contact: Professor Skye Mcdonald
Email of contact: s.mcdonald@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400941
CIA Name: Prof Stephen Lord
Main RFCD: Geriatrics and Gerontology
Admin Inst: University of New South Wales
Start Year: 2006
End Year: 2008
Total funding: $355,878
Grant Type: NHMRC Project Grants
Title of research award: Understanding fear of falling and risk taking in older people
Lay Description (from application):
Fear of falling is a very significant issue for many older people. Estimates of the prevalence of fear of falling in
older community-dwelling people range from 29 to 92% in those who have suffered previous falls, and 12 to 65%
in those have not. Fear of falling can lead to restriction and curtailment of activity, reduced quality of life, anxiety,
depression and social isolation. To date, all studies addressing fear of falling have simply considered no fear to be
"good" and presence of fear to be "bad", and have not attempted to assess whether this fear is rational or irrational
in relation to actual balance abilities or physical functioning. In this study, we aim to find out which
psychological, physical, health and lifestyle factors distinguish between older people with and without an
irrational fear of falling based on their actual physical falling risk. We also wish to understand the role that fear of
falling and other psychological factors (anxiety, depression and avoidance) play in causing older people to fall;
and to measure how falls can lead to increased fear of falling, anxiety and depression and reduced physical
functioning. The complex nature of psychological risk factors of falling and the limited background information
on this subject, hampers its integration in falls prevention programs. Although there is growing awareness of this
problem among health care providers, additional research is needed about why older people develop a fear of
falling in order to fully understand fear of falling and to tailor specific intervention and prevention strategies.
Research achievements (from final report):
To date, all studies addressing falls efficacy have simply considered high falls efficacy to be "good" and low falls
efficacy to be "bad", and none have attempted to categorise people in relation to their actual balance abilities or
physical functioning. This is vital as it has important implications for understanding falls efficacy and developing
appropriate intervention strategies.
In this study 500 community-dwelling older people (age: 70+) were assessed. At baseline, participants completed
assessments of fear of falling, physical functioning, activity levels, depression, anxiety, health status, risk-taking
behaviours and neuropsychological performance. Participants were followed up monthly for falls and threemonthly for fear of falling over a one-year period, with a final physical reassessment at 12 months.
For statistical purposes participants were categorised in relation to how well their perceived fall risk (i.e. fear of
falling) matched their actual fall risk (based on physical tests). This resulted in four groups: adaptive, phobic, risktaking and vigorous.
The findings indicate that an excessive concern about falling increases the risk of falls. This elevated concern
appears to be related to anxiety, depression and reduced neuropsychological functioning. On the other hand, an
underestimation of concern does not appear to increase the risk of falls. Having a low concern of falling and a
positive outlook on life, irrespective of physical fall risk, appears not to lead to excessive risk taking and may
promote an active and healthy lifestyle.
Expected future outcomes:
We hope to develop an explanatory model of the association between fear and falls, in order to provide a solid
foundation from which treatment providers can put in place, safe, appropriate and effective interventions.
Name of contact: Stephen R Lord
Email of contact: S.Lord@powmri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 222751
CIA Name: Prof Elspeth McLachlan
Main RFCD: Neurosciences not elsewhere classified
Admin Inst: University of New South Wales
Start Year: 2003
End Year: 2005
Total funding: $378,300
Grant Type: NHMRC Project Grants
Title of research award: IMMUNE-MEDIATED INFLAMMATION IN DORSAL ROOT GANGLIA AFTER
PERIPHERAL NERVE INJURY AND IN SENSORY NEUROPATHIES
Lay Description (from application):
Damage to the nervous system can occur because of accidental or iatrogenic trauma, toxins, infection, metabolic
disorders, and even normal ageing. The consequences can outweigh the direct effects of the injury. Almost all
injury to the nervous system results in loss of nerve cells and consequently modified sensation and movement.
Nerve damage may also be followed by sensory disturbances, ranging from tingling, numbness and abnormal
temperature sensations to spontaneous pain, allodynia (painful sensations from light touch) or hyperalgesia
(increased sensitivity to a damaging stimulus). Some of these symptoms are encountered in older people as they
lose sensory neurones. The problems are chronic and most are intractable to drugs. This project will clarify how
immune-mediated inflammation of dorsal root (sensory) ganglia (DRGs) contributes to these sequelae. Even the
simplest form of neural damage following peripheral nerve injury can produce changes in regions of the nervous
system far from the parts directly involved in the injury. Our recent work has described for the first time the
involvement of the immune system in triggering changes in DRGs following transection of a distant peripheral
nerve in rats. T-cell activation leads to invasion of macrophages and production of proinflammatory cytokines.
These substances can activate sensory neurones and may be responsible for progressive neuronal death. Thus we
have established a simple system in which we can evaluate the influx of T-cells and macrophages of different
kinds into DRGs after injury and other insults. We intend to use this to define the sequence of cellular events
involved in recruitment of immune cells and compare it with other experimental interventions known to produce a
neuroimmune response in this system. This will identify whether the DRG is a special site for neuroimmune
interactions and so should be a target for therapy.
Research achievements (from final report):
This project has advanced our knowledge about the body's response to damage of the peripheral nervous system.
Following injury of a major nerve trunk, usually in a limb, abnormal activity develops in sensory pathways which
can progress to chronic (neuropathic) pain through mechanisms that are not understood. Our experiments have
revealed details of the factors that determine how transection of the axons (processes) of sensory nerve cells leads
to inflammation around their cell bodies in sensory ganglia. We are trying to clarify whether the role of the
immune system is destructive or protective. We have characterized the inflammatory process. Inflammatory cells
release of substances that raise the excitability of sensory nerve cells and may cause them to fire abnormally. We
have also identified that some small sensory nerve cells of the type that normally signal painful stimuli die after
nerve injury more easily if they are surrounded by other damaged nerve cells, and that inflammatory cells are
involved in this process. The results are relevant not only to nerve injury and neuropathies but also for other
neurodegenerative disorders where axonal destruction leads to death of the damaged neurones weeks to months
later. For example, spinal cord injury may be followed by continuing loss of function over many years.
Understanding the contribution of inflammatory processes to abnormal activity and neuronal death will enable the
underlying mechanisms to be targetted and the causes of chronic pain and functional loss after damage to the
nervous system to be removed.
Expected future outcomes:
Many of our experiments are still being analysed and the results will be prepared for publication over the next few
months. These will describe the effects of a previous injury, how axonal injury signals to the immune system and
the effects of different injuries on the pattern of neuroinflammation.
Name of contact: Elspeth McLachlan
Email of contact: e.mclachlan@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568626
CIA Name: A/Pr Richard Fitzpatrick
Main RFCD: Motor Control
Admin Inst: University of New South Wales
Start Year: 2009
End Year: 2011
Total funding: $304,099
Grant Type: NHMRC Project Grants
Title of research award: Neurophysiology of human posture and balance
Lay Description (from application):
Whether holding the arm still or standing, the brain uses a silent proprioceptive sense that unconsciously detects
and controls our movements. Key sensory receptors for this sense are located within the muscles that are also
contracting. This is a project to discover how proprioception is affected by muscle contraction and how this affects
postural control. This will improve the management of many common disorders that affect movement and
balance.
Research achievements (from final report):
We have shown how muscle activation both enhances and diminishing proprioceptive sensibility, and a
corresponding effect that muscle weakness impairs sensory signals that arise from muscles making relatively
weaker older adults have worse postural control. A major study has shown that the sense of muscle force arises
through a return signal from muscles rather than from within the brain, as current theories propose. By studying
subjects with a rare sensory loss, it was shown that a central effort mechanism exists and its gain was measured.
However, by fatiguing muscles differently in normal subjects, evidence is provided that a peripheral signal
dominates this sense. By paralysing muscles with curare it was shown that lifted objects feel lighter and that this is
through reafference from muscle spindle, contrary to current theories of spindle function. This result is the target
of current and planned studies. We have shown that the ability to control posture depends on the elastic stiffness
of the load being held and how muscle and tendon contribute to this. By muscle ultrasound, it was shown that
there is no simple relationship between muscle length and joint angle but that it is a dynamic function of
frequency depending strongly on load stiffness. At resonance, the load and joint oscillate on the end of a
compliant tendon without significant transfer of movement to the contractile portion, thus constituting an effective
proprioceptive and control blind spot. This muscle-tendon behaviour is a major determinant of muscle reflexes
and sets limits on human postural control.
Expected future outcomes:
Future work will: (i) explore the origin of the sense of muscular force and fatigue, (ii) explore the mechanisms of
adaptation in proprioceptive sensation identified in this project, and (iii) use techniques developed to discover how
the different sensory systems calibrate each other
.
Name of contact: Richard Fitzpatrick
Email of contact: r.fitzpatrick@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209632
CIA Name: A/Pr James Brock
Main RFCD: Autonomic Nervous System
Admin Inst: University of New South Wales
Start Year: 2002
End Year: 2004
Total funding: $229,917
Grant Type: NHMRC Project Grants
Title of research award: Peripheral mechanisms involved in autonomic hyperreflexia
Lay Description (from application):
Bladder distension or minor unheeded injuries below the lesion in spinally injured people often lead to episodes
of high blood pressure that may cause stroke or death. These events require emergency hospitalization and are
expensive as well as dangerous. After spinal injury, the control of sympathetic nerves that supply arteries and
regulate blood pressure is lost. However, the nerves below the injury remain in place and the spinal cord below
the lesion contains connections that can activate them. Signals from the bladder or skin enter the remaining lower
part of the spinal cord and activate the sympathetic supply generating a rise in blood pressure. This project will
test the hypothesis that increased sensitivity of arteries to the chemicals released from the sympathetic nerves
leads to excessive vessel constriction, contributing to the exaggerated increase in pressure. We will investigate
arteries removed from rats with experimental spinal transection. We will test the contractions of the arteries (a) to
sympathetic nerve stimulation and (b) to the chemicals noradrenaline, adenosine 5'-triphosphate (ATP) and
neuropeptide Y that are normally released during nerve activity. We will determine whether release of
noradrenaline and ATP from nerves is normal or augmented using electrochemical and electrophysiological
techniques. We will compare the responses with those in normal arteries, those in arteries whose nerves have been
silenced by removing all connections from the spinal cord and those in arteries that have lost all their nerve
supply. This will enable us to identify whether the mechanisms for release of transmitter substances are modified
and whether the arterial muscle is hypersensitive to these substances. The results will help in the design of safer
treatment for these potentially lethal emergencies in spinal patients.
Research achievements (from final report):
Bladder distension or minor unheeded injuries below the lesion in spinally injured people often lead to episodes of
high blood pressure (autonomic dysreflexia) that may cause stroke or death. These events require emergency
hospitalization and are expensive as well as dangerous. The project investigated whether an increase in the
response of arteries to nerve activation in two major vascular beds (splanchnic and cutaneous) can account for the
exaggerated vasoconstriction that underlies autonomic dysreflexia in patients with spinal cord injury. The project
demonstrated that: (1) Arteries from spinalized rats are much more readily activated by sympathetic nerve
stimulation; (2) The sympathetic nerve-mediated contractions of arteries from spinalized rats are larger and
abnormally prolonged; (3) In arteries from both intact and spinalized animals, sympathetic nerve-mediated
contractions are due almost entirely to the actions of released noradrenaline; (4) Arteries from spinalized rats have
an increased sensitivity to application of chemicals that mimic the effects of noradrenaline. These arteries are also
more readily contracted by other agents, suggesting the vascular muscle is generally more 'reactive'. (5) Silencing
the ogoing nerve activity by cutting the preganglionic axons (decentralization) produced similar changes to those
observed in arteries from spinalized animals, indicating that it is the decrease in nerve activity following spinal
transection that produces the increase in nerve evoked response. These changes in the behaviour of arteries could
play a major part in the dysreflexic episodes.
Expected future outcomes:
The experiments to date have demonstrated spinal injury can produce a major change in the response of arteries
to nerve stimulation. We now have to understand the underlying causes of this change. This knowledge will allow
us to propose new strategies for controlling/preventing autonomic dysreflexia.
Name of contact: James Brock
Email of contact: j.brock@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401105
CIA Name: Prof Vaughan Macefield
Main RFCD: Autonomic Nervous System
Admin Inst: University of New South Wales
Start Year: 2006
End Year: 2008
Total funding: $295,313
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
I have established world-class laboratories at the Prince of Wales Medical Research Institute and at the University
of Western Sydney where I undertake detailed human neurophysiological studies that are unique in Australia. The
research work involves recording from (or stimulating) individual nerve fibres via tungsten microelectrodes
inserted percutaneously into the peripheral nerves of human subjects (microneurography). I work collaboratively
with colleagues at a national and international level and my research is applied to clinically relevant problems by
establishing collaborations with clinical specialists. In addition to research examining the changes in control of the
autonomic nervous system following human spinal cord injury, my research over the last 8 years has extended to
clinical studies of various cardiovascular and respiratory disease states: congestive heart failure, obstructive sleep
apnoea syndrome, chronic obstructive pulmonary disease and essential hypertension.
During the tenure of my Fellowship I have hosted five sabbatical visitors to my laboratory - three from overseas
and two from Australian universities - and hosted six postdoctoral scientists who have come with their own
funding. My research group has grown from two in 1995 to eight by 2005. I currently have four postdocs working
with me and am also supervising one Honours and three PhD students.
I have written 65 papers and reviews that have been published in the leading international journals in their fields
(e.g. 15 papers in the Journal of Physiology), of which 36 have been published during the tenure of my
Fellowship.
Expected future outcomes:
Impacting positively on our quality of life as we age, research into the role of the sympathetic nervous system and
cardiovascular control using microneurography techniques and brain imaging (fMRI) will increase our
understanding of how normal blood pressure is maintained and how different disease states influence this control.
Name of contact: Prof Vaughan G Macefield
Email of contact: v.macefield@uws.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510375
CIA Name: A/Pr Richard Fitzpatrick
Main RFCD: Motor Control
Admin Inst: University of New South Wales
Start Year: 2008
End Year: 2011
Total funding: $420,872
Grant Type: Career Development Fellowships
Title of research award: Human Sensorimotor Physiology
Lay Description (from application):
We stand without falling by using silent senses from muscles and the balance organs of the inner ear to
unconsciously detect and control our movements. Since the leg muscles provide both the force and the sense, and
critically rely on good circulation, they are vitally important. I propose to study how these sensory and muscle
functions are used to control balance, posture and stepping reflexes, making it easier to identify older people who
will fall and design new preventative strategies.
Research achievements (from final report):
Human balance during standing and walking requires the different senses to be combined properly. This research
investigates the fundamental physiology by which the three senses critical for movement, vision, proprioception
(body sense), and the vestibular sense of gravity create a unified perception of the body in the world. The research
is directed at understanding the causes of falls in older people and identifying specific strategies to prevent them.
A technique has been developed that allows us to stimulate the human vestibular system electrically. With this we
are investigating the sense of self-motion, orientation and balance. We have shown how signals from the two
vestibular organs are combined for balance control and revealed a long-term adaptation of motion signals within
the brain. Studying the proprioceptive sense we have shown that muscle weakness impairs sensory signals from
muscles, an interaction unknown previously and vitally important for understanding age-related declining
function. A major study has shown that the sense of force when muscles are contracted arises through a return
signal from the muscles rather than being generated within the brain itself, as current theories propose. Applied
research has shown that older people at risk of falls have difficulty knowing when they are vertical and have
problems knowing the precise location of objects that they might trip on. Stepping is a critical reflex that prevents
falls. We have identified a range of problems that are associated with disordered stepping in older people and are
progressing with studies to understand the mechanisms and identify solutions.
Expected future outcomes:
Future work will: (i) identify basic physiology of the human stepping reflex and apply it to the problem of falling
in older people, (ii) use techniques developed to discover how the different sensory systems calibrate each other,
and (iii) explore the origin of the sense of muscular force and fatigue.
Name of contact: Richard Fitzpatrick
Email of contact: r.fitzpatrick@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568637
CIA Name: Dr Gila Moalem-Taylor
Main RFCD: Peripheral Nervous System
Admin Inst: University of New South Wales
Start Year: 2009
End Year: 2011
Total funding: $470,052
Grant Type: NHMRC Project Grants
Title of research award: The role of proinflammatory interleukin-17 (IL-17) and IL-17-producing T cells in
neuropathic pain
Lay Description (from application):
Peripheral nerve injury often results in persistent and debilitating neuropathic pain. My overall objective is to
understand the immunological mechanisms responsible for such pain. I plan to test the hypothesis that the
proinflammatory cytokine interleukin-17 promotes neuroinflammation and contributes to increased pain
sensitivity after nerve injury. This study promises to enhance our understanding of neuroimmune activation in
neuropathic pain and offers new opportunities for pain management.
Research achievements (from final report):
Neuropathic pain is a chronic pain caused by a lesion or disease of the somatosensory nervous system and
characterised by debilitating sensory abnormalities and increased pain sensitivity. Neuropathic pain affects 5% of
the general population, causes substantial disability, and lacks adequate treatments. Recent studies have
demonstrated that small signaling protein molecules, termed cytokines, play an important role in the neuroimmune
processes of neuropathic pain. In particular, an imbalance between algesic proinflammatory cytokines and
analgesic anti-inflammatory cytokines has been implicated. The fundamental aim of this research is to elucidate
basic immunological mechanisms responsible for neuropathic pain, with particular reference to the role of the
proinflammatory cytokine interleukin-17 (IL-17) in neuroinflammation and pain hypersensitivity following injury
to the nervous system. We found that mice deficient in IL-17 have significantly decreased mechanical pain
hypersensitivity as well as decreased infiltration of leukocytes to the injured nervous system tissue following
nerve injury. Further, administration of IL-17 into the hind-paw and the sciatic nerve of intact animals caused pain
hypersensitivity associated with significant inflammatory response. In addition, we found that mice deficient in
IL-17 have better locomotor recovery, smaller lesion size and decreased inflammatory cell infiltration following
spinal cord contusion injury. In summary, we have demonstrated an important role for IL-17 in regulating
neuroinflammatory responses, thus contributing to neuropathic pain after peripheral nerve injury and secondary
degeneration after spinal cord injury. This work identifies IL-17 as a potential therapeutic target in neuropathic
pain due to peripheral nerve injury and in recovery from spinal cord injury.
Expected future outcomes:
This study significantly enhances our understanding of the involvement of cytokines in nervous system injury and
offers hope for new approaches to therapeutic intervention by means of immune modulation. In particular, new
biologic drugs that block IL-17 may prove useful in the treatment of neuropathic pain and spinal cord injury.
Name of contact: Gila Moalem-Taylor
Email of contact: gila@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455433
CIA Name: Prof Stephen Lord
Main RFCD: Geriatrics and Gerontology
Admin Inst: University of New South Wales
Start Year: 2007
End Year: 2011
Total funding: $765,883
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
I am an applied physiologist determining risk factors for falls and strategies for prevention in older people and
clinical groups with balance disorders. I pursue this research primarily through epidemiological studies.
Research achievements (from final report):
As a Senior Principal Research Fellow I have pursued work in the areas of applied neurology, instability, falls,
fractures and transport injury in older people. In this period (since January 2007) I have published 100 original
peer-reviewed journal articles, 6 invited reviews, 5 other articles and 4 book chapters. With colleagues at
Neuroscience Research Australia (NeuRA) I also completed a second fully revised edition of our book on Falling
in Older People: Risk factors and Strategies for Prevention to be published by Cambridge University Press.
Overall, my papers have been cited over 7,000 times in the scientific literature and my H index is 47.
Since 2007, I have been awarded $13.7 million grant funding from the NHMRC and $2.0 million from other
sources (total $15.7 million) as a chief investigator. I currently hold two NHMRC project grants, an NHMRC
capacity building grant in population health, 4 grants from other sources as and two recently awarded NHMRC
Partnership Grants which will provide the means of maintaining my research productivity into the future.
I have collaborated directly with health care providers both within Australia and overseas to incorporate evidencebased risk assessment tools for use in clinical settings to identify high risk populations who might benefit from
interventions. My methodology and approach to the problem of physiological aging measurement and falls-risk
assessment has been adopted by many researchers around the world. Finally, I have played a key role in
developing health policy. I have contributed to policy development for NSW Health and was the Chair of the
Expert Panel for the development of the revised Best Practice Guidelines for Preventing Falls in the Community,
Hospitals and Residential Aged Care Facilities. These very significant developments greatly enhance the
translation of my research findings into policy and practice.
Expected future outcomes:
I am continuing to work as an NHMRC Senior Research Fellow. As outlined in my renewal application, I am
embarking on new projects aimed at understanding fall risk in older people and designing and implementing fall
prevention strategies. I continue to work actively in research translation.
Name of contact: Stephen R Lord
Email of contact: s.lord@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568724
CIA Name: Prof Stephen Lord
Main RFCD: Preventive Medicine
Admin Inst: University of New South Wales
Start Year: 2009
End Year: 2011
Total funding: $390,394
Grant Type: NHMRC Project Grants
Title of research award: Development of a novel intervention for training stepping ability to reduce the risk of
falls in older adults.
Lay Description (from application):
Stepping is often the last protective option to prevent a fall. This study will first modify and validate an
interactive system for training stepping ability in older adults. The system will be also provide the capability of
acquiring indeices of stepping ability in the home. We will investigate the effect of an in-home training program
using this system on stepping ability and falls risk. Findings will inform future interventions for preventing falls.
Research achievements (from final report):
This project has enabled us to develop and evaluate a novel telehealth technology for delivery of strength and
balance training exercses to reduce the risk of falls directly into the homes of older adults. Furthermore our
technology will enable remotely located researchers and clinicians to track indices of fall risk at regular intervals
overtime. Our technology has leveraged existing exercise-based videogame technology that is readily available to
the consumer. As such we are beginning to explore a method for delivering fal prevention training programs at
scale.
We have established that the way in which older adults play exercise videogames, like a modified version of
Dance Dance Revolution, suggests the possibility for tracking a proxy measure for fall risk over time. Results of
our initial exploration of this have been published in the British Journal of Sports Medicine, 45(5), 441-445
Furthermore, we have been able to develop a technology solution based on Dance Dance Revolution that enables
us to measure a correlate of fall risk, previously only possible from laboratory-based measurement, in the homes
of older adults. We have published a validity and reliability study of a dance mat-based Choice Stepping Reaction
Time (CSRT) test in the Archives of Physical Medicine and Rehabilitation, 92(6), 947-953.
In a recent pilot study where we randomised older adults into an 8-week step training intervention or usual care
control group, participants completing the intervention (n=15) were significantly faster on the CSRT measure of
stepping performance and performed better on sway and contrast subtest of the Physiological Profile Assessment
for fall risk that those participants completing in the control (n=17). In the intervention group around half also self
reported improvement in balance confidence (8/15) and balance performance(7/15). No adverse incidents were
reported suggesting that our approach is a safe method for delivering unsupervised fall prevention training.
Expected future outcomes:
We aim to extend these initial investigations to address dose-response effects on fall risk. We also aim to address
the effect of building social connectivity tools around the step training system to increase compliance with
exercise interventions. Our technology can be translated to other research questions and we are currently looking
to trial our device in people living with Multiple Sclerosis.
Name of contact: Stuart Smith
Email of contact: s.smith@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351140
CIA Name: Prof Leonie Ashman
Main RFCD: Oncology and Carcinogenesis
Admin Inst: University of Newcastle
Start Year: 2005
End Year: 2007
Total funding: $454,500
Grant Type: NHMRC Project Grants
Title of research award: Role of the tetraspanin CD151 in epithelial biology and cancer
Lay Description (from application):
A cell surface protein identified in this laboratory has been linked to cancer progression and metastasis. This
project aims to examine the molecular basis of the action of the protein in regulating cell migration, and to
establish model systems to provide definitive evidence as to its role in the development and progression of cancer.
The models will also provide systems for future studies to evaluate the potential of antibodies and other inhibitors
of the action of this protein as therapeutics in a range of human cancers.
Research achievements (from final report):
This project used resources (monoclonal antibodies, gene knock-out mice) previously developed in the laboratory
to investigate the function of the CD151 protein in vivo. The most significant results were demonstration of a role
for CD151 in skin wound healing and in kidney function. These studies were complemented by analysis of CD151
function in tissue culture models. The CD151 gene knock-out was back-crossed for 10 generations onto a different
mouse strain suitable for analysis of the role of CD151 in breast and prostate tumour initiation and progression
and these experiments were initiated.
Expected future outcomes:
This and follow-on projects will improve our understanding of mechanisms of tissue repair and tumour metastasis
and will lead to new biomarkers for classification of breast and prostate cancer and potentially new approaches to
treatment. The unexpected demonstration of a role for CD151 in kidney function will be followed up and should
give new insights into the pathogenesis of human renal disease
Name of contact: Professor Leonie Ashman
Email of contact: leonie.ashman@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455527
CIA Name: A/Pr Jonathan Hirst
Main RFCD: Foetal Development and Medicine
Admin Inst: University of Newcastle
Start Year: 2007
End Year: 2009
Total funding: $450,703
Grant Type: NHMRC Project Grants
Title of research award: Neurosteroid mediated protection after birth: approaches for maximising protective
steroid levels in the neonatal brain
Lay Description (from application):
Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the
newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are
a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an
inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels
of these protective steroids are remarkably high in the fetal brain and levels rise further in response to fetal stress.
The placenta contributes steroid precursors that help maintain these high neurosteroid levels. This placenta-fetal
brain interaction comprises an internal mechanism that protects the fetal brain from adverse events during
pregnancy. At birth, however, there is a dramatic decline in neurosteroid concentrations in the brain after the loss
of the placental precursor supply. The fall in concentrations is even greater in animals that are born growth
restricted. This suggests that newborns, particularly those from compromised pregnancies, are at increased risk of
brain damage due to low neurosteroid levels. We believe that certain commonly used steroid therapies may also
lower steroid levels in the brain and result in increased vulnerability to brain damage during birth or in the early
neonatal period. Alternatively, we propose that replacement of neurosteroid precursors in the newborn may raise
brain neurosteroid levels and protect against brain damage. In the proposed studies we will evaluate treatments
that can raise the concentration of steroids and determine the best strategy for reducing brain injury following
complications during pregnancy, at birth and during the early newborn period. This work will determine the best
therapeutic approaches for maximising neurosteroid-induced brain protection and for reducing the risk of brain
damage.
Research achievements (from final report):
The objectives of the work were to examine the neurosteroid responses at the fetal to neonatal transition and
to determine if these responses are required for neuroprotection and are defificent in compromised pregnencies.
This work required the establishment of a model of intrauterine growth restriction (IUGR) in guinea pigs. We
found that of growth restriction reduced levels of key 5alpha-reductase enzymes, in the placenta and brain. This
result suggests that reduced expression in the brain may continue after birth and lead to the reduced neurosteroid
levels neonates. We also found if neurosteroid production was reduced by 5alpha-reductase inhibition there was a
marked increase in cell death in the fetal brain supporting a neuroprotective action for these steroids. We also
established a model of birth asphyxia that markedly increased apoptotic cell death in the brain if the fetus was
already growth restricted. We found that administration of allopregnanolone prevented the asphyxia-induced
increase in cell death and improved outcome after asphyxia in the IUGR fetus. We then explored if preterm birth
leaves the neonatal brain more vulnerable to hypoxia due to reduced neurosteroid synthesis. We found that the
expression of both 5alpha-reductase isoforms was lower in the human placenta collected after preterm labour,
suggesting that preterm birth increases the risk of brain injury due to the lower neurosteroid exposure. Together,
this suggests that the preterm neonate may be at risk of brain injury due to their lower capacity to produce
neurosteroids around the time of birth. The more marked effect we found with male fetuese may explain their
greater vulnerability.
Expected future outcomes:
The results of this project support the proposal that steroid supplementation may be valuable in protecting the
brain after preterm birth. Future studies will evaluate different steroid treatments. We showed that the preterm
NHMRC Research Achievements - SUMMARY
neonates have deficient in neurosteroid concentrations in the brain increasing vulnerability to siezures, which
could be treated using neurosteroid replacement.
Name of contact: Jonathan Hirst
Email of contact: Jon.Hirst@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401244
CIA Name: Prof Robert Callister
Main RFCD: Sensory Systems
Admin Inst: University of Newcastle
Start Year: 2007
End Year: 2008
Total funding: $441,473
Grant Type: NHMRC Project Grants
Title of research award: Descending control of pain pathways
Lay Description (from application):
Current treatments for chronic pain are limited in their success. This emphasises the need for new insights into the
basic mechanisms and nervous system circuitry underlying altered or chronic pain states. Work in animals and
patients with chronic pain shows that certain brainstem centres communicate, via descending spinal cord
pathways, with small nerve cells in the superficial dorsal horn (SDH) of the spinal cord. These SDH neurones
receive and process pain-signalling information from the skin and internal organs, and receive inputs from
descending pathways. This descending input can either inhibit or enhance the activity of SDH neurones and
subsequent pain perception. Till now it has been difficult to "directly" examine how descending pain pathways
influence the small SDH neurones in the spinal cord. A new approach, which has been developed in our
laboratory, now allows us to record from these very small SDH neurones in the spinal cord of an intact deeply
anaesthetized mouse. In addition, our technique allows us to examine the recorded SDH neurone s responses to
functionally relevant stimuli (brushing or pinching the hindpaw) as well as its physiology and anatomy. This
project will use our new techniques to examine the effects of activating descending brainstem pathways that alter
the way painful stimuli are processed in the spinal cord. The effects of altered levels of inhibition in the spinal
cord will also be studied by using mice with naturally occurring mutations in their inhibitory glycine receptors.
We believe a more complete understanding of pain processing mechanisms will be achieved by examining the role
of descending pathways in an intact animal preparation. Such data are essential for the development of drug
therapies that can successfully target pain syndromes.
Research achievements (from final report):
This focus of this application was to study the effects of stimulating nerve fibres, originating in the brain or skin,
on the responses of nerve cells in the region of the spinal cord involved in pain. We can now do this routinely in
the laboratory mouse. Because the mouse is the species of choice for genetic technologies (ie, making transgenic
and knockout mice) the methods and results of the project have tremendous potential for exploring the roles of
genes in pain processing. Major outcomes were:
1) We can now routinely obtain recordings from spinal neurons AND record their responses after stimulating
nerve cells in the brain or periphery of the mouse.
2 We know how recording temperature affects responses of spinal neurons. This is important, as a major goal of
this project was to relate new information recorded intact animals (ie, in vivo at 37 degrees C) to the huge
literature obtained in spinal cord slices (recorded at 23 degrees C).
3) We have also published the first study where the effects of a genetic mutation are examined in single neurons
within the nervous system of an intact mouse.
4) We also developed a horizontal spinal cord slice preparation that allows recording in spinal cord neurones
while stimulating pathways from the barin. This preparation will be invaluable for future detailed pharmacological
analysis of the synaptic mechanisms at connections between brainstem and SDH neurones. This sort of analysis
cannot be carried out in slice preparations.
5) We have established when, during development, the circuitry and neurons within the SDH can be considered
functionally mature.
6) Written a major review on the spinal neurons involved in pain processing.
Expected future outcomes:
We will continue to use our in vivo mouse preparation to examine the effects of altered genes on spinal cord pain
processing mechanisms.
Name of contact: Robert Callister
Email of contact: robert.callister@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401565
CIA Name: Prof Brian Key
Main RFCD: Sensory Systems
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2008
Total funding: $496,321
Grant Type: NHMRC Project Grants
Title of research award: Deciphering the mechanisms for constructing the olfactory system
Lay Description (from application):
The olfactory (smell) system is a unique part of the nervous system; nerve cells are generated throughout life and
it can regenerate even after injury. It therefore provides an excellent model for examining the growth,
development and maintenance of nerve cells. This project will examine the effects on the organisation of the
olfactory system when some guidance signals are altered. Information we obtain about how this system develops
and regenerates may be useful in treating brain disorders and spinal injuries The results of these experiments will
provide important information on the the initial growth and targeting of these nerve cells which may have
implications for regeneration of these as well as other nerve cells.
Research achievements (from final report):
The essential steps in forming a normal functioning brain occur during life as an embryo. If these processes go
haywire, there can be serious repercussions for life after birth. This project has understand how the brain forms
during embryonic stages so that better treatments and procedures can be developed to deal with developmental
problems.
Expected future outcomes:
There is know the opportunity to identify particular molecules that are responsible for key developmental events
in brain formation. These molecules are potential drug targets that could be used for therapeutic purposes.
Name of contact: Brian Key
Email of contact: brian.key@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351479
CIA Name: Prof Andrew Boyd
Main RFCD: Central Nervous System
Admin Inst: University of Queensland
Start Year: 2005
End Year: 2007
Total funding: $491,000
Grant Type: NHMRC Project Grants
Title of research award: Is EphA4 the major molecular regulator of axonal regeneration?
Lay Description (from application):
Spinal cord injury affects a substantial number of Australians each year. Around half the number of spinal cord
injury cases result in quadriplegia, with loss of function to a varying degree in the upper as well as the lower
limbs. The limited degree of repair of spinal axons following injury means that such paralysis is usually
permanent. Although the inability to walk is a serious issue, the limited function of the arms and hands results in a
loss of independence which is a major factor contribuing to the enormous personal, financial, and community
costs of this problem, estimated to cost the Australian community $200 million a year. In recent years advanced
anatomical and molecular approaches to the problem of repair of the central nervous system have provided great
insights into the neuronal and glial reactions to neural damage that appear to govern the success or failure of
neural regeneration. Our preliminary data indicate that a receptor tyrosine kinase, EphA4, which is important for
axonal pathfinding in the developing nervous system, is a potent inhibitor of neural regeneration following spinal
cord injury. In this project we will determine the mechanisms by which EphA4 exerts its inhibitory effects, and
examine the effect of neutralizing EphA4 signalling on neural regeneration. Success in achieving this result will
lead to the development of a therapeutic intervention that we will test in mouse models.
Research achievements (from final report):
This project sought to investigate whether EphA4 was a dominant target for therapy in spinal cord injury. We
have shown that blocking EphA4 by use of soluble Eph inhibitors promotes significant re-innervation and
functional recovery following 2 weeks of treatement. We also showed that the dominant effect of therapy is to
enable re-innervation rather than inhibiting the gliotic response.
Expected future outcomes:
These studies pave the way to the development and testing of therapies for use in human spinal cord and brain
injury.
Name of contact: Andrew Boyd
Email of contact: Andrew.Boyd@qimr.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143061
Start Year: 2001
CIA Name: Prof Peter Koopman
End Year: 2003
Main RFCD: Genetic Development (incl. Sex Determination)
Total funding: $468,564
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Title of research award: Transcriptional control of blood vessel development by Sox18
Lay Description (from application):
Blood vessels play an essential role in maintaining the supply of nutrients to every organ and tissue in the body.
Improper development of blood vessels in the embryo can compromise survival of the embryo, and defects in the
ability of blood vessels to grow, regenerate and adapt to change during adult life can be life-threatening. The
growth of new blood vessels (angiogenesis) is also an important factor in the ability of solid tumours to grow
during the progression of cancer. It is therefore of fundamental importance in the health sciences to gain an
understanding of how blood vessels form and regenerate. As a result of our collaborative research efforts, we
have discovered a gene, Sox18, that appears to regulate blood vessel development by controlling the formation
and/or behaviour of endothelial cells, which line the blood vessels and make them impermeable. Our research so
far indicates that MICE WITH DEFECTS IN SOX18 DIE FROM VASCULAR DEFECTS, underlining the
importance of this gene. THIS PROJECT IS CONCERNED WITH FINDING OUT HOW SOX18 WORKS exactly what goes wrong in mice lacking this gene, whether Sox18 can influence endothelial cell behaviour in cell
culture, how Sox18 comes to be active in endothelial cells, what genes are switched on by Sox18, and what genes
Sox18 co-operates with in its role in endothelial cells. The answers to these questions will not only provide
fundamental basic information about how blood vessels development is controlled, but also sow the seeds for
possible future therapies in which blood vessel development could be stimulated (eg in wound healing) or
suppressed (eg in tumour progression) through pharmaceutical intervention.
Research achievements (from final report):
We are researching the genetic mechanisms by which blood vessels form - an issue of critical importance to
normal embryo development, physiological functioning and many diseases including cancer. We have discovered
one of the key genes in the process, a gene called Sox18. In this project we discovered a wealth of information
regarding what Sox18 does, how it achieves its roles in the cell, and how it contributes to development, wound
healing and cancer. Our data raise the exciting possibility that future therapies aimed at speeding up or slowing
down blood vessel development could be based on the Sox18 gene.
Expected future outcomes:
We are now exploring further the link between Sox18 and cancer, with a view to developing new therapies
involving inhibiting growth of blood vessels.
Name of contact: Neville Young
Email of contact: n.young@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301137
CIA Name: Prof Jennifer Stow
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: University of Queensland
Start Year: 2004
End Year: 2006
Total funding: $470,750
Grant Type: NHMRC Project Grants
Title of research award: LPS-regulated SNAREs and control of cytokine secretion in macrophages.
Lay Description (from application):
TNF(tumour necrosis factor alpha) is a potent proinflammatory cytokine secreted by immune activated
macrophages. TNF has essential roles in host defense, tumour killing and energy metabolism. Excessive secretion
of TNF in acute and chronic inflammatory conditions, such as septic shock, Crohn s disease, rheumatoid arthritis
and in cancer has many severe, even fatal, consequences. Improved anti-TNF therapeutics are needed for clinical
management in all of these conditions. Our studies are focused on investigating how macrophages synthesize and
secrete TNF, with the ultimate goal of characterizing the molecules and vesicles in the TNF secretory pathway.
Our recent findings show the expression of SNARE proteins, part of the vesicle docking and fusion machinery, is
regulated in concert with cytokine secretion and other trafficking changes in activated macrophages. We
identified the proteins Syntaxin4, Munc-18c and SNAP-23 as the specific t-SNARE complex that regulates TNF
delivery to the cell surface. In the proposed studies we will investigate how SNAREs are regulated during
macrophage activation by studying their gene expression and protein modifications. We have developed a singlecell assay to measure TNF trafficking in macrophages; this allows the identification of molecules with roles in
TNF secretion and it will be used in a series of experiments to identify the specific v-SNARE proteins that partner
the t-SNARE for TNF delivery. Finally we will use live cell imaging to investigate how and where TNF is
delivered to the macrophage cell surface and membrane fractionation to examine a role for membrane
microdomains in organizing SNARE-mediated TNF secretion. Manipulation of SNAREs, using data generated by
these studies, holds potential for the development of new anti-TNF therapies.
Research achievements (from final report):
We have discovered new and unexpected cellular pathways that lead to the releae of cytokines or chemical
messengers from immune cells. These cytokines have necessary roles in inflammation and describing their
pathways for release generates a new level of understanding in this area. However the excess secretion of these
cytokines, TNF and IL-6, causes the chronic symptoms of inflammatory dieases like IBD and arthritis. Our
findngs identify, for the first time, molecules important for cytokine secretion that can potentiallly be targeted by
drugs for alternative and improved approaches to treating inflammation.
Expected future outcomes:
Our findings uncover potentially drug targets and strategies for blocking TNF secretion that could lead, in the
future, to new medicines for inflammatory disease.
Name of contact: Jennifer Stow
Email of contact: j.stow@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301239
CIA Name: Prof Gwendolen Jull
Main RFCD: Therapies and Therapeutic Technology
Admin Inst: University of Queensland
Start Year: 2004
End Year: 2004
Total funding: $110,633
Grant Type: NHMRC Development Grants
Title of research award: Cranio-Cervical Dynamometry in the Rehabilitation of Neck Pain
Lay Description (from application):
Research has demonstrated that exercising particular neck muscles in a specific manner is effective in reducing
painful neck symptoms. A device has been developed to quantify the performance of specific neck muscles,
permitting more precise rehabilitative exercise, tailored to an individual’s abilities and needs. The effectiveness of
this device in the rehabilitation of chronic neck pain will be tested in a clinical trial against other commonly used
forms of neck exercise.
Research achievements (from final report):
Neck pain is a common and costly problem in the community. Training of neck muscles has been shown to be
effective in reducing neck pain and disability. This study compared a new tecnology for rehabilitating the muscles
of the neck to other commonly used methods in clinical practice. Results have shown the new technology was as
effective as other commonly used methods of rehabilitation in reducing painful symptoms, as well as
demonstrating some superior results in neck muscle performance gains compared to the other methods. The new
technology was also adaptable for use in home setting, which has increased its commercial potential.
Expected future outcomes:
The Neckmetrix technology has undergone further development to refine the commercial attractiveness of the
device. Negotiations with potential licencees are in progress. Further clinical trials are planned.
Name of contact: Dr Shaun O'leary
Email of contact: s.oleary@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455836
CIA Name: Prof Matthew Brown
Main RFCD: Quantitative Genetics
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2011
Total funding: $677,383
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellows
Lay Description (from application):
I am a clinican-scientist and rheumatologist studying genetic determinants of common chronic human
musculoskeletal diseases. My research aims are to define for key genes how specific genotypes promote diease
phenotypes, using in vitro and in vivo approac
Research achievements (from final report):
I have developed human gene mapping approaches using genomewide association studies and next generation
sequencing. In doing so I have identified genetic loci associated with a wide variety of common and rare diseases
including ankylosing spondylitis, rheumatoid arthritis, osteoporosis, multiple sclerosis, psoriasis, and ocular
diseases. I have contributed to the development of study designs for genetic studies, and pioneered the use of
sequencing based approaches in human genetics. My group has also determined mechanisms underlying genetic
associations with disease, notably in ankylosing spondylitis investigating the mechanisms of association of the
genes IL23R and ERAP1, from which therapies are either in use or in development respectively.
Expected future outcomes:
I expect my research will lead to the development of curative therapies for the common autoimmune disease
ankylosing spondylitis, and likely psoriasis and inflammatory bowel disease.
Name of contact: Matthew Brown
Email of contact: matt.brown@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 252829
CIA Name: Prof Brian Key
Main RFCD: Sensory Systems
Admin Inst: University of Queensland
Start Year: 2003
End Year: 2005
Total funding: $440,250
Grant Type: NHMRC Project Grants
Title of research award: A molecular approach to constructing the olfactory system
Lay Description (from application):
The olfactory (smell) system is a unique part of the nervous system; nerve cells are generated throughout life and
it can regenerate even after injury. It therefore provides an excellent model for examining the growth,
development and maintenance of nerve cells. This project will examine the effects on the organisation of the
olfactory system when some guidance signals are altered. Information we obtain about how this system develops
and regenerates may be useful in treating brain disorders and spinal injuries In the current project we will
examine the effects of specific nerve cell guidance molecules by generating transgenic mice that produce these
molecules only in the olfactory system. We can then determine what changes occur to the nerve cells when these
extra molecules are produced. The results of these experiments will provide important information on the the
initial growth and targeting of these nerve cells which may have implications for regeneration of these as well as
other nerve cells.
Research achievements (from final report):
This project has led to a better understanding about how one of the most regenerative regions of the nervous
system forms during development and matures into old age. The region of the nervous system associated with
smell is called the olfactory system. It is unique because its nerve cells are continually dying throughout life and
being replenished by progrenitor cells that mature into new nerve cells. In contrast, in other regions of the
nervous system nerve cells typically die with age and are never replenished. This makes the olfactory system
interesting for regneratine purposes. In this project we have begun to understand how the olfactory nerve cells are
able to conitunally grow throughout life. It is hoped that this infromation will lead to the design of therapeutic
approaches ot injury in the nervous system.
Expected future outcomes:
The long term outcomes of this work is the developemnt of strategies to assist in repairing nervous systems
damaged by either physical insult or due to disease and pathologies. An important future outcome is to induce
growth and regeneration in other regions of the nervous system at levels comparable to that observed in the
olfactory system.
Name of contact: Brian Key
Email of contact: brian.key@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 142958
CIA Name: Prof Mark Forwood
Main RFCD: Orthopaedics
Admin Inst: University of Queensland
Start Year: 2001
End Year: 2003
Total funding: $301,018
Grant Type: NHMRC Project Grants
Title of research award: Prostaglandin G/H synthase-2 (PGHS-2) is a key regulator of skeletal adaptation and
remodelling
Lay Description (from application):
Knowledge of the biology underlying bone formation is important for developing novel approaches to stimulate
new bone formation in skeletal diseases associated with ageing or disability, or for maintenance of new bone
around orthopaedic or dental implants. The discovery that a prostaglandin enzyme (PGHS-2) is a key factor in
activity-related bone formation and normal bone turnover, as well as a pharmacological target for reducing
inflammation, has considerable clinical significance. Specific inhibition of PGHS-2 by recent anti-inflammatory
drugs avoids formation of gastric ulcers, but their influence on normal bone remodelling and fracture repair is not
known and must be investigated. Many such inhibitors are in advanced clinical trials, but their effect on bone
metabolism has not been published. This project is important because it employs novel experimental models to
advance our knowledge of prostaglandin biology in skeletal adaptation, and elucidates important clinical
consequences for specific inhibition of PGHS-2 in the skeleton. This project will investigate the regulation of
prostaglandin production by PGHS enzymes following mechanical loading in vivo. It will use cell, molecular and
histochemical techniques to determine if the genes that regulate the enzymes are influenced by mechanical stimuli,
and if they are dependent on other molecules, associated with structural proteins (stress fibres) within the cell. It
will investigate if inhibition of PGHS-2 by antiinflammatory drugs or stress-fibre inhibitors, depresses normal
bone turnover and healing responses. The outcome of these experiments could indicate new approaches to
stimulate bone formation, preserve bone mass, or minimise adverse skeletal effects of anti-inflammatory
treatments related to orthopaedic or dental procedures.
Research achievements (from final report):
The experiments showed that PGHS-2 (or COX-2) gene expression (normally related to inflammation) is
increased in bone tissue following loading. It also provided experimental evidence that PGHS-2 inhibition reduces
bone turnover which can prevent menopause related bone loss. This was shown to be related to decreases in
osteoclast surface and activity - the cells that remove bone. PGHS-2 inhibitors (anti-inflammatory drugs) also
slowed the remodelling and consolidation of woven bone on the periosteal surface following loading. This would
lead to increased healing time for fractures, but would not jeopardise the strength of those healing fractures. The
findings above suggest that there is a clinical implication for COX-2 inhibition in terms of regulating bone
turnover, but this has not yet been translated into a direct clinical outcome.
Expected future outcomes:
Evidence that new antinflammatory drugs not only reduce inflammation, but may have a role in managing and
regulating bone diseases associated with rapid bone loss, will be investigated. The role of COX-2 in bone biology
is being pursued in mice producing excess levels of this enzyme to study whether this exacerbates conditions of
bone loss or enhances adaptive mechanisms associated with loading
Name of contact: Mark Forwood
Email of contact: m.forwood@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301026
CIA Name: Prof Brian Key
Main RFCD: Cellular Nervous System
Admin Inst: University of Queensland
Start Year: 2004
End Year: 2006
Total funding: $447,750
Grant Type: NHMRC Project Grants
Title of research award: Molecular and cellular mechanisms of axon guidance in the vertebrate nervous system
Lay Description (from application):
There are, at least, two major obstacles that have to be overcome in the design of therapies to assist the repair of
injured brain tissue. First, the nerve cells that are damaged have to be encouraged to regrow - typically this
regrowth is inhibited in the brain; and second, this regrowth has to be directed so that the correct connections are
re-established. This project will begin to unravel some of the mechanisms that nerve cells use to wire up together
during development. This information can be used to assist in trying to modulate and facilitate directed regrowth
following injury.
Research achievements (from final report):
There are, at least, two major obstacles that have to be overcome in the design of therapies to asssist the repair of
injured brain tissue. First, the nerve cells that are damaged have to be encouraged to regrow - typically this
regrowth is inhibited in the brain; and second, this regrowth has to be directed so that the correct connections are
re-established. This project has begun to unravel some of the mechanisms that nerve cells use to wire up together
during development. This information will be used to assist in trying to modulate and facilitate directed regrowth
following injury. We have been the first to characterise the interaction between three molecules during the period
in early development when a template of the nerve connections is being formed. This work has contributed
significantly to our understanding of how genes control nerve fiber growth.
Expected future outcomes:
This work will lead to a better understanding of how molecules regualte the growht of nerve fibres in the brain. It
is expected that techniques will be developed that will allow these molecules to be regualted both in time and
space so as to facilitate the repair of damaged tissue in the brain following either direct injury or disease states.
Name of contact: Brian Key
Email of contact: brian.key@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 456040
CIA Name: A/Pr Helen Cooper
Main RFCD: Cellular Nervous System
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2009
Total funding: $513,947
Grant Type: NHMRC Project Grants
Title of research award: Wnt-Ryk signaling in the establishment of major axon tracts in the embryonic mouse
brain
Lay Description (from application):
The corpus callosum is the major interhemispheric commissure in the human brain, comprising approximately 3
million myelinated fibers which connect homologous regions in the neocortex. To date more than 50 different
human congenital syndromes have been described in which the corpus callosum does not form leading to epilepsy
and mental retardation. We have identified a new guidance molecule (Ryk) which is crucial for corpus callosum
formation. This project aims to dissect that molecular mechanisms controlling Ryk signaling during corpus
callosum development. Our analysis of Ryk function will advance our understanding of the molecular
mechanisms underlying the formation of this important commissure.
Research achievements (from final report):
This project has provided fundamental insights for basic researchers interested in identifying the molecular
pathways controlling the formation of the mammalian brain. Identification of these signaling molecules will lead
to a better understanding of how nerve fibres grow and precisely navigate to their correct targets elsewhere in the
nervous system. Moreover, this knowledge will enhance our undestanding of stem cell biology and the production
of new neurons in both the embryo and adult.
This project will also benefit clinicians, as well as the general public, as it will provide important knowledge for
understanding the aberrant molecular mechanisms underlying the failure of nerve tract formation in the brain.
Such failures lead to autism, many forms of mental retardation, and epilepsy. We have also identifed new
compounds that may enhance the regrowth of axons after injury due to trauma or neurodegeneration.
Expected future outcomes:
Our discoveries will:
o
provide the groundwork for more detailed studies on the fundamental molecular mechanisms underlying
brain development.
o
provide a greater understanding of the mechanisms reponsible for autism, mental retardation and epilepsy.
o
identify novel drugs with the potential to promote regeneration of nerve tracts after injury.
Name of contact: Helen Cooper
Email of contact: h.cooper@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519702
CIA Name: Prof Jeffrey Lipman
Main RFCD: Intensive Care
Admin Inst: University of Queensland
Start Year: 2008
End Year: 2011
Total funding: $612,859
Grant Type: NHMRC Project Grants
Title of research award: Antibiotic dosing in the
Lay Description (from application):
The appropriate dosing of antibiotics for patient admitted to ICU after a traumatic injury is poorly defined and
based on intuition rather than evidence. Doctors need to predict which patients may develop very high antibiotic
clearances and dose accordingly so that potentially life-threatening infections do not occur. Given these patients
are unknown, this research seeks to identify such patients and recommend which antibiotic and which dose is
appropriate to ensure adequate treatment.
Research achievements (from final report):
This study has collected extensive physiological and pharmacokinetic data in critically ill patients and the work
will be cited frequently by major papers trying to understand why critically ill patients need different antibiotic
dosing approaches to other patient groups. Various publications in high impact factor journals have also been
made possible by this grant. The results of this project would be considered of landmark significance. The
potential benefits of this research are manifest initially in improved antibiotic treatment in patients with high
morbidity and mortality, that is critically ill patients with sepsis and with significant trauma. The other potential
benefits include industry partnerships to develop equipment and software to develop evidence based predictors of
antibiotic dosing for these 'at risk' patient groups. This translational work could also then be extended to other
difficult patients such as burns, febrile neutropenic patients.
Expected future outcomes:
Translational research that accurately predicts antibiotic dosing requirements for critically ill patients without the
need for therapeutic drug monitoring data to guide drug dosing.
Name of contact: Prof Jeffrey Lipman
Email of contact: j.lipman@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143021
CIA Name: Prof Justin Kenardy
Main RFCD: Mental Health
Admin Inst: University of Queensland
Start Year: 2001
End Year: 2003
Total funding: $185,889
Grant Type: NHMRC Project Grants
Title of research award: A prospective study of traumatic stress in children involved in motor vehicle accidents
Lay Description (from application):
Motor vehicle accidents (MVAs) are relatively frequent major life trauma that represent significant life
threatening experiences. Not surprisingly evidence suggests that MVAs represent a frequent trigger for the
development of post traumatic stress disorder (PTSD), although studies have typically focussed upon adult
survivors. Local statistics indicate a significant proportion of children will experience a MVA of sufficient
severity to warrant attendance at hospital. This project is of significance because it will provide badly needed
information about the prevalence and course of emotional and behavioural problems in children following
exposure to a serious MVA. More broadly the study should provide valuable information on post-traumatic stress
responses in children. Furthermore, it will enable us to identify the factors that place children at particular risk of
developing psychological problems following a MVA. This will provide information to help design of
interventions to prevent the development of PTSD and other forms of psychopathology following MVAs. Such
data will also permit identification of those children who are at particular risk of psychological morbidity after
MVA trauma and for whom preventive interventions are most likely to be beneficial.
Research achievements (from final report):
This project investigated the prevalence of post traumatic stress reactions in children injured in accidents, with
follow-up of families occurring within two weeks after the child's accident, at one month after the accident and
again at six months after the child's accident. Children were aged 7 to 15 at the time of the accident. The research
employed measures of child functioning as well as parental functioning. The study found that although a
significant number of children suffered initial distress at two weeks after the accident, the majority of children
made a relatively good psychological recovery. However, children who suffered significant distress at one month
after the accident were likely to still suffer from post traumatic symptomatology at six months after the accident.
This indicates that early identification of children suffering significant psychological distress allows for early
treatment of children who are unlikely to recover without intervention.
Expected future outcomes:
The outcomes of this research will form the basis of development of an intervention program aiming to prevent
and/ or minimise development of post traumatic stress disorder and other psychological disorders in children
injured in accidents. The risk factors identified in the original study allow early identification of children at risk
for development of these disorders.
Name of contact: A/Prof. Justin Kenardy
Email of contact: jkenardy@somc.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519781
Start Year: 2008
CIA Name: Dr Shaun O'Leary
End Year: 2010
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $117,229
Admin Inst: University of Queensland
Grant Type: Early Career Fellowships (Australia)
Title of research award: The classification of motor function impairment in chronic neck pain
Lay Description (from application):
Disability due to painful neck disorders is a serious health issue. Changes in control of neck movement and
muscle function are known problems in neck pain sufferers yet management of these issues remains poorly
understood. This project aims to develop classifications that better identify movement and muscle problems in the
neck with the goal to facilitate better rehabilitation. This project is likely to significantly improve the management
of neck pain in the community.
Research achievements (from final report):
This research training fellowship has investigated muscle function in individuals with chronic neck pain. From
these studies we have demonstrated that individuals with neck pain have issues with the way they use their
muscles as well as changes in the physical conditioning of their muscles, particularly those with a whiplash
disorder. We have further shown that muscle dysfunction is linked to the severity of the symptoms a person is
experiencing. Of great clinical interest, we have shown that when you train muscles for the management of neck
pain, you will get a favourable reduction in pain from more than one type of exercise approach even though the
different exercise approaches will give very different outcomes in terms of muscle fitness. Therefore, we now
know that when managing a patient with neck pain, clinicians have some flexibility with the approach they choose
with regards to pain, but need to be very specific with regards to the patients muscle fitness needs.
Expected future outcomes:
The findings from the work conducted in this fellowship has raised many additional questions. These questions
underpin our current series of studies all designed to answer the following question - How do I best manage this
patients neck pain?
Name of contact: Shaun O'leary
Email of contact: s.oleary@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569666
CIA Name: Prof David Pow
Main RFCD: Neurosciences not elsewhere classified
Admin Inst: University of Queensland
Start Year: 2009
End Year: 2011
Total funding: $526,878
Grant Type: NHMRC Project Grants
Title of research award: A novel marker of distressed neurons in the hypoxic brain: Regulation, function and
potential clinical utility.
Lay Description (from application):
The brain is easily damaged by lack of oxygen (hypoxia). We have recently identified a novel protein called
GLAST1b which is expressed in distressed neurons. This protein is a glutamate transporter. Glutamate is
implicated as a toxic agent hypoxia. This study will investigate what regulates the expression of GLAST1b, what
the consequences of expression are, and whether this marker can be developed as a diagnostic tool for identifying
the presence of, and distribution of brain damage.
Research achievements (from final report):
This project investigated the idea that novel forms of a class of protein called glutamate transporters were
effective markers of distressed neurons in the brain. This study confirmed this in animal models and in human
brains. During this study we needed to examine the morphology of the astrocytes surrounding the stressed
neurons, and we accomplished this with associated papers being published. We also examined the testis as it has
properties like the brain (it has a blood testis barrier) and this gave us new leads into transporter splicing in the
brain. We also found an entirely new and abundant form of the glutaate transporter GLAST during these studies.
We have discovered changes in expression of new forms of the transporters we have investigated in the human
brain. Perhaps most excitingly we discovered novel forms of a protein called EAAT5 in brain which may be the
key regulators of excitability in the brain and a new NHMRC grant application has been submitted to study them.
Expected future outcomes:
The application has identified the key ways that alternate splicing of glutamate transportes may contribute to brain
disease, and in doing so has identified new forms of these critical proteins. They are now the subject of ongoing
investigatons and new grant applications.
Name of contact: David Pow
Email of contact: david.pow@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519716
CIA Name: Prof John Fraser
Main RFCD: Systems Physiology
Admin Inst: University of Queensland
Start Year: 2008
End Year: 2010
Total funding: $455,160
Grant Type: NHMRC Project Grants
Title of research award: Hyperpolarized Helium MRI to quantify regional lung damage and ventilation for
improvement of recruitment strategy.
Lay Description (from application):
Many lung injuries need mechanical ventilation to reopen collapsed lung airspaces and supply oxygen to the
patient. This study uses two methods to monitor the lungs during ventilation: Hyperpolarised helium MRI to
image the airspace, and electrical impedance tomography to measure lung volume. This information will allow
adjustment of ventilator pressure to maximize oxygen transfer without increasing lung damage. Quicker repair of
lung damage and patient recovery are the benefits of this study.
Research achievements (from final report):
This grant has allowed the development and comparison of two techniques of imaging of the lung in ventilated
patients.
Hyperpolarised Helium MRI was successfully carried out in the rat using a high resolution MRI. Whilst this is not
the first time this has been done, our group is the only Australsian group who can do this, and one of the few to
have developed in house hyperpolarisation of helium combined with a custom designed rodent ventilator allowing
the maximum polarisation time to be achieved and all the 3He to be used in imaging.
Electrical Impedance Tomography (EIT) was successfully undertaken in the same rats as Hyperpolarised Helium
MRI. We are the first group to perform EIT reliably in the rat and the first group to be able to compare the two
imaging techniques. This is of great significance as, while Hyperpolarised Helium MRI can be seen as a "gold
standard", it cannot be applied at the bedside or done frequently. Whereas, EIT is a somewhat novel technique
that can be done on a continuous basis at the bedside.
Expected future outcomes:
Three additional publications are under submission and review currently.
Sadly, the worldwide supply of Helum 3 dramatically reduced during the course of this grant, which greatly
restricted the number of studies that could be performed. However, should Helium 3 become more readily
available, we have identified how this methodology could e used to optimise ventilation in the criticilly ill.
Name of contact: John Fraser
John Fraser
Email of contact: John_Fraser@health.qld.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301099
CIA Name: A/Pr Helen Cooper
Main RFCD: Cellular Nervous System
Admin Inst: University of Queensland
Start Year: 2004
End Year: 2006
Total funding: $432,750
Grant Type: NHMRC Project Grants
Title of research award: Dissecting the molecular mechanisms driving cell migration during neurulation
triggered by the netrin receptor, neogenin
Lay Description (from application):
In humans, abnormalities in brain and spinal cord formation during early embryogenesis result in congenital
syndromes such as spina bifida and anencephaly. These defects occur at a rate of 1/1000 pregnancies and are
therefore a major contributor to pre- and perinatal deaths. In the early embryo, the brain and spinal cord begin as a
hollow tube of cells (the neural tube) that subsequently expands into the complex structures seen at birth. It is
known that the neural tube is formed by a complex process in which early neural cells migrate toward the midline
of the embryo and subsequently coalesce. This project seeks to determine the function of one molecular signaling
pathway (the neogenin pathway) that has been implicated in driving these cell migration events. We will initially
use the frog, Xenopus laevis, as our embryonic model since the developmental processes that form the Xenopus
neural tube closely parallel those ocurring in the human embryo. This model will allow us to identify the
molecules in the neogenin signaling pathway. We will also create mice that carry a mutation in the neogenin gene
so that we can study neogenin function in the mammal. We anticipate that these studies will provide important
insights into the development of the central nervous system and also into the aberrant molecular processes
underlying neural tube defects in man.
Research achievements (from final report):
Cell migration is one of the principal events in laying out the architectural plan of the central nervous system
during embryogenesis. The netrins and their receptor, Neogenin, are now emerging as a major guidance system
driving neural migration the embryo. Our recent studies have used Xenopus (frog) embryos as our developmental
model to demonstrate that Neogenin is a key receptor responsible for the correct formation of the neural tube, the
earliest identifiable brain structure. We have shown that loss of Neogenin impairs neural migration resulting in
significant morphological abnormalities in the neural tube. Furthermore, these abnormalities eventually
suppresses neuron production throughout the developing brain. Similar abnormalities are seen during human
neural tube formation leading to anencephaly and spina bifida. Such failures in neural tube development occur in
1/1000 human pregnancies. Therefore, understanding the role of Neogenin in neural tube development is
providing new insights into prevalent human central nervous system developmental abnormalities.
Expected future outcomes:
We have identified a possible novel molecular drug target for the prevention of neural tube defects in the embryo.
We are now exploring this idea further.
Name of contact: Helen Cooper
Email of contact: h.cooper@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519771
Start Year: 2008
CIA Name: Prof Michele Sterling
End Year: 2011
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $331,674
Admin Inst: University of Queensland
Grant Type: Career Development Fellowships
Title of research award: Whiplash injury: Classification, prediction and directives for improved management
strategies.
Lay Description (from application):
Whiplash is a costly condition with many people developing chronic symptoms. This research aims to improve
the diagnosis and classification of the condition from the time of injury until either recovery or the development
of persistent pain. This will facilitate the early identification of those at risk of poor recovery and will lay the
foundations for the development of improved early management, particularly in primary care.
Research achievements (from final report):
This research has further developed and validated prognostic models for poor recovery following whiplash injury
allowing clinicians and stakeholders greater confidence in identifying people at high risk of developing chronic
pain and disability. It has also demonstrated the importance of psychological symptoms following the injury,
particularly symptoms of posttraumatic stress. Not only are these factors predictive of poor recovery but they also
show a relationship with physical features namely, morphological muscle change. The results of this research
demonstrate the clear importance of both physical and psychological aspects of this condition and that they interrelate. The research demonstrated that by addressing posttraumatic stress symptoms in people with an already
chronic condition, that pain, disability and distress were alleviated. The research has made a marked impact on the
field. The results have been included in current clinical practice guidelines and clinicians now routinely evaluate
patients for the presence of these factors. Treatment of Whiplash Associated Disorders is changing as a result.
Expected future outcomes:
It is expcted that this research will pave the way for the development and testing of novel and new interventions to
prevent the development of chronic pain and disability following whiplash injury.
Name of contact: Prof Michele Sterling
Email of contact: m.sterling@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569826
CIA Name: Dr Stella Bjorkman
Main RFCD: Neurology and Neuromuscular Diseases
Admin Inst: University of Queensland
Start Year: 2009
End Year: 2011
Total funding: $547,971
Grant Type: NHMRC Project Grants
Title of research award: GABA excitotoxicity, neuroprotection and the perinatal brain
Lay Description (from application):
Approximately 3.5% of babies die each year from brain damage due to perinatal asphyxia, a shortage of oxygen
to the developing brain. Babies that survive face lifelong neurological disabilities, placing enormous burden on
health, social and economic resources. Current treatments are inadequate. We will examine what occurs when
there is a shortage of oxygen to the developing brain and investigate pathways to hypoxic brain injury that offer
opportunities for therapeutic intervention.
Research achievements (from final report):
We established the normal developmental profile of the GABAA receptor a1, a3, b2 and NKCC1 and KCC2
proteins in 4 cortical regions and hippocampus from piglet across several gestational timepoints. We have
demonstrated a switch in expression between the a3 and a1 proteins around birth which is similar to that
previously reported in other species and, a coincident upregualtion of KCC2 expression which togther may
constitute the maturation of inhibitory function of the GABAA receptor. we also showed that this switch was
regionally and temporally dependant. NKCC1 was found to be stably expresssed across gestation in the piglet
brain. The effect of HI on GABAA receptor a1, a3 and NKCC1 and KCC2 proteins resulted in significant
decreases in expression that was further exacerbated by the presence of seizures. Establishing the normal
developmental profile of these systems and understanding the effect of seizures on these proteins will allow us to
better direct future research on antiepileptic treatments specific and appropriate for the developing newborn brain.
The GABA system may also offer another potential avenue for neuroptotection following HI injury.
Expected future outcomes:
Results from this study have provided insights as to the excitotoxic role of the GABA system in newborn HI brain
injury and have laid the foundation for pursuing alterantive pathways to neuroprotection and treatment of seizures.
Name of contact: Dr Tracey Bjorkman
Email of contact: t.bjorkman@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351519
CIA Name: Dr Sheree Cross
Main RFCD: Intensive Care
Admin Inst: University of Queensland
Start Year: 2005
End Year: 2007
Total funding: $342,375
Grant Type: NHMRC Project Grants
Title of research award: Management of burn injury: Fluid dynamics and antibiotic pharmacokinetics
Lay Description (from application):
It is well known that major burns, as well as being relatively common injuries, are notoriously difficult to
manage. Patients exhibit significant variability due to a combination of anatomic, physiologic, hormonal and
immunologic alterations occurring both at the wound site and, more importantly, in other body compartments and
vital organ systems. Skin burn injury results in the release of multiple inflammatory mediators in addition to
significant fluid loss. The distribution of inflammatory mediators and wound bacteria to central organs can cause
complex physiological changes that may lead to multiple organ failure, with serious infections occurring in around
50% of patients with serious burns. Antibiotic distribution kinetics, such as bioavailability, clearance, volume of
distribution, elimination half-life and unbound fraction in plasma can be significantly altered in burn patients.
Without detailed knowledge of changes and relationships between factors such as wound pH, tissue oxygenation,
protein concentrations of fluid leaked from the local wound microvasculature, tissue binding, oedema and changes
in burned and non-burned tissue induced by resuscitation therapies, the optimisation of both local and systemic
infection contriol therapies can hardly be expected to advance. This project aims to determine how changes the
physiology of burn patients, in particular in the burn wound environment, affect antibiotic penetration and
distribution into tissues. We also believe that these changes will vary between patients and are aiming to
determine whether certain parameters can be used to give an indication of the best antibiotic dosing regimens for
individual patients.
Research achievements (from final report):
Patients with severe burns are at great risk of life threatening infections. Effective antibiotic therapy is crucial to
the survival of patients with extensive burns and to the optimal operation of hospital burns units. Burn patient
physiology is very complex and changes dramatically over the first week of treatment. Before commencement of
this project there was a lack of scientific data on the use of antibiotics in burn surgery. We applied a combination
of cutting-edge and time-honoured research techniques to thoroughly investigate the pharmacokinetics of
antibiotics during burn debridement operations. We were able for the first time to monitor local tissue levels of
antibiotics throughout burn surgery. The results permitted scientifically qualified recommendations on
perioperative burn antibicrobial prophylaxis to be published. The study identified key predictors of sub-optimal
antibacterial dosing in burn patients and made recommendations for intra-operative redosing during surgery. Our
clinical research was backed by an extensive program of healthy volunteer studies and laboratory science which
has lead to additional evaluative publications in scientific and clinical journals.
Expected future outcomes:
This research is expected to contribute significantly to future optimisation of antimicrobial usage in patients with
burns.
Name of contact: Sheree Cross
Email of contact: s.cross@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351408
Start Year: 2005
CIA Name: Prof Gwendolen Jull
End Year: 2007
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $382,550
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Title of research award: Effective management of acute whiplash injuries requires a pragmatic approach: An
RCT with stratified treatments
Lay Description (from application):
Whiplash injuries from a motor vehicle crash continue to incur substantial personal and financial costs to the
community and the insurance industry. The current approaches to an acute whiplash injury in Australia and
internationally have failed to lessen the rate of how many people develop chronic neck pain. Between 40 and 60%
still have pain 6 months after injury. Motor Accident Insurance Commission (Qld) figures indicate that 20% of
patients with chronic whiplash account for 60% of the costs. Transition from an acute to a chronic condition must
be prevented. A new direction in management in the acute stage is urgently required as once the pain has become
chronic, it is difficult to help. This research will conduct a novel randomised controlled trial for acute whiplash. It
will test individually prescribed multi-professional management against usual care with the aim to lessen the
numbers who go on to develop chronic pain. It will be the first clinical trial that acknowledges from the outset that
the whiplash injuries and affects people in different ways. Our previous research with acute whiplash patients has
documented the variations in presentation from physical, physiological and psychological perspectives. In this
trial, management will be prescribed as directed by measurable pain, muscle and psychological impairments in the
individual, rather than regard all patients as the same as in other trials. This trial will offer individualised
treatments; medical, physiotherapy and/or psychological using an empirically derived treatment algorithm. Costeffectiveness of the program will be evaluated against that incurred during usual care. It is predicted that early
multi-professional management will be less expensive in the long term than existing approaches. This RCT stands
to extend knowledge in the management of whiplash associated disorders (WAD).
Research achievements (from final report):
The presentations of persons who suffer an acute whiplash injury from a motor vehicle crash vary
significantly,from minor neck pain only to severe pain which can be accompanied by considerable distress and
post-traumatic stress. Symptoms may persist for many years. Currently guidelines for management of acute
whiplash are general and focus broadly on activity and exercise, without considering variability in presentation.
This clinical trial examined whether a multiprofessional approach (medical, physiotherapy and/or health
psychology) provided to the particiant as indicated by their individual presenting complaints would be better than
current usual care in alleviating the condition and preventing ongoing symptoms. The costs of care were also
investigated. The results of the trial indicated that the pragmatic multiprofessional approach overall offered no
significant benefits over usual care in the short or long term, although there were indications that persons who
reported high levels of pain and disability following the whiplash injury benefited more with multiprofessional
managment. Multiprofessional management cannot be justified for the acute whiplash state for the majority of
patients.
Expected future outcomes:
Prospective studies have shown that high inital pain and disability is one of the strongest prognostic indicators for
poor outcome following injury. The results of this clinical trial would suggest that this group be the target of
future research into multiprofessional management methods.
Name of contact: Professor Gwendolen Jull
Email of contact: g.jull@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210146
CIA Name: Dr James St John
Main RFCD: Sensory Systems
Admin Inst: University of Queensland
Start Year: 2002
End Year: 2004
Total funding: $256,320
Grant Type: NHMRC Project Grants
Title of research award: Defining the role of EphA5 in olfactory axon growth, guidance and fasciculation
Lay Description (from application):
The olfactory (smell) system is a unique part of the nervous system; nerve cells are generated throughout life and
it can regenerate even after injury. It therefore provides an excellent model for examining the growth,
development and maintenance of nerve cells. This project will examine the effects on the organisation of the
olfactory system when some guidance signals are altered. Information we obtain about how this system develops
and regenerates may be useful in treating brain disorders and spinal injuries In the current project we will
examine the effects of specific nerve cell guidance molecules by generating transgenic mice that produce these
molecules only in the olfactory system. We can then determine what changes occur to the nerve cells when these
extra molecules are produced. In addition, we will also examine the behaviour of live cells as they are growing. In
the past all attempts to understand how nerve cell connections are formed in the olfactory system have used dead
tissue that has been permanently preserved. In this project we have the unique opportunity to visualise living nerve
cells to enable us to determine how the cells react to the guidance signals. The advantage of this approach is that it
allows us to identify important interactions as they occur, rather than attempting to decipher them after they have
occurred. An analogy would be watching a football game live and observing how goals were scored and
appreciating the performance of individual players versus trying to guess from the final score how the game was
played and who the key performers were. The results of these experiments will provide important information on
the regeneration of olfactory nerve cells, as well as on the initial growth and targeting of these nerve cells.
Research achievements (from final report):
The olfactory (smell) system is a unique part of the nervous system; nerve cells are generated throughout life and
it can regenerate even after injury. It therefore provides an excellent model for examining the growth,
development and maintenance of nerve cells. This project has examined the effects on the organisation of the
olfactory system when some guidance signals are altered. Nerve cells find their appropriate target by following a
combination of guidance cues. However different guidance molecules are likely to present in the young animal
compared to the adult and therefore regeneration may be different in animals of different ages. We have examined
how nerve cells find their targets following widespread regeneration in the adult and found that targeting is often
inaccurate with nerve cells terminating in numerous inappropriate sites. These results support the notion that the
coordinated expression of a suite of guidance cues is required for correct nerve cell targeting during development
and during regeneration in the adult. Our results have provided an excellent understanding of how the sense of
smell develops and regenerates and these results may be useful in treating brain disorders and spinal injuries.
Expected future outcomes:
Design of drug and cell-based therapies for brain and spinal regeneration
Name of contact: James St John
Email of contact: james.stjohn@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631629
Start Year: 2010
CIA Name: Prof Justin Cooper-White
End Year: 2011
Main RFCD: Regenerative Medicine (incl. Stem Cells and Tissue Engineering) Total funding: $296,867
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Title of research award: TAKING THE LIMP OUT OF CARTILAGE REPAIR
Lay Description (from application):
In Australia osteoarthritis is the leading cause of pain and disability with the majority of individuals displaying
radiographic evidence of this condition by age 65. We are developing two novel technologies which use patients'
own stem cells to repair damaged cartilage. This project involves both the advancement of these technologies as
well as their evaluation using a sheep cartilage repair model. These technologies offer significant promise for
those suffering joint pain.
Research achievements (from final report):
This project aimed to produce highly functional cartilage cells (chondrocytes) from mesenchymal stem cells
(MSCs) using our novel low oxygen micropellet (LOM) differentiation process and a novel in vitro culture
system, which prevents matrix loss to the bulk medium, to generate fully functional ex vivo cartilage tissue plugs.
We have successfully demonstrated that LOMs can be readily assembled into larger tissue constructs suitable for
cartilage defect repair. Further, we have optimized MSC chondro-induction medium, to enhance early
chondrogenic differentiation, and subsequently enhance the matrix output of mature cells. The effects of the
presence/presentation of extracellular matrix (ECM) molecules on the conversation of MSCs to chondrocytes have
been thoroughly investgated and these insights have been translated to the formulation design of novel hydrogel
scaffolds. This scaffold system is capable of displaying ECM molecules and can be optimised to match cartilage
tissue mechanics. MSCs have been successfully encapsulated within the hydrogels and cultured under inductive
conditions. These outputs confirm the utility of our novel in vitro protocols for functional cartilage tissue
formation, in readiness for in vivo assessment.
Expected future outcomes:
The ultimate aim of our work into cartilage tissue engineering is to generate functional ex vivo cartilage tissue
from MSCs and test its suitability for cartilage repair in humans. The results obtained from this in vitro
investigation have provided the necessary proof-of-concept data to permit this novel approach to move into in
vivo assessment within appropriate small animal models.
Name of contact: Justin Cooper-White
Email of contact: j.cooperwhite@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 142931
Start Year: 2001
CIA Name: Prof Jenny Strong
End Year: 2003
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $105,794
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Title of research award: Inter-rater reliability and predictive validity of a new functional capacity evaluation for
chronic back pain
Lay Description (from application):
Back pain costs the Australian community tens of billions of dollars. Back pain is one of the main causes of work
injury and lost time from work. The longer a person is off work, the harder it is to get them back to work.
Workers' compensation systems around Australia aim at getting the injured worker with back pain back to work as
soon as possible. One of the difficulties in this process is determining what the person with back pain can
physically do in the workplace. An evaluation technique, called functional capacity evaluation (known as FCE), is
one method used to find out what the person with back pain physically can and cannot do. In a FCE, a trained
health professional such as an occupational therapist, observes the person performing a range of physical activities
like the ones he or she may have to perform in a job. The therapist closely observes the person performing
activities such as lifting, carrying, kneeling, crouching, balancing, and walking and notes any limitations in the
person's ability to complete the activities. The therapist makes comments about what difficulties the person may
have on the job and recommendations about how these could be reduced or eliminated. The information gained
from these evaluations can be valuable for the treating doctor in deciding whether the person is ready to go back to
work and what duties the person can and cannot do on the job. Because of such value they provide, FCE is
commonly used in rehabilitation programs endorsed by workers' compensation systems around Australia. This
widespread use and endorsement of FCE occurs despite limited research on the soundness of the ratings made
from these evaluations. There is a need to see whether recommendations made from FCEs are consistent between
therapists (i.e. reliable) and to see if the FCE accurately predicts the person's physical capacity for work. This
research will examine these issues with injured workers with back pain.
Research achievements (from final report):
This project has made a major advance in the development of a new, safe and reliable approach to evaluating the
ability of people with back injuries causing pain, to return to the workforce. The approach, known as the Gibson
Approach to Functional Capacity Evaluation, or GAPP FCE, has now been through a series of tests, using both
healthy volunteers and people with back injuries, and has been found to be both safe to use and to provide a
reliable evalaution. Functional capacity evaluation is an important tool for rehabilitation professsionals who assist
workers who have had injuries, to return to the workforce. They are considered to provide more useful data than
can be obtained from clinical impression or self-report alone. Previously however, there were limited data to
support the psychometric properties of commonly used FCEs. We have found the GAPP FCE to be safe, through
the use of a prescribed pre-screening procedure, and through the monitoring of biomechanisical, physiological and
psychophysical parameters during the performance of tasks. We found the results from the GAPP FCE to be
reliable when silently observed by multiple therapists, that is, the overall recommendations for return to work
made by independent therapists had reliability ratings (ICC [2,1]) of 0.73 and 0.75.
Expected future outcomes:
Since publication of key papers in peer reviewed journals in 2005, dialogue with other research groups has begun,
to enhance the science of FCEs. Our research team will continue to work on developing the FCE so it can be
available for day-to-day use in many settings around Australia. The team is meeting to plan the steps in the
commercialisation process over the coming months.
Name of contact: Professor Jenny Strong
Email of contact: j.strong@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301143
CIA Name: Prof Mark Forwood
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2004
End Year: 2006
Total funding: $440,750
Grant Type: NHMRC Project Grants
Title of research award: Investigation Of COX-2 Regulation Of Bone Turnover And Mechanically Induced
Bone Formation By Genetic overexpression.
Lay Description (from application):
This project is important because it uses novel experimental models to advance our knowledge of prostaglandin
biology in normal and pathological bone remodelling, and the response of the skeleton to increased physical
activity. We expect that a genetic modification in mice to increase the normal production of key prostaglandin
enzymes, cyclooxygenase-2 (COX-2), in bone cells will increase the number of cells that remove bone
(osteoclasts), and increase bone loss and the rate of bone turnover when compared to normal mice. We believe this
will occur via the effect of prostaglandins on expression of genes that control osteoclast formation. This will be
tested by examining the structure of the skeleton, and the expression of certain genes, in transgenic mice at
different ages from 2-8 months. These effects may be exacerbated in conditions of increased bone turnover, such
as postmenopausal bone loss. This will be tested by examining the bone structure and gene expression in adult
mice following removal of their ovaries. Due to the role of COX-2 in adaptation of bone to mechanical loading,
we also expect the load-bearing skeleton to be more sensitive to increased weight-bearing activity. We will
investigate this hypothesis by applying mechanical loads to the tibiae of mice in a controlled manner and then
analysing the bone structure. Knowledge of specific pathways by which bone formation can be stimulated is
important for developing novel approaches to induction and augmentation of osteogenesis in skeletal diseases
associated with ageing or disability, or for maintenance of new bone around implants. The discovery that COX-2
is a key enzyme in mechanotransduction and osteoclastogenesis in bone, and a pharmacological target for
modulating inflammation, has considerable clinical significance. Exploiting this knowledge requires precise
knowledge of the role of this enzyme in bone remodelling and adaptation and our experiments will contribute
significantly to that knowledge
Research achievements (from final report):
This project used novel experimental models to advance our knowledge of prostaglandin biology in bone health
and disease. We used a genetic modification in mice that allowed us to increase the normal production of
prostaglandins in bone cells, alone. This was done by increasing the synthesis of an important enzyme in bone
resorbing cells called osteoclasts. The enzyme, cyclooxygenase-2 (COX-2) is normally found during
inflammation, but is also crucial for bone cell function. We observed that osteoclasts from these mice did indeed
express high levels of COX-2 when cultured in vitro. Importantly, using micro-computed tomography,
preliminary analysis of bone architecture of these mice revealed an osteoporotic phenotype compared to control
mice, suggesting the importance of this enzyme in such diseases. We believe this is mediated via the effect of
activated osteoclasts to increase bone turnover. This is now being tested. Generated in this project, COX-2 overexpressing mouse models could also be extremely valuable for evaluation of the in vivo effects and efficacy of
new, as well as existing, inhibitors of COX-2 activity. It is also possible that overexpression of COX-2 in either or
both cell types of bone can become a useful model(s) of disorders of bone turnover and remodelling, e.g.
osteoporosis.
Expected future outcomes:
We will use these mice to test the physiological role of COX-2 in the skeleton in these conditions where it is being
overexpressed. These experiments will examine the response of bone to mechanical loading, the loss of bone
following ovariectomy, and the role of COX-2 during fracture healing.
Name of contact: Mark Forwood
Email of contact: m.forwood@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 252771
Start Year: 2003
CIA Name: Prof Gwendolen Jull
End Year: 2005
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $264,750
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Title of research award: Physiological mechanisms of efficacy of cervical flexor muscle retraining
Lay Description (from application):
Neck pain is a significant problem in society and its frequency is beginning to match the proportions of back pain,
probably reflecting our increasingly sedentary lifestyles. Several problems have been identified in the muscle
system in persons who suffer from neck pain. Therapeutic exercise has been found to have benefit in preventing
and relieving pain and improving the neck function. Currently there are several, quite different methods of
exercise and there is controversy regarding how therapeutic exercise works. It has been argued that parameters
such as changes in muscle strength, endurance, joint position sense or muscle coordination may be responsible for
the clinical efficacy. It is difficult to disentangle the effective component of exercise strategies and thus prescribe
the most effective exercise strategies. This series of experiments will evaluate the physiological factors that
change with a specific exercise intervention and to compare different exercise modalities in order to identify the
most effective means to induce these changes. Cervical muscle training, using a proven exercise intervention
strategy for chronic neck pain and headache, has been chosen as the model to investigate these questions. This
exercise strategy has been chosen not only because it has been shown to be effective, but also because it does not
conform to contemporary rationales for strength or endurance training. Thus while effective in relieving pain, it is
unlikely to produce changes in these parameters. Thus other mechanisms are likely to be responsible for the
clinical change. This research stands to make a significant contribution to exercise therapeutics by identifying the
effective components of different exercise methods and investigating the pain relieving effects of the specific
exercise. This knowledge will lead to the construction of a research based exercise program for neck pain patients,
rather than have the current situation of often arbitrary choice of exercise.
Research achievements (from final report):
Neck pain is a significant problem in society and its frequency is beginning to match the proportions of low back
pain. Changes in neck muscle function have been identified in people with neck pain and therapeutic exercise
programs designed to address these deficits, have demonstrated efficacy in relieving neck pain. However, several,
quite different methods of exercise have been proposed and there is controversy regarding optimal exercise
selection and how exercise achieves pain relief. It has been argued variously that parameters such as changes in
neck muscle strength, endurance, joint position sense or muscle coordination may be responsible for the clinical
efficacy.
A series of experiments was undertaken to evaluate the effect of various exercise regimes on physiological
measures of neck muscle function which are known to be impaired in people with neck pain. The results indicated
that specificity in training is required to most effectively change neck muscle impairment. This knowledge has
translated to the construction of a research based, progressive exercise program for neck pain patients, rather than
the current situation of an arbitrary choice of exercise. The efficacy of this exercise approach is currently being
tested in a randomised clinical trial for neck pain following a whiplash injury.
Expected future outcomes:
The results of the research will guide further development of specific therapeutic exercise interventions for the
management and prevention of neck pain, based scientifically on the physiological responses to training.
Name of contact: Gwendolen Jull
Email of contact: g.jull@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276415
CIA Name: A/Pr Edith Gardiner
Main RFCD: Endocrinology
Admin Inst: University of Queensland
Start Year: 2004
End Year: 2006
Total funding: $496,500
Grant Type: NHMRC Project Grants
Title of research award: Anabolic Bone Gene Pathways
Lay Description (from application):
Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive
loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current
treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in
the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to
work together to increase bone formation. This proposal is aimed at characterising these genes and the ways in
which they work to determine whether they may be good targets for new osteoporosis treatments. We will
examine the patterns of these genes in bone. We will also use cell cultures in which bone forming cells develop
and function, to determine when the genes are expressed and how they function. We will test the ability of the
candidate genes to cause an increase in the amount of bone forming activity in these cell cultures. An increase in
bone formation may be caused by an increase in the number bone-forming cells, an increase in the activity of the
cells, a decrease in cell death, or a combination of these changes. Each possibility will be tested. This research is
important because of the need for new osteoporosis therapies to repair weakened bones. The knowledge resulting
from this proposal has the potential to provide an important contribution to skeletal health and thus aged health
worldwide.
Research achievements (from final report):
Osteoporosis is a condition in which bones are fragile, at least in part because of a decrease in bone mass. In
osteoporosis research, the Wnt regulatory pathway is being studied because it can increase bone mass by
increasing the activity of osteoblasts, which are the bone forming cells. How the Wnt pathway stimulates
osteoblast activity is not well understood, however, and in this project we have unexpectedly discovered that
under some circumstances, Wnt pathway activation can inhibit the bone forming activity of osteoblasts. In
experiments designed to explain how this unusual observation could occur, we have demonstrated that Wnt can
alter the expression of key genes that control the development and maturation of osteoblasts. We have also
discovered a novel mechanism of interaction between the Wnt pathway and another major regulator of osteoblasts,
the vitamin D response pathway. The knowledge gained in these experiments is important because any future
osteoporosis therapies based on Wnt pathway activation must take into account the potential negative as well as
positive effects of such interventions. Better understanding of the range of consequences of Wnt activation
including the effects on the osteoblastic vitamin D response will aid in the development of effective strategies for
both Wnt and vitamin D based therapies.
Expected future outcomes:
Future studies will determine why the negative effects of Wnt activation on bone formation occur under some
circumstances but not others.
Name of contact: Edith Gardiner
Email of contact: e.gardiner2@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401553
CIA Name: Prof Mark Forwood
Main RFCD: Orthopaedics
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2008
Total funding: $412,653
Grant Type: NHMRC Project Grants
Title of research award: Molecular and histopathological investigation of stress fracture healing and effects of
anti-inflammatory drugs.
Lay Description (from application):
Stress fractures are debilitating injuries affecting children, adolescents and adults in sport, and army recruits.
They also occur in horse and greyhound racing, often resulting in euthanasia of the animals involved. They incur
considerable costs in medical expenses, time lost from sport and interruption to military training. But, there is
almost no information on the mechanism of healing of these fractures. Non-steroidal anti-inflammatory drugs
(NSAIDs) are still the most widely used medication in management of musculoskeletal injuries, yet their effect on
healing of stress fractures is unknown. NSAIDs delay fracture healing, but until recently there has been no
standardised way of studying stress fractures. We have created, for the first time, a well-characterised, noninvasive model of stress fractures in the forearm of rats that closely resembles the clinical situation. This provides
a novel and unique opportunity to determine the histological and molecular mechanism of stress fracture healing,
and to investigate effects of antiinflammatory/analgesic medications on this process. Rats will have an
experimental stress fracture produced in one forelimb, and its healing will be examined up to ten weeks using
microscopic investigation and analysis of the genes that are turned off or on to initiate the process. Groups of rats
will also be treated with antiinflammatory drugs such as ibuprofen, specific COX-2 inhibitors and a new class of
drugs that target early immune responses called C5a receptor antagonists. The analgesic Paracetamol will also be
investigated as an alternative to the NSAIDs described above. There is widespread use of anti-inflammatory
agents in managing stress fractures, so it is vital that their effects on stress fracture healing be examined. This
project has enormous significance for optimising approaches for clinical management of stress fractures and for
understanding the interaction of anti-inflammatory or analgesic agents in that process.
Research achievements (from final report):
1. We have provided the first detailed analysis of the biological mechanisms of healing of stress fractures.
2. We have reported original observations on gene expression for molecules that are important to signal new bone
remodelling that is targeted towards healing the stress fracture. These data were accepted for oral presentation at
the Annual Meeting of the American Society of Bone and Mineral Research, the largest international meeting in
the field at which only 30% submissions achieve orals. This work attracted a New Investigator Award for Ms Lisa
Kidd who presented the data (these data accepted for publication in the journal Bone).
3. We demonstrated that non-steroidal anti inflammatory drugs retard the rate of healing of stress fractures, with
distinct effects on bone formation or resorption depending on the specificity of their action.
4. We demonstrated that osteoporosis drugs like bisphosphonates retard the early resorption phase of remodelling
of stress fracture healing.
These outcomes provide unique insights in to the mechanisms of healing of stress fractures that may inform
approaches to surgical intervention in the case of non-healing stress fractures. They also highlight the potential for
altered healing when common aniinflammatory drugs are used, or stress fractures occur in the context of antiresorption therapy.
Expected future outcomes:
Based on these data, we are investigating an approach to re-activate bone remodelling at sights where stress
fracture healing is incomplete
Name of contact: Mark Forwood
Email of contact: m.forwood@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511212
CIA Name: Prof Perry Bartlett
Main RFCD: Central Nervous System
Admin Inst: University of Queensland
Start Year: 2008
End Year: 2010
Total funding: $622,361
Grant Type: NHMRC Project Grants
Title of research award: The use of soluble antagonists of EphA4 in spinal cord injuries
Lay Description (from application):
Permanent and limited recovery of function following spinal cord injury is a direct result of the lack of nerve
regrowth through the injury. Our preliminary data suggest that antagonising the effects of EphA4, a protein
involved in brain development, leads to substantial functional recovery simultaneous with nerve regrowth. In
addition to designing new, more effective blockers of EphA4, we will study the signalling pathways that EphA4
activates to inhibit nerve regrowth.
Research achievements (from final report):
Spinal cord injuries result in movement and sensory deficits for individuals. With no successful drug or treatment
to improve recovery from spinal cord injuries currently available, suffers of spinal cord injuries generally
experience permanent movement and sensory loss. We have previously shown that mice lacking the EphA4
receptor display remarkable functional recovery after a lateral cut to their spinal cord. In addition, these mice
demonstrate nerve regeneration across the cut site. In this grant, we generated and tested a recombinant protein,
EphA4-Fc, for its use as a future therapeutic. EphA4-Fc blocks the EphA4 receptor, preventing its activation.
When EphA4-Fc is delivered after injury in normal mice, their functional recovery is significantly improved
compared to untreated mice, duplicating the effects we observed in mice that lack the EphA4 receptor. We have
now tested this protein in rats with a contusive spiinal cord injury. This injury more closely mimics that which is
observed in humans. Treated rats also show significant improvements in their functional outcomes compared to
untreated rats. EphA4-Fc does not show any adverse side effects during or after treatment. Antagonists of EphA4
are proving to be promising candidates for therapeutics for not only spinal cord injury, but possibly other
traumatic central nervous system injuries as well.
Expected future outcomes:
We have demonstrated that EphA4-Fc has considerable therapuetic potential for the treatment of spinal cord
injuries. We are currently performing optimisation and other pre-clinical studies that will justify the significant
investment to proceed to clinical trials.
Name of contact: Professor Perry Bartlett
Email of contact: pa@qbi.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401599
Start Year: 2006
CIA Name: Prof Paul Hodges
End Year: 2010
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $664,574
Admin Inst: University of Queensland
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Movement is changed in pain, but the mechanism underlying this change has been poorly understood. Works
undertaken over the five years of this Principal Research Fellowship has led to a new understanding of not only
the mechanisms that cause movement to change (culminating the development and publication of a new theory to
explain the movement adaptation in pain), but also the development of new interventions to treat pain related to
the spine and the limbs, clinical trials that confirm the efficacy of these approaches, trials that show why these
interventions are effective, and initial evidence of techniques to identify individuals who may derive greatest
benefit from the exercise programs. The work highlighted changes in the function and organisation of the nervous
system including the motor regions of the brain in people with pain, and the potential for this to be resolved with
exercise. Long-term studies revealed that conditions that compromise the function of the back muscles, such as
incontinence and breathing disorders, are associated with development of spinal pain, providing potentially
modifiable risk factors for pain. Other work has identified changes in coordination of leg muscles in triathletes at
risk of stress fracture, changes in control of back muscles in older people with osteoporosis and fractures of the
spinal vertebra, mechanisms for back pain in horses, an new understanding of mechanisms for the control of
continence in men and women.
Expected future outcomes:
Future work, based on the foundations set during the Principal Research Fellowship, is anticipated to identify
clinical techniques to identify individuals with back pain who are likely to benefit most from exercise
interventions and methods to best individualise treatments. Other work aims to identify men at risk for urinary
continence after prostatectomy and more effective methods for treatment.
Name of contact: Paul Hodges
Email of contact: p.hodges@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569830
CIA Name: Prof Matthew Brown
Main RFCD: Immunogenetics
Admin Inst: University of Queensland
Start Year: 2009
End Year: 2011
Total funding: $536,680
Grant Type: NHMRC Project Grants
Title of research award: The immunogenetics of ankylosing spondylitis: a genetic and functional investigation
of IL23R and related genes
Lay Description (from application):
Ankylosing spondylitis (AS) is a common inflammatory arthritis which causes primarily back pain and stiffness,
and affects 1/250 individuals. Our group identified association between tagging genetic markers in the gene
IL23R and AS, and our preliminary data suggests some related genes are involved as well. This study aims to
identify the key genetic variants involved and determine the mechanism by which they cause AS.
Research achievements (from final report):
Ankylosing spondylitis (AS) is a common form of inflammatory arthritis affecting over 20,000 Australians with
an annual cost upto $500 million which targets the spine and pelvis. In a major breakthrough we demonstrated that
mutations in the gene IL23R were associated with AS. IL-23R is a key factor in the regulation of the
proinflammatory cytokine IL-17 which is thought to play a role in a number of inflammatory diseases. The exact
mechanism underlying the association between IL23R and AS is unknown so this grant undertook to elucidate
those mechanisms.
To date IL23R has only been associated with AS in white European patients. To establish that IL23R plays a role
in different ethnic populations that also suffer from AS we looked in Han Chinese which suffer similarly to white
Europeans from AS. Although the same IL23R mutations did not play a role in white Europeans as in Han
Chinese, we discovered different mutations in IL23R in Han Chinese associated with AS further emphasising the
importance of the IL23 pathway in AS.
We also looked at the functional role of IL23R in AS. We looked at immune cells from AS patients and controls
and investigated whether there were differences in the cells that utilise IL23 signalling. We discovered that there is
a subset of immune cells that are more responsive to IL23 and produce more IL17 that are more prevalent in AS
patients. These cells were IL23R+ IL17+ gamma delta T cells and we hypothesise these play a key role in AS.
Expected future outcomes:
Confirming a role for the IL23R pathway in non-Caucasian populations further supports development of
therapeutics based on targeting IL23 signalling
Name of contact: Dr Gethin Thomas
Email of contact: gethin.thomas@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 456003
CIA Name: A/Pr Geoffrey Goodhill
Main RFCD: Biophysics
Admin Inst: University of Queensland
Start Year: 2008
End Year: 2009
Total funding: $493,305
Grant Type: NHMRC Project Grants
Title of research award: The dynamics of gradient sensing by growth cones: timelapse imaging and
mathematical modelling
Lay Description (from application):
Problems in the wiring up of the brain underlie several nervous system disorders. The goal of this project is to
understand better how this wiring normally forms. This will ultimately lead to a better understanding of what can
go wrong with brain wiring, and how to fix such problems. It will also lead to a better understanding of how to
make axons regenerate after injury. Our approach is to use a combination of timelapse imaging of neurons in
culture, and mathematical modelling, to understand how the tips of the wires growing between neurons sense their
environment. By comparing our experimental measurements with our theoretical results we will arrive at a
detailed and accurate model of this sensing process. This will allow us to make predictions about how these
developmental events normally occur in vivo, and what can go wrong.
Research achievements (from final report):
Axon guidance by molecular gradients plays a crucial role in wiring up the nervous system. However, the
mechanisms axons use to detect gradients are largely unknown. This project combined theoretical modelling with
quantitative experimental measurements of axon trajectories and the behaviour of neuronal growth cones in
precisely controlled molecular gradients. Firstly, we developed a Bayesian "ideal observer" analysis of gradient
detection by axons, based on the hypothesis that a principal constraint on gradient detection is intrinsic receptor
binding noise. Secondly, from this model we derived an equation predicting how the degree of response of an
axon to a gradient should vary with gradient steepness and absolute concentration. Thirdly, we confirmed this
prediction quantitatively by performing the first systematic experimental analysis of how axonal response varies
with both these quantities, using the response of rat dorsal root ganglia to gradients of nerve growth factor as a
model system. We found experimentally that a measurable response can be seen to gradients as shallow as 1
molecule per millimetre, a degree of sensitivity much higher than previously reported for any chemotacting
system. Together these results reveal both the quantitative constraints that must be satisfied for effective axonal
guidance and the computational principles that may be employed by the underlying signal transduction pathways,
and allow predictions for the degree of response of axons to gradients in a wide variety of in vivo and in vitro
settings.
Expected future outcomes:
N/A
Name of contact: Prof Geoffrey Goodhill
Email of contact: g.goodhill@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401598
Start Year: 2006
CIA Name: Prof Paul Hodges
End Year: 2008
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $296,453
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Title of research award: Pain and trunk muscle control: Effects, mechanisms and consequences
Lay Description (from application):
Twenty-one percent of Australians report long-term back problems. This makes back pain the most common
chronic pain in Australia and most prevalent disorder among the National Health Priority Areas. For the majority
with recurrent and chronic problems, the cause is unknown but changes in control of the spine are thought to be
important. It is well accepted that pain and injury to the low back affect the way that we control the back muscles
and this leads to changes in spinal function. However, despite considerable investigation of this problem, there is a
distinct lack of consensus for how the control of movement is changed during pain, why it changes, and whether
these changes lead to further problems in the long term. The objective of this series of studies is to determine how
the adaptation to pain changes the control of the spine. We will use a range of techniques that include tests of the
strategies used by the brain to control the spine and mathematical models to estimate the effect that these changes
have on the spine when people are given back pain by injecting sterile salty water into the back muscles. These
studies will be backed up by measures of mechanical properties of the spine and by comparison to people with
clinical pain. This combination of methods has not been used previously and is likely to help resolve the problem
of how muscle control is chaged in back pain. We will also test a range of hypotheses regarding how pain has its
effect on muscle activity. A final series of studies aims to determine whether the failure of these changes in
muscle control to resolve after an epiosde of back pain leads to increased recurrence of pain in the long-term. The
importance of this project is highlighted by the significance of back pain as a major health issue, the lack of
consensus regarding the effect and mechanisms of pain on trunk muscle control (despite extensive investigation),
and the potential for the findings to guide rehabilitation and management.
Research achievements (from final report):
The results of this program of research have redefined the understanding of how movement changes in people
with back pain. In recent years there has been an explosion of exercise interventions that aim to make the spine
more stable. Terms like "core stability" and "stabilisation exercise" are commonly used to describe exercise for
back pain in gyms and the media. This exercise approach is based on the assumption that the spine is unstable. We
proposed a different hypothesis, that many people with back pain use strategies to increase spine stability to
prevent further pain and injury, and that these "protective" strategies may be problematic in the long-term. This
series of studies developed novel methods to study mechanical spine properties and control of trunk muscles in
healthy individuals, and people with clinical or experimentally induced back pain. Results showed that rather than
being unstable, people with back pain have increased stiffness and this is associated with increased muscle activity
consistent with protection of the spine. Other studies provide understanding of the underlying mechanisms for
these changes and the potential negative consequences. The studies also provide the first evidence that dynamic
control is compromised in back pain, which is a new target for intervention. In summary this research challenges
the assumptions of a very common clinical intervention and provides new directions for future developments for
management of people with back pain, which is one of the most common and costly health conditions in Australia.
Expected future outcomes:
This work has provided the basis for a new program or research that aims to investigate the association between
spine control and recurrence or persistence of back pain, and the association with psychological and social
parameters. The research also opens avenues for development and refinement of rehabilitation strategies.
Name of contact: Paul Hodges
Email of contact: p.hodges@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157203
CIA Name: Prof Paul Hodges
Main RFCD: Not Allocated
Admin Inst: University of Queensland
Start Year: 2001
End Year: 2005
Total funding: $484,676
Grant Type: Established Career Fellowships
Title of research award: Physiology and pathophysiology of trunk control mechanisms
Lay Description (from application):
Not Available
Research achievements (from final report):
The work undertaken during the 5 years of the Research Fellowship involved investigation of the physiology and
pathophysiology of movement control in people with a range of conditions including low back pain, respiratory
disease and incontinence. Using physiological and epidemiological methods in human and animal experiments the
studies provide novel data of a range of factors that challenge the control of the trunk muscles, and have led to the
development of intervention strategies. Examples include:
. Animal experiments showed that injury to an intervertebral disk leads to rapid atrophy of the deep back muscles.
. Evaluation of a large population of Australian women showed that incontinence and breathing disorders are a
risk factor for the development of back pain. Other studies suggest that this may be due to competition between
the contribution of the trunk muscles to spinal control, continence and breathing.
. Studies show that pain and fear of pain lead to complex changes in the control of the trunk muscles. This
suggests that patients who are fearful of injury control movement as if they have pain. These studies point to
changes in control of the muscles, rather than strength and endurance.
. Similar changes in muscle control were also identified in people with neck pain, knee pain and shoulder pain.
. Clinical trials of exercise strategies based on these studies provided evidence of clinical efficacy in people with
back, neck and knee pain. Other studies showed that the improvement in symptoms is associated with
improvements in muscle control.
Expected future outcomes:
The completed studies have provided evidence of a range of factors that are candidates as risk factors for the
development and recurrence of low back pain. Current and future work aims to determine whether clinical
interventions can change these factors and improve the long term prognosis for those at risk for back pain.
Name of contact: Paul Hodges
Email of contact: p.hodges@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569829
CIA Name: Prof Matthew Brown
Main RFCD: Immunogenetics
Admin Inst: University of Queensland
Start Year: 2009
End Year: 2011
Total funding: $568,612
Grant Type: NHMRC Project Grants
Title of research award: Major Histocompatibility Complex (MHC) Genetics of Ankylosing Spondylitis
Lay Description (from application):
Ankylosing spondylitis (AS) is the prototypic condition of a group of types of inflammatory arthritis called
'seronegative spondyloarthropathies'. These conditions are the most common form of inflammatory arthritis in
white populations and occur worldwide. One third of the risk of developing AS is determined by genes within a
region called the 'major histocompatibility complex' (MHC), in addition to the gene HLA-B27, the main gene
causing AS. We aim to identify the remaining MHC genes.
Research achievements (from final report):
o
The identification of an HLA-B27 tagSNP, rs4349859, which acts as a nearly perfect surrogate of HLAB27 (within the level of HLA-B27 genotyping accuracy). This SNP can be genotyped for <1% of the cost of
current HLA-B27 typing methods; as HLA-B27 typing is one of the most widely used genetic screening tests
performed worldwide, this will have a major impact on reducing costs. A patent application has been lodged
regarding this finding (Australian Provisional Patent Application No. 2009905817).
o
Using this finding, we demonstrated that there were no other common variants with significant MHC
associations in AS. This was published in Nature Genetics (P001085096).
o
We used this finding to investigate differences between HLA-B27 positive and -negative disease, thereby
identifying the restriction of the association of ERAP1 with AS, the first confirmed example of gene-gene
interaction in any common human disease. This was published in Nature Genetics (P001085096). The finding is
of major importance in AS research as it indicates that the mechanism by which HLA-B27 induces AS must
involve aberrant peptide handling, with increased presentation of peptides by ERAP1 to HLA-B27 increasing the
risk of disease. This narrows the potential mechanisms by which HLA-B27 induces AS substantially.
o
Having identified that interaction, we hypothesized and then confirmed that HLA-Cw6 interacted with
ERAP1 in a similar way. This was published in Nature Genetics (P000790258). This indicates that HLA-Cw6
likely operates in psoriasis by a similar mechanism to which HLA-B27 operates in AS.
Expected future outcomes:
This will enable cheap population screening for AS, and inform development of AS and psoriasis therapies.
Name of contact: Matthew Brown
Email of contact: matt.brown@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301037
Start Year: 2004
CIA Name: Prof Bill (Guglielmo) Vicenzino
End Year: 2006
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $192,625
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Title of research award: Foot orthotics in the treatment of patellofemoral pain syndrome: A randomised control
trial in primary care
Lay Description (from application):
Musculoskeletal conditions account for the third leading cause of health systems expenditure in Australia.
Patellofemoral pain syndrome or pain about the knee cap is such a condition and is often treated in primary care.
Both the individual and community are affected by this condition with an estimated 1 in 4 suffers still having
problems and pain up to 20 years after first being afflicted. Importantly it interferes with activities such as
walking, jogging, gym classes and aerobics, which are often prescribed to prevent serious conditions of the heart,
diabetes and obesity. Hence it negatively impacts on the health and well being of our nation. Two popular
treatment options that are commonly prescribed for the management of patellofemoral pain syndrome are
physiotherapy and foot orthotics. To date there is some evidence supporting physiotherapy, especially current best
practice methods such as a combined program of therapeutic exercise, manual therapy and kneecap taping. There
is a lack of evidence for the use of orthotics in treating patellofemoral pain syndrome. This project will conduct a
randomised clinical trial to evaluate the relative benefits of orthotics as the sole treatment of patellofemoral pain
syndrome and also when combined with physiotherapy. Factors associated with predicting the results of orthotic
therapy will be studied to see if there are any tests that a health care practitioner can perform to provide
information early on in a consultation regarding possible treatment outcomes. A cost-benefit analysis will also be
conducted to calculate the relative economic merits of the treatments. A tangible outcome of this project will be
the development of clinical guidelines for the most effective method of treating patellofemoral pain syndrome in
primary health care.
Research achievements (from final report):
Patellofemoral pain syndrome (pain at the front of the knee) is a common musculoskeletal condition that
substantially interferes with physical activity (e.g., walking on flat, stairs or hills; jogging; cycling) and may last
for many years. This project addressed the issue of timely managing this condition by systematically reviewing
reports of other up to date research as well as conducting the first full scale clinical trial of the role of physical
treatments, such as, foot orthoses and physiotherapy. Previous research identified in the systematic reviews
indicated that there might be a beneficial effect of foot orthoses, but that the findings of those preliminary studies
were not conclusive. To the contrary physiotherapy in the form of exercises, manual therapy and taping was
beneficial. Our clinical trial tracked 179 patients over 12 months and found a poorer prognosis for those who had
severe pain for longer and had lower functional levels, irrespective of their age, gender or general body shape.
This trial also evaluated the clinical benefits of treatment with pre-formed foot orthoses in 179 patients and found
that foot orthoses were more effective than flat shoe inserts in the short-term, but that they were not substantially
different to physiotherapy (or combined orthoses and physiotherapy) over 12 months. Interestingly, the foot
orthoses were more almost twice as effective in people with mobile feet who were relatively older, shorter and had
less severe pain. In summary, it would appear that foot orthoses might be used to hasten recovery in
patellofemoral pain syndrome.
Expected future outcomes:
The clinical trial was published in a high impact medical journal and has attracted attention (e.g., reprinted in
British Journal of Sports Medicine, invitation to speak at national and international conferences), which sets a
platform for uptake of this research in clinic and research - with downstream improved health of active young
people, thereby preventing complications of inactivity.
Name of contact: Bill Vicenzino
Email of contact: b.vicenzino@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351678
Start Year: 2005
CIA Name: A/Pr Deborah Falla
End Year: 2008
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $280,742
Admin Inst: University of Queensland
Grant Type: Early Career Fellowships (Overseas)
Title of research award: An investigation of the mechanisms of cervical muscle impairment in people with
chronic neck pain.
Lay Description (from application):
Not Available
Research achievements (from final report):
Neck pain is a common complaint which affects up to 70% of individuals at some point in their lives with an
increasing incidence. Neck pain is associated with impairment of muscle performance which can be assessed at a
functional level. Functional deficiencies reflect altered mechanisms of muscle control and changed muscle
properties. Although the basic physiological mechanisms underlying pain have been extensively investigated and
the functional impairments associated with neck pain are well documented, the cause-effect relationship between
neck pain and impaired neuromuscular control is poorly understood. This is due to the difficulty in translating
basic physiological findings into the variable and complex scenario of clinical pain conditions. Given the
difficulties in interpreting the relationship between pain and motor control in clinical studies, the work undertaken
during this Fellowship involved experimental induction of neck pain in healthy individuals with the aim of
improving our understanding of the immediate effects of pain on neck muscle function. The experimental studies
conducted have clarified both the direct and indirect effects of neck pain on neuromuscular function and have
assisted in interpreting clinical findings. The results of this research have contributed to the development of
contemporary exercise programs for the management of neck pain. These exercises have been evaluated in
randomized controlled trials and have proven to be effective for reducing neck pain and disability and for
improving neuromuscular control of the spine in people with neck pain.
Expected future outcomes:
It is expected that this work will result in a number of future studies including the evaluation of specific exercise
as a component of a multimodal / multidisciplinary intervention for the management of neck pain and evaluation
of the effect of this intervention on the recurrence of neck pain.
Name of contact: Deborah Falla
Email of contact: deborah.falla@bccn.uni-goettingen.de
NHMRC Research Achievements - SUMMARY
Grant ID: 456106
CIA Name: Prof Roy Kimble
Main RFCD: Surgery
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2009
Total funding: $209,669
Grant Type: NHMRC Project Grants
Title of research award: First aid for burns: the use of ice water and ice?
Lay Description (from application):
Millions of people worldwide receive burn injuries every year and last year the Royal Children's Hospital in
Brisbane alone treated more than 500 children with new burn injuries. Many of these children with burn injuries
will heal burn wounds with unsightly scars and impaired skin function. Cooling burns as first aid has been used
since ancient time and is proved to be the most effective way to reduce skin temperature, lessen pain, minimize
the depth of injury, and ultimately improve wound healing outcome. However, despite the evidence that cooling
burns using ice water <4 C may be beneficial to burns, current first aid recommend to only use cold water 8-25 C
and the use of ice/ice water is strongly discouraged for fear of the potential to cause hypothermia and deepen the
existing burn injury. In this application we will examine the effect of ice/ice water 2 C on wound healing outcome
compared to 15 C water as first aid, in an in vivo model. The wound healing will be clinically assessed by
experienced clinicians weekly for six weeks, and then will also be assessed histologically and mechanically at
week six. We will also determine the optimal cooling temperature and duration for injured tissue in burn wounds
to recover and the conduction of cold through skin. With the coming new knowledge we wish to design an optimal
cooling burn treatment which will maximize the beneficial of cooling to the burns but avoid adverse effect of
excessive cooling. The success of this project will advance our knowledge on first aid treatment or burn cooling
treatment and also wound healing process. It will enable us to offer better first aid treatment which may lead to
wound healing with less scars, otherwise can not achieved by other current available treatments. The better
healing of burn wounds will significantly improve burn patients' lives, particularly children with burn injuries. It
will also release the burden on much needed health funds.
Research achievements (from final report):
This project has provided in vivo evidence to support the use of first aid on burns using a large animal model
where skin closely resembles humans and has advanced our current knowledge and the mechanism of the first aid
on burn wound healing.
The findings from this project support the current first aid guidelines of immediate application of cold tap water
(approximately 15C) for 20 minutes and recommend the delay application of cold tap water even up to 3 hours
post-burn. Additionally, it finds that 2C water is beneficial to burn wound healing and, nonetheless, has limited
clinical application as first aid due to its close association with hypothermia. Ice should not be used as first aid for
burns. This project also shows that other popular alternative first aid, such as aloe vera and tea tree oil, has no
beneficial effect on burn wound healing. The findings of this project demonstrate unknown factors other than
reducing the temperature of burns may contribute to the better outcome of burn healing for cold running water,
since both ice and 2C running water can equally and effectively cool burns and ice does not enhance burn wound
healing. This project does not find that ice/ice water is detrimental to burn wounds as some suggested in this field.
The findings from this project re-define the burn first aid and reinforce the importance of the proper application
of burn first aid. This valuable information will be available to relevant regulatory bodies for the formulation of
optimal burn first aid. This information will also reach to general public through media and awareness campaigns.
Expected future outcomes:
The findings from this project will lead to revised guidelines for burn first aid which will then be used to educate
the public. The increased application of optimal burn first aid will be followed in general public and in hospitals.
This will ultimately leads to significantly less scarring from burn healing and consequently improve burn patients'
lives, particularly children with burn injuries.
Name of contact: Roy Kimble
Email of contact: royk@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569744
Start Year: 2009
CIA Name: Prof Paul Hodges
End Year: 2012
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $417,882
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Title of research award: Reconsideration of the motor adaptation to pain
Lay Description (from application):
Pain changes movement. Although undisputed, there is a surprising lack of agreement regarding the underlying
mechanisms. This project involves an innovative mix of neurophysiological methods to investigate the drive to
muscle cells from the nervous system and changes in the mechanics of contraction. These studies will resolve the
perplexing problem of how pain changes our ability to activate muscle. Clear understanding of the underlying
mechanisms can guide rehabilitation.
Research achievements (from final report):
We aimed to explore a new theory to explain movement changes in pain. It was our contention that exploration of
movement control at the micro level (motoneuron discharge/muscle fibre activation) would provide important
insight, and ultimately provide new directions for development of rehabilitation techniques for people with pain.
The work formed the basis for 2 keynote lectures, 2 invited reviews, 12 conferences presentations and published 4
journal articles.
We showed that: 1) the population of muscle fibres used to produce force changes during pain; 2) this change is
observed across a range of muscles and contraction types; 3) similar changes in muscle fibre activation occur
when pain is induced in muscular and non-muscular tissue, 4) similar changes occur when the pain is anticipated
but not present; 5) Pain increases the synchronisation of motor unit activity (that is, the liklihood that multiple
muscle fibres contract at the same time) within a muscle and decreases synchronisation between muscles; 6)
Changes in muscle fibre activation during pain are associated with a change in the direction/angle that force is
produced; 7) Both distribution of muscle activity and direction of force produced are independent of pain location
and 8) The activation of the muscle during pain appears to preferentially target larger muscle fibres (those that
generate greater force) rather than the smaller muscle fibres (that are used for more precision tasks) during pain.
All of these changes help explain how movement is changed in pain and some of the potentially problematic
outcomes of these changes.
Expected future outcomes:
One manuscript is submitted, 3 manuscripts are in final stages of preparation. This work has established
fundamentals of movement adaptation and provided the basis for ongoing work that includes tasks with increased
complexity, during sustained pain. We aim to bridge-the-gap between studies of acute experimental pain and
clinical pain conditions.
Name of contact: Dr Kylie Tucker
Email of contact: k.tucker1@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157085
CIA Name: Prof Paul Hodges
Main RFCD: Motor Control
Admin Inst: University of Queensland
Start Year: 2001
End Year: 2005
Total funding: $168,958
Grant Type: NHMRC Project Grants
Title of research award: Physiology and pathophysiology of trunk control mechanisms
Lay Description (from application):
The overall aim of this series of experiments is to understand how the spine is controlled and how this changes in
disease. Altered control has been identified in people with low back pain, yet we still know very little about the
normal mechanisms for protection and support of the spine. Back pain is a common affliction that affects about
5% of Australians each year and is the most common and expensive work-related injury in western society. An
understanding of normal control and the mechanism of dysfunction is critical for identification of risk factors and
development of strategies for rehabilitation and prevention. The experiments are divided into two series. The first
series addresses normal spinal control. The questions to be asked deal with how the brain copes with the challenge
of using trunk muscles for breathing and spinal control at the same time, how the activity of the trunk muscles is
affected by input from sensory receptors in the joints, ligaments and muscles of the spine, and whether intraabdominal pressure can support the trunk. The second series deals with clinical populations. The first aim is to
identify whether people with respiratory diseases use trunk muscles for spinal control and breathing at the same
time. If they cannot, we predict that they will be more prone to low back pain. We will test this in a large study of
incidence of low back pain in people with and without respiratory disease. The second study will investigate the
pelvic floor muscles which are important for continence and assist with spinal control. We will investigate
whether people with incontinence have poor spinal control and whether this leads to back pain. The final
experiment will identify whether people with low back pain interpret sensory information from the spine
differently. By answering these questions we hope to intervene in the enormous personal, social and economic
consequences of LBP which affects between 60-90% of the population at some stage in their life.
Research achievements (from final report):
This project involved a series of clinical and experimental studies to investigate the strategies used by the nervous
system to control the spine and changes that occur in pain and disease. The studies provide a range of important
outcomes that can guide the management and prevention of low back and pelvic pain. Key outcomes include:
. Injury to a disc in the lumbar spine causes unexpectedly rapid atrophy of back muscles. This is likely to
compromise control of the spine. These data provide a physiological rationale for exercise in back pain. This study
was awarded the ISSLS prize, the premier international award for spine research.
. A novel series of experiments studied the consequences of competition between the contribution of the spinal
muscles to control of movement and stability and the contribution of these muscles to respiration and continence.
The results show that increased demand for breathing and continence, due to disease or a function-specific
challenge (e.g. breathing increased carbon dioxide, increased bladder volume), is associated with compromised
control of the spine. This was linked to epidemiological data that showed an increased risk for development of
back pain in individuals with breathing difficulties and incontinence.
. Studies also show that low back pain, when induced experimentally, leads to dramatic changes in coordination of
spinal muscles.
The studies provide evidence of factors that compromise control of the spine. These findings have led to changes
in evaluation and management of back pain. Ongoing work aims to assess the efficacy of these refined
interventions.
Expected future outcomes:
The studies completed in this program provide a basis for a range of strategies that have the potential to refine the
management and prevention of low back and pelvic pain. Future studies are required to determine the magnitude
of the clinical effect.
Name of contact: Paul Hodges
Email of contact: p.hodges@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301103
CIA Name: Prof Justin Kenardy
Main RFCD: Health, Clinical and Counselling Psychology
Admin Inst: University of Queensland
Start Year: 2004
End Year: 2006
Total funding: $482,250
Grant Type: NHMRC Project Grants
Title of research award: Cognitive impairments and post traumatic stress symptoms in children with traumatic
brain injury: A longitudinal study
Lay Description (from application):
Traumatic brain injury in children is common with more than 2000 new cases a year in Queensland and Victoria
alone. Many children who experience a brain injury go on to have long-term difficulties such as significant
educational and social problems. Post-traumatic stress occurs in children following traumatic physical injury.
However it is not clear to what extent this is so for children who have received a traumatic brain injury.
Furthermore, when there is a traumatic brain injury and traumatic stress, it is not clear how these interact, how
they influence long-term outcomes, and what factors such as pre-injury functioning and family support and
distress mediate outcomes. These issues are very important since effective rehabilitation of children following
traumatic brain injury is essential to maximise long-term functioning and minimise disability. To be effective,
rehabilitation must be guided by the knowledge about key factors that determine the recovery process. This study
aims to provide answers to these questions by following two cohorts of children (aged 6-14) over 18 months after
receiving a traumatic brain injury. In total 240 children will be recruited from Brisbane and Melbourne hospitals.
They will be assessed at three, six, twelve and eighteen months post-injury using measures of cognitive,
psychological and social functioning. Information on parent distress and behaviours will also be obtained. The
information obtained will provide the basis for the development of a specific rehabilitation strategy for children
with traumatic brain injury, including information on strategies to help prevent any confounding impact of posttraumatic stress on recovery.
Research achievements (from final report):
The primary aim of this research was to investigate the psychological and cognitive sequelae of traumatic brain
injury (TBI) in children to examine the relationship between cognitive impairment and post-traumatic stress,
adjustment to injury, and the long-term impact on recovery. This study aims to describe the changing relationships
among key factors predicting outcome from childhood TBI (injury factors, pre-morbid child characteristics, and
family factors) up to 18 months post-injury. The recruitment of children with TBI was completed at the end of
2006. During 2007 the first four assessment time points (pre-injury, three, six, and twelve months) were
completed and we are in the final stages of completing the eighteen month assessments. This study is the largest
head injury study with children in the world examining both cognitive and emotional outcomes. To date, five
papers have been presented at both national and international conferences. Two of the conference presentations
are being developed into papers for submission to peer-reviewed journals. The results indicate a) children's preinjury behaviour does not appear to influence the severity of children's TBI, b) the psychological responses of
children following TBI are better assessed with clinical interviews (CAPS-CA) in comparison to self report
measures (TSCC), c) among children with TBI executive functioning deficits include speed of information
processing and high-order cognitive flexibility, but no apparent deficits in goal setting or reasoning, and, d)
parental distress is associated with the severity of children's TBI and children's psychological reactions but not
their neuropsychological outcomes.
Expected future outcomes:
Final assessments (18-months) will be completed by end of 2008. The next stage of data analysis is to examine
post traumatic stress symptoms over time, the relationship between PTSD and cognitive and behavioural
outcomes, and PTSD and TBI severity, and to explore theoretical issues such as the diagnosis of PTSD in children
with TBI.
Name of contact: Professor Justin Kenardy
Email of contact: j.kenardy@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401579
CIA Name: A/Pr Peter Noakes
Main RFCD: Cellular Nervous System
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2008
Total funding: $463,145
Grant Type: NHMRC Project Grants
Title of research award: The role of central and peripheral synaptic activity in the developmental death of
motoneurons.
Lay Description (from application):
Information processing in the nervous system relies on the effective communication between neurons and their
target cells which make up our neuronal circuitry. At the centre of all this is the synapse, the specialized contact
between a neuron and its target cell, be it another neuron in the brain or a target organ such as skeletal muscle.
Our primary goal is to determine how the formation of synaptic connections during development regulates
neuronal survival. In this proposal we have focussed on the neuromotor system as it is a well characterised part of
the nervous system. During development, 50% of motoneurons die at a time when they are making contact with
skeletal muscle, and when contacts onto motoneurons by other neurons are being established. We believe that the
formation of effective synaptic contacts onto motoneurons, as well as connections by motoneurons onto muscle
are the key regulators of motoneuron survival. We are in a position to be able to address what regulates
motoneuron death; as we have a number of mice which lack key molecules needed for the formation of
specialisations that allow neuronal contacts to be made between motor neurons and their muscle, and with other
neurons within the spinal cord. By examining the function of motoneurons, counting them and screening for
molecular changes in these mice, we will be able to dissect out the mechanism of how a motoneurons' fate is
determined during developmental motoneuron death. This research could help in developing strategies aimed at
improving neuronal connections to improve neuronal viability. Our research will have important implications for
our understanding about the basis of adult neuro-degenerative diseases, such as motor neuron disease and
Alzheimer's, which are in part characterised by a molecular breakdown in neuronal connections that ultimately
result in neuronal death.
Research achievements (from final report):
The role of synaptic activity in determining motoneuron (MN) survival is a key question in the developing
neuromotor system. In this grant, we have shown that genetic manipulation of neuromuscular synaptic activity
shows that relay of central synaptic activity to the periphery (muscle) is important. We have also demonstrated
that glycinergic and to a lesser extent GABAergic transmission, plays an essential role in regulating central neural
circuit activity, during the development of the neuromotor system. Specific achivements include:
1) Mice missing postsynaptic specializations at neuromuscular synapses shows increased MN survival during
development. We are writing this up. By contrast, mutations to genes that encode for transcription factors that
govern the number of post-synaptic receptor (e.g. Gabp-a) in muscle doesn't alter innervating MN numbers. This
we have published (PN12).
2) Mice lacking GABAergic transmission show regional changes in MN numbers. This change is depends upon
the switch from excitatory to inhibitory transmission for this neurotransmitter, which occurs in a rostral to caudal
sequence during development. We are examing if altering Glycinergic and GABAergic transission during
developent leads to changes in MN morphology within the spinal cord. Such changes are likely to determine the
number of pre-synaptic connections made onto MNs by other neurons within the spinal cord. We expect to write
later this year (2009). Parts of this work was presented at the following meetings: Soc. Neurosci (USA) 2007; 4th
Internat. Congress of Federation of Asian and Oceanic Neurosci. Soc. Hong Kong (2006); ComBio Conf. (2007;
2008); and Aust. Soc. Neurosci.(2009).
Expected future outcomes:
1) Submit for publication the above mentioned papers ( 2to 3 publications).
2) Create novel mutant lines of mice that will allow us to determine if there is a direct influence of pre-synaptic
connections on the development and survival of motoneurons, independent of muscle feedback to motoneurons.
Name of contact: Peter G. Noakes
NHMRC Research Achievements - SUMMARY
Email of contact: p.noakes@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569855
CIA Name: Prof Istvan Toth
Main RFCD: Pharmaceutical Sciences and Pharmacy
Admin Inst: University of Queensland
Start Year: 2009
End Year: 2010
Total funding: $209,471
Grant Type: NHMRC Development Grants
Title of research award: Neuropathic pain drugs based on the endogenous opioid peptide Endomorphin 1.
Lay Description (from application):
We have developed a new pain drug based on the natural pain killing opioid peptide, Endomorhin 1. The new
drug exhibits activity similar to morphine and gabapentin against neuropathic pain in animals but seems to act
through a different mechanism. We will complete our preclinical investigation of this compound by assessing its
side effect profile and tolerance inducing properties in animals. We will also continue our development of an
orally active analogue of this important peptide
Research achievements (from final report):
Neuropathic pain is a condition associated with nerve damage and is a common complication of diabetes,
musculoskeletal injury, and cancer. The treatment of neuropathic pain is a major unmet medical need. Currently,
opioid drugs are used to treat neuropathic pain, but result in a range of side effects, particularly tolerance,
respiratory depression, and constipation. Endomorphin-1, an endogenous opioid peptide, has the potential to treat
neuropathic pain but is unsuitable for clinical application due to poor metabolic stability and poor oral absorption
in its native form.
We created a range of derivatives aimed at improving the drug-like properties of Endomorphin-1. These
derivatives were screened in vitro to determine the μ-opioid receptor binding and agonist activity. Promising
candidates progressed to in vivo screening in a rat chronic constriction injury model of neuropathic pain. The
results of in vivo testing identified Endomorphin-1 derivatives with dose-dependent activity when delivered
intravenously. Oral analgesic potential was also evaluated and was comparable to that of morphine. Less tolerance
developed to the analgesic effect of the lead Endomorphin-1 derivative than morphine at equipotent doses. The
Endomorphin-1 derivative produced less side effects (respiratory depression, constipation, tolerance) than
morphine at antinoiciceptive doses.
Our findings suggest that Endomorphin-1 derivatives have the potential to be developed as novel opioid analgesic
agenst to treat neuropathic pain with a wider therapeutic window in respect to constipation and respiratory
depression. Further development of the lead Endomorhpin-1 derivative may result in the production of a clinical
therapeutic for neuropathic pain.
Expected future outcomes:
After completion of further preclinical examinations we will pursue business partners to progress to clinical trials.
Name of contact: Prof Istvan Toth
Email of contact: i.toth@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353619
CIA Name: Prof Boris Martinac
Main RFCD: Therapies and Therapeutic Technology
Admin Inst: University of Queensland
Start Year: 2005
End Year: 2007
Total funding: $424,500
Grant Type: NHMRC Project Grants
Title of research award: Bacterial mechanosensitive channels as novel targets for antibacterial agents
Lay Description (from application):
The focus of this research is the development of new antibiotics to combat bacterial antibiotic resistance. Since
their discovery antibiotics have had a profound effect on the health and well being of mankind, providing ready
effective treatment for otherwise intractable infections. Although pencillin was initially effective against a large
range of infections by the 1950s it was apparent that some bacterial strains had become resistant to this antibiotic.
Partially in response to this resistance new antibiotics such as streptomycin, chloramphenicol and tetracycline
were developed. These new drugs were potent against both Gram-positive and Gram-negative bacteria. However,
there were early signs that resistance to these drugs was also emerging. For example, in 1953, during a Shigella
outbreak in Japan, a strain of the dysentery bacillus was isolated which was multi-drug resistant, exhibiting
resistance to chloramphenicol, tetracycline, streptomycin and the sulfanilamides. Multidrug-resistance in
pathogenic strains of bacteria has in the last decade presented an increasing problem in treatment of bacterial
infections and diseases. In 1994 a Melbourne public hospital reported a new antibiotic resistant strain of bacteria.
This bacterium was resistant to vancomycin (the antibiotic used when all others have failed) and is known as VRE
or vancomycin resistant enterococcus. Now strains of "golden staph" resistant to all antibiotics have appeared.
The re-emergence of tuberculosis (TB), which kills more than 3 million people annually and which is spreading
rapidly throughout the world, is also a serious threat, particularly as many strains are now multi-drug resistant.
New antibiotics are needed that overcome bacterial drug resistance. It is anticipated that this research will lead to
new antibiotics by exploiting molecular components of bacteria that have only recently been identified.
Research achievements (from final report):
In this project we have completed a series of experiments testing a number of different compounds including
parabens (alkyl esters of p-hydroxybenzoic acid) as well as eriochrome cyanine R and its derivatives in functional
patch-clamp experiments and shown that they acted as bacterial MS channel (MscL and MscS) openers (Nguyen
et al., 2005). Using in silico ligand docking and ligand database canning of 2000 compounds we have identified
20 further compounds, which could serve as lead compounds in development of novel antibiotics targeting MscL
channels. Several of these compounds were tested in vitro by the patch clamp, in vivo (growth assays)
experiments and by electron spin resonance (EPR) spectroscopy. A PhD thesis describing a project based on this
research was accomplished last year (T. Nguyen: The pharmacology of the mechanosensitive channels of
Escherichia coli. PhD thesis, University of Western Australia, 2007). An Honours (First Class) project on in silico
studies of several of the 20 compounds was accomplished in 2005 (R. Boulos: Bacterial mechanosensitive
channels as novel targets for anti- bacterial agents, Honours thesis, University of Western Australia, 2005). This
has been followed by chemical synthesis of novel compounds in a PhD project (R. Boulos) that started at the
beginning of 2006. We also used two different testing methods, the checkerboard and the disk diffusion methods,
to compare in vivo efficacies of eriochrome cyanine in combination with macrolides, aminoglycosides and
penicillins against two pathogens, E.faecalis and S.aureus. In addition, we tested by the patch clamp the effect of
the spider peptide GsMTx4 shown to have antibacterial properties on the activity of MS channels of small
conductance of E. coli.
Expected future outcomes:
Further screening and investigations of potential lead compounds for novel type of antibiotics targeting MS
channels of bacterial pathogens based on this project should in not too distant future result in patentable
compounds, which could be tested in animal cells and animal models.
Name of contact: Prof Janet M Wood, University Of Guelph, Canada
Email of contact: jwood@uoguelph.ca
NHMRC Research Achievements - SUMMARY
Grant ID: 455941
CIA Name: Dr Allison Pettit
Main RFCD: Orthopaedics
Admin Inst: University of Queensland
Start Year: 2007
End Year: 2009
Total funding: $564,964
Grant Type: NHMRC Project Grants
Title of research award: Role of bone-associated macrophages in bone remodelling and bone disease
Lay Description (from application):
Musculoskeletal diseases, including osteoporosis and osteoarthritis, are a national and international health and
research priorities. Over 3 million Australians suffer from arthritis and musculoskeletal conditions and their social
and economic impact is expected to dramatically increase in the next 20 years as a result of the aging population.
Early diagnosis, prevention and treatment of many musculoskeletal diseases are currently inadequate.
Consequently, there is a high demand for effective treatment options. This project grant application proposes a
novel line of scientific investigation that will provide greater understanding of the contribution of macrophages (a
cell type that has important roles in normal tissue maintenance and defense against infection) in bone remodelling
and disease. Bone is continuously remodelled and replaced to maintain skeletal strength and mineral metabolism.
We have shown that a population of macrophages is intimately associated with bone and propose that these cells
play an important part in regulating bone remodelling. Macrophages have been implicated in many diseases that
have damaging consequences on bone, including osteoporosis and several forms of arthritis, linking aberrant
macrophage function to disease-associated bone damage. This project aims to characterize this population of
bone-associated macrophages and determine their ability to influence the function of other cells integrally
involved in bone remodelling. We will also undertake studies in animal models to determine whether these cells
are required for bone remodelling and/or damage. Detailed description of the novel role of macrophages in bone
biology will facilitate the development of superior therapeutics, preventatives and cures for bone diseases.
Research achievements (from final report):
Bone diseases and injury have substantial social and economic impact both nationally and internationally.
Osteoporotic hip fractures alone are predicted to cost $240 billion annually by 2045 in the USA. These statistics
clearly indicate the importane of maintaining lifelong bone health and preventing and/or improving fracture repair.
There are few effective bone building treatments available and their development is a clear research priority.
Research undertaken during this project grant showed that a discreet population of macrophages (traditionally an
immune cell) reside in the specilized tissues associated with bones. We designated this macrophage population
'osteomacs'. Data indicated that osteomacs are unlikely to be a precursor population for the related osteoclast cell
(specilized cell that removes bone). Strikingly, osteomacs were stratigically located at sites of new bone
formation. Presence of osteomacs in both mouse and human tissues was confirmed using a combination of
macrophage specific marker molecules and cell location. Using multiple approaches molecular markers that
distinguished osteomacs from other closely related macrophage populations were not yet discovered. However,
specific cell culture conditions were developed to generate an osteomac-like population that promoted bone
generation by osteoblast (specialized bone building cells). Subsequently osteomac-expressed factors that
potentially induce this bone formation outcome were identified. In a bone injury model, osteomacs were required
for optimal bone formation during healing. Notably, treatment with a factor that increased osteomacs within bone
injury sites also increased bone formation and accelerated bone repair. This study demonstrated that osteomacs are
an unexpected and important cell participant in bone formation.
Expected future outcomes:
Osteomacs are prime cellular targets for promoting bone repair and development of treatments that either enhance
or replicate osteomac function will improve outcomes in bone diseases and fracture repair. Identification of
osteomacs reveals greater links between the immune and bone systems and the potential for both benefit and
detriment of immune contributions to bone disease/injury.
Name of contact: Allison Pettit
Email of contact: a.pettit@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210347
Start Year: 2002
CIA Name: Dr Tamara Ownsworth
End Year: 2006
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $214,230
Admin Inst: University of Queensland
Grant Type: Early Career Fellowships (Australia)
Title of research award: Impaired self-awareness & employment outcome following acquired brain injury:
Evaluation of an employment rehabilitation
Lay Description (from application):
Not Available
Research achievements (from final report):
This 4 year project investigated the relationship between metacognitive skills (i.e., self-awareness and selfregulation) and functional outcomes following acquired brain injury (ABI). In the first stage of the project 86
individuals with ABI were involved in a 12-month longitudinal study of return to work and other psychosocial
outcomes. In the second stage of the project a series of rehabilitation interventions were evaluated involving
approximately 38 individuals, and included a case series (n=3), single case experimental designs (n=2) and a
randomised controlled trial (n=33).
The key findings of the project were as follows:
- Impaired metacognitive skills were associated with poor problem solving and error self-regulation;
- Impaired metacognitive skills and depression predicted employment outcome and independent living skills;
- Improvement in self-awareness over time was associated with obtaining employment;
- Individuals with ABI were distinguished into 4 clusters according to awareness. These include: (1) poor selfawareness due to executive dysfunction, (2) high defensiveness and low symptom reporting, (3) high symptom
reporting and low defensiveness and (4) good self-awareness. These clusters predicted emotional well-being and
psychosocial outcomes.
- Metacognitive skills can be enhanced through group rehabilitation and individual occupation-based programs in
the community. This training leads to significant clinical gains in goal attainment, emotinal well-being and
psychosocial adjustment.
From a clinical perspective, the findings highlighted the importance and effectiveness of training metacognitive
skills during rehabilitation to enhance return-to-work outcomes, independent living skills and interpersonal
relationships. Our evidence-based practice guidelines for rehabilitation are published in leading journals such as
Clinical Psychology Review, Journal of the International Neuropsychological Society, and Neuropsychological
Rehabilitation.
Expected future outcomes:
Various publications are in press and continue to be submitted as a result of the project. The randomised
controlled trial which commenced during the NHMRC project is near completion (funded by CONROD) and will
be submitted for publication. International collaborative research, involving the application of the research
methodology to other clinical populations, is ongoing.
Name of contact: Dr Tamara Ownsworth
Email of contact: t.ownsworth@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143054
CIA Name: Prof John Mattick
Main RFCD: Medical Bacteriology
Admin Inst: University of Queensland
Start Year: 2001
End Year: 2003
Total funding: $407,546
Grant Type: NHMRC Project Grants
Title of research award: Genetic dissection of the biogenesis and function of type IV fimbriae of Pseudomonas
aeruginosa
Lay Description (from application):
Pseudomonas aeruginosa is a common bacterium which causes serious life-threatening infections of individuals
with cystic fibrosis, AIDS or who have suffered severe burns or are undergoing cancer chemotherapy. This
pathogen, and a number of other important infectious bacteria use surface filaments, called fimbriae, like
grappling hooks to attach to the cells of the body and to move across host tissues. These fimbriae are produced in
response to environmental conditions, and are assembled by a process that is also used in the export of toxins and
other pathogenic molecules. This project will characterise genes which specify and control this system, as a
means to design better treatments against such bacteria, many of which are resistant to antibiotic treatment.
Research achievements (from final report):
Twitching motility occurs in most if not all bacterial pathogens. It is mediated by surface filaments termed type
IV pili and is central to the infection process, as well as to protective immunity - strains with non-functional pili
are non-infectious and antibodies against type IV pili prevent disease. The model experimental organism for this
system is Pseudomonas aeruginosa, which is an important pathogen in its own right affecting individuals with
cystic fbrosis, burns, or who are suffering HIV-AIDS or undergoing cancer chemotherapy. Other pathogens with
type IV pili are those causing gonorrhea, menigitis, and conjunctivitis. During the course of this project we
discovered several new genes controlling twitching motility in Pseudomonas aeruginosa, bringing the number of
genes and proteins known to be involved to over 40. We also discovered that extracellular DNA is required for
biofilm formation, a process that is itself central to host colonization and which involves twitching motility. This
discovery was published in the leading journal Science with wide accompanying publicity, and will open up new
avenues for preventing biofilm formation and disease. We also discovered that, contrary to previous reports,
quorum sensing is not required for twitching motility but rather that mutants in this system create regulatory
imbalances that favour mutations in other regulators, including those controlling twitching motility, with
important ramifications for how mutational studies are interpreted in bacteriology as a whole. We also
characterized two regulatory systems which control twitching motility, including a chemosensory system that
includes the most complex signal transduction protein yet described in any organism. Finally as acknowledged
leaders in this field we were invited to publish a comprehensive review on type IV pili and twitching motility by
the Annual Review of Microbiology, which will stand for some time as the definitive reference on the subject.
Expected future outcomes:
New protocols for screening for antibiotics that inhibit twitching motility. New approaches to the rational design
of antibiotics against twitching motility. New approaches to preventing bactertial biofilm formation.
Name of contact: Professor John Mattick
Email of contact: j.mattick@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453442
CIA Name: A/Pr Cory Xian
Main RFCD: Orthopaedics
Admin Inst: University of South Australia
Start Year: 2007
End Year: 2009
Total funding: $366,302
Grant Type: NHMRC Project Grants
Title of research award: Roles of injury-induced inflammatory response in regulating bony repair at injured
growth plate cartilage
Lay Description (from application):
Children's growth plate cartilage is responsible for bone lengthening. Due to popularity of sports and play,
trauma-induced growth plate damage and subsequently bone growth defects are common in children, with up to
30% of growth plate injury cases resulting in growth abnormality, for which the present surgical correction is
highly invasive and not fully effective. Although we know that the growth plate injury-induced bone growth
defects result from bony repair of the injured growth cartilage, we largely don't understand why and how this bony
repair occurs. Understanding mechanisms for this "faulty" bony repair of injured growth plate will be critical prior
to effective biological treatments can be developed. Recently, using an injury model in young rats, we found that
bony tissue formation at injured growth plate is preceded sequentially by inflammatory, fibrogenic, chondrogenic
and osteogenic responses. The inflammatory response is an initial event and our recent studies suggest that
inflammatory response recruits inflammatory cells and produces important molecules that could significantly
influence subsequent fibrogenic, chondrogenic and osteogenic events leading to the bony repair of the injured
growth plate cartilage. The current proposal further addresses roles of the inflammatory response and the
molecular pathways of this response in regulating downstream bony repair events. This project will generate novel
understanding on the "faulty" bony repair of injured growth plate, and will provide valuable information for
developing cost-effective and simple therapeutic intervention that aims to prevent bony repair and to enhance
cartilage regeneration of the injured growth plate in children.
Research achievements (from final report):
Growth plate injuries are common and are often repaired by bony tissue which causes limb length
discrepancy/angulations. In past 3 years, using a rat model, we have confirmed 4 phases of injury responses
(inflammatory, fibrogenic, chondrogenic/osteogenic, and bone bridge formation/maturation) and involvement of
intramembranous and endochondral ossification mechanisms in the bony repair. Our global gene expression
(microarray) analysis revealed altered Wnt and BMP signalling pathways during growth plate bony repair. We
observed that some cytokines and growth factors were upregulated during the inflammatory phase, and that
infiltrated marrow stromal progenitor cells are responsive to PDGF and TNF-a in migration; to PDGF, TGF-a,
FGF-2, and TNF-a in proliferation; and to TGF-b1 and BMP in chondrogenesis. We have shown that inhibition of
osteogenic transcription factor Osx by blocking PKD activation appears to suppress bony repair and enhance
cartilage repair at the injury site. Using a sheep model, we demonstrated that ovine bone marrow mesenchymal
stem cells (MSC) are multipotential and can form cartilage-like tissue when transplanted etopically in mice, and
that in a growth plate injury model in lambs, autologous marrow MSC failed to promote growth plate cartilage
regeneration. Summary: In the last 3 years with this grant, we have achieved a good understanding of the
mechanisms for the "faulty" bony repair of injured growth plate, and have identified some potential targets (eg,
infiltration of stromal progenitors prior to bony repair) for investigating potential biological strategies for
preventing the faulty bony repair and promote cartilage regeneration of the injured growth plate.
Expected future outcomes:
Further increased understanding of the pathophysiology for the growth plate faulty repair will be achieved from
follow-up studies. Further studies will be carried out to investigate therapeutic potential of ex vivo expanded
autologous MSC in promoting growth plate regeneration, and to explore strategies to enhance growth plate
regeneration by mobilising endogenous MSC.
Name of contact: Prof Cory Xian
Email of contact: cory.xian@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570870
Start Year: 2009
CIA Name: Prof Simon Chapman
End Year: 2011
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $447,174
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: What characterises influential population-oriented public health policy research in
Australia?
Lay Description (from application):
This project examines the characteristics of Australian research and researchers whose work is judged to be
influential in influencing public health policy in 6 areas: tobacco control, cancer screening, injury prevention,
cardiovascular disease prevention, illicit drugs and alcohol control. The project involves work with both
researchers and those who are in positions to advocate and enact policy (politicians, government officials,
journalists, public health agencies).
Research achievements (from final report):
Not Available
Expected future outcomes:
Further papers expected to be published
Name of contact: Simon Chapman
Email of contact: simon.chapman@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 107203
Start Year: 2000
CIA Name: Prof Kathryn Refshauge
End Year: 2002
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $234,602
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: Exercise or advice for sub-acute low back pain?
Lay Description (from application):
Low back pain (LBP) is highly prevalent and enormously expensive to society: total payments made by
Workcover for injuries to the low back were in excess of $530 million in NSW in 1996. Chronic LBP (pain
lasting more than 3 months) accounts for up to 90% of these costs. Prevention of a large part of this costly
problem could be achieved by effective treatment at the earlier sub-acute phase of LBP (6 weeks to 3 months
duration). Exercise and advice are two widely-used treatments for sub-acute LBP, yet remarkably, their efficacy
is unknown. For the first time, this study will rigorously evaluate the effectiveness of both a supervised exercise
program and advice to return to normal activity for sub-acute LBP. When this study is completed, Australian
practitioners will be able to adopt evidence based practice when managing sub-acute LBP. In addition, the study's
results will enable practitioners to select the most effective treatment for each individual patient. The results of
this study should lead to a large reduction in the incidence of chronic LBP, therefore the results should lead to
significant savings in terms of social and economic costs.
Research achievements (from final report):
N/A
Expected future outcomes:
We will complete analysis of three month and 12 month outcome data within the next three months. We will also
analyse the data about predictors of prognosis for subacute low back pain, determining who responds best to
exercise or advice. Our findings to date provide evidence that exercise and advice are effective treatments to
decrease pain and disability for subacute low back pain. However, there are many different types of exercise
programs, and we investigated only one form of exercise. We will continue this research program by investigating
the most effective types of exercise and the most successful methods of implementation. In addition, we are
currently extending the findings of the systematic review by conducting a rigorous study to determine accurately
the prognosis of acute low back pain. We will also determine the accuracy of diagnosis of spinal pathology from
questions asked in the history. The ultimate benefits of our research progam are that patients with low back pain
will be treated more effectively, and more accurate predictions of prognosis can be made.
Name of contact: N/A
Email of contact: N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 211031
CIA Name: Prof Robert Cumming
Main RFCD: Preventive Medicine
Admin Inst: University of Sydney
Start Year: 2002
End Year: 2004
Total funding: $403,892
Grant Type: NHMRC Project Grants
Title of research award: Improving vision to prevent falls: a randomized trial
Lay Description (from application):
More than 30% of older Australians fall over at least once a year. Poor eyesight, another very common problem
among older Australians, increases the risk of falling. In fact, recent evidence from the Blue Mountains Eye Study
suggests that poor vision is one of the strongest risk factors for falls and fractures yet identied. Our project is
designed to assess whether improving vision will decrease the chance of falls and fractures. We will recruit 1200
people aged 75 years and over from among those attending community-based aged care services in the inner
western suburbs of Sydney. If they consent to participate, people will be randomly allocated to either an
intervention or control group. Those in the intervention group will receive a simple, yet comprehensive, series of
vision and eye tests. These tests will be done by an optometrist, either in subjects' homes or at the study centre.
Our previous research suggests that nearly 50% of subjects will benefit from having new glasses and 10% might
require cataract surgery. If necessary, treatment will be paid for from study funds. Some vision problems cannot
be fixed. In these cases, an occupational therapist will arrange appropriate home modifications to improve visionrelated function. Subjects will be followed-up for 12 months to assess the frequency of falls in the intervention
and control groups. We hope to find a 33% reduction in falls in the intervention group. We will follow subjects for
a further year to identify fractures.
Research achievements (from final report):
This is a 3-year randomized trial evaluating vision testing and treatment for prevention of falls in older people.
Final follow-up of subjects is only just complete and data analysis is underway. No results are yet available.
Expected future outcomes:
This project will provide important information about the need for additional eye services to prevent falls in older
people
Name of contact: Robert G Cumming
Email of contact: bobc@health.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402564
CIA Name: A/Pr Robert Vandenberg
Main RFCD: Basic Pharmacology
Admin Inst: University of Sydney
Start Year: 2006
End Year: 2008
Total funding: $509,018
Grant Type: NHMRC Project Grants
Title of research award: Molecular and Cellular Basis for the Analgesic Properties of N-Arachidonyl amino
acids
Lay Description (from application):
Chronic pain affects 20% of the population of Australia, but current treatments for chronic pain are often
problematic. A recently described class of compounds, the arachidonyl amino acids, show particular promise as
analgesic agents, but at present there is very little understanding of how these compounds mediate their analgesic
effects. In this project we will apply a variety of molecular, cellular and behavioural approaches to understand
how the arachidonyl amino acids provide pain relief.
Research achievements (from final report):
This project has identified a series of new compounds that have the potential to be developed as drugs for the
treament of pain. We have characterized the actions of these compounds at the molecular level, the cellular level
and in animal models of pain.
Expected future outcomes:
This project has opened up a number of a new approaches for the treatment of pain. Further work in this area may
lead to alternate drug therapies for pain, which are devoid of some of the side effects of current theraputics
Name of contact: Robert Vandenberg
Email of contact: rvan9242@mail.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570884
Start Year: 2009
CIA Name: Prof Chris Maher
End Year: 2012
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $620,557
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: A randomised controlled trial of a promising new treatment for chronic whiplash
Lay Description (from application):
Following a whiplash injury about one third of people develop persisting pain and disability i.e. chronic whiplash.
In a series of pilot trials we have developed a new physiotherapy treatment for chronic whiplash. Initial results are
very promising. We now propose to definitively establish the effectiveness of this new treatment in a large clinical
trial. At the same time we will evaluate the cost-effectiveness of the treatment.
Research achievements (from final report):
Whiplash is a common injury that typically leads to long term (chronic) pain. At present there are no clearly
effective treatments. We completed a clinical trial to evaluate the effectiveness and cost-effectiveness of a new
treatment for chronic whiplash.
Expected future outcomes:
The trial will inform decisions about allocating resources for management of whiplash.
Name of contact: Prof Chris Maher
Email of contact: cmaher@george.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 358372
CIA Name: Prof Ian Cameron
Main RFCD: Health and Community Services
Admin Inst: University of Sydney
Start Year: 2005
End Year: 2006
Total funding: $405,250
Grant Type: NHMRC Project Grants
Title of research award: Improving adherence with the use of hip protectors, in community, residential aged
care and hospital settings
Lay Description (from application):
Hip protectors are plastic shields or foam pads worn over the hip in specially adapted underwear. A number of
studies in older people have shown that hip protectors are very effective if worn when a fall occurs and these have
been available for the last few years in Australia. Unfortunately it has been difficult for older people to wear the
hip protectors reliably and because of limited compliance with their use they have not been fully effective. This
study will compare provision of a brochure, with supply of the older person's choice of hip protectors , with or
without cost, and with or without contact with a nurse who will assist with use of the hip protector. After six
months the level of use of the hip protectors will be checked. The new strategies tested in this study may increase
compliance with hip protectors to a level where they will be effective if used at home in the community, in
residential aged care facilities, and in hospitals.
Research achievements (from final report):
Hip protectors have the potential to prevent more that 50% of hip fractures. The project has shown that it is
possible to improve adherence with the use of hip protectors. However, there remain substantial barriers to their
use due to issues related to the hip protector itself, the older person who is the user of the hip protector and the
environment in which hip protectors are used.
Expected future outcomes:
Recommendations are made to improve the use of hip protectors, and an international collaborative group has
been formed to devise standards and to design future clinical trials.
Name of contact: Ian Cameron
Email of contact: ianc@mail.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 253673
CIA Name: Prof Garth Nicholson
Main RFCD: Neurogenetics
Admin Inst: University of Sydney
Start Year: 2003
End Year: 2005
Total funding: $235,500
Grant Type: NHMRC Project Grants
Title of research award: Molecular genetics of hereditary motor and sensory neuropathy with pyramidal signs
Lay Description (from application):
This project aims to determine the molecular cause of hereditary motor neuropathies with pyramidal signs by
chromosomal linkage studies and to screen suitable families to locate genes with disease causing mutations. We
propose to use the resources of the human genome project to locate the defective gene. In previous studies we
have used these methods to identify genes of two other hereditary diseases of nerve. Our data suggests that this
disorder forms part of the largest group of hereditary neuropathies yet to be defined. Because this disorder affects
long spinal cord neurones, identifying the mutated gene and studying its function may shed light on possible
mechanisms involved in other spinal cord diseases. This research is a systematic search and should lead to
identifying the abnormal gene causing disease. Once the gene involved is known then an effective diagnostic test
will be developed. When a test for the disease is available, it is likely that we will find that the disorder is more
common than previously recognised. Knowledge of the function of the gene will lead to an understanding of how
the disease develops and will eventually enable development of effective treatments.
Research achievements (from final report):
This project resulted in the identification of the Mitofusin 2 gene causing a pyramidal CMT. This finding has
opened up new biology in peripheral nerve and the maintenance of spinal neuron function. Identification of the
gene has provided a direct diagnostic test, useful for genetic counselling and has provided targets for the
development of drug therapies to prevent or treat the disease.
Expected future outcomes:
Expected future outcomes will lead to the development of drug therapies that could be used to prevent or treat the
degeneration of long spinal cord neurons and lead to an understanding of how the disease develops. Work to
generate an animal model for the disease will be invaluable for testing potential drug therapies.
Name of contact: Garth Nicholson
Email of contact: molmed@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457140
CIA Name: Dr Lisa Keay
Main RFCD: Epidemiology
Admin Inst: University of Sydney
Start Year: 2007
End Year: 2010
Total funding: $331,652
Grant Type: Early Career Fellowships (Overseas)
Title of research award: Epidemiology of eye disease and impact of visual rehabilitation on falls in the elderly
Lay Description (from application):
Not Available
Research achievements (from final report):
This fellowship provided the opportunity for completion of a post-doctoral fellowship at Johns Hopkins
University in the United States. During this part of my fellowship I was able to work with several leading
researchers in the field of ophthalmology, public health and injury. I have developed international research
collaborations with colleagues in the United States, India, China and across other institutions in Australia.
Expected future outcomes:
I am continuing to develop a research program in aging and injury. I have been awarded funding for an ARC
discovery project to commence in 2012 on safe mobility for older drivers.
Name of contact: Prof Rebecca Ivers
Email of contact: rivers@george.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511966
CIA Name: Prof Rebecca Ivers
Main RFCD: Epidemiology
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2011
Total funding: $380,559
Grant Type: Career Development Fellowships
Title of research award: Road traffic injury prevention: a public health approach
Lay Description (from application):
The proposed research program will have a positive impact on road safety in Australia, particularly for young
drivers, by using a series of intervention and observational studies to provide strong evidence for policy makers,
and build research capacity. Furthermore, the development and adaptation of effective road safety interventions
for low income countries in the region has the potential to improve health and economic conditions for many
people in these countries.
Research achievements (from final report):
This award has allowed me to contibute significantly to research aimed at reducing the burden of road injury both
in Australia and in the region. Over the past 4 years I have built a substantial program of research in Indigenous
road injury, in prevention of injury in India and Vietnam, and in other vulnerable populations. I have contributed
to substantial policy reports and supervised multiple PhD students to completion, and my research has resulted in
significant policy change in road injury in several areas.
Expected future outcomes:
My research program continues to expand my previous work in the area of prevention of injury in vulnerable, high
risk populations.
Name of contact: Rebecca Ivers
Email of contact: rivers@georgeinstitute.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211256
Start Year: 2002
CIA Name: Prof Ian Cameron
End Year: 2004
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $209,865
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: Enhancing mobility after hip fracture
Lay Description (from application):
Many older people who fracture their hip do not recover to their previous level of function. This study will test
whether it is possible to help recovery of function, particularly walking, after hip fracture by using different and
more intensive physiotherapy treatment. The treatment will concentrate on exercise when standing, will be
provided twice daily and will continue after the person with hip fracture has returned home. Four months after the
hip fracture it is expected that walking ability, strength and balance will be improved by the new treatment
methods.
Research achievements (from final report):
The project has investigated what constitutes effective retraining of mobility after hip fracture in older people. A
randomised trial has been conducted with masked outcome assessment. The novel treatment is an intensive
weight-bearing exercise program, while the control group has had a conventional exercise program. The
treatments have been well tolerated and the full study sample of 160 people have been recruited. It has been
shown that frail older people can participate in an intensive exercise program after hip fracture.
Expected future outcomes:
Details of the effective mobility retraining program will be published
Name of contact: Ian Cameron
Email of contact: ianc@mail.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 253836
CIA Name: A/Pr Thiagarajan Sitharthan
Main RFCD: Mental Health
Admin Inst: University of Sydney
Start Year: 2003
End Year: 2005
Total funding: $361,000
Grant Type: NHMRC Project Grants
Title of research award: A controlled trial of an opportunistic intervention to reduce suicide risk among alcohol
and other substance misusers
Lay Description (from application):
Hopelessness, depression and suicidal ideation are common among people who misuse alcohol and other
substances. A general relationship between alcohol/substance abuse and self-harming / suicidal behaviour has
been recognised for decades. From the point of view of diagnosed substance abusers there is a correspondingly
high incidence of suicide and self-harm. The lifetime risk for suicide in alcohol dependence is higher than for
schizophrenia or affective disorder. Despite the public health and personal burden associated with suicidality, the
general lack of skills and focus on management of self-harm in specialised drug and alcohol services is of great
concern. In this study, all patients attending drug and alcohol services will be screened for suicide risk, and
offered a comprehensive psychological treatment to reduce suicide risk and the use of alcohol and other
substances.
Research achievements (from final report):
This project created an awareness among clinicians to target depression, hopelessness, and suicide risk among
alcohol and substance misusing populations. In particular, the clinical trial demonstrated that such negative
emotions can be modified via psychological interventions and assist in reducing alcohol / substance misuse.
Clinical assessment measures and clinical treatment manuals developed for the trial are used as part of training the
workforce and has led to improvements in service delivery. Papers are prepared for publication.
Expected future outcomes:
We plan to conduct clinical workshops to assist clinicians to be better aware and more skilled in the detection and
management of depression and suicide risk
among alcohol / substance misusers. To publish results in peer-reviewed journals.
Name of contact: A/Prof T.Sitharthan
Email of contact: thiagarajan_sitharthan@wsahs.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 632903
CIA Name: Prof Janet Keast
Main RFCD: Peripheral Nervous System
Admin Inst: University of Sydney
Start Year: 2010
End Year: 2012
Total funding: $287,110
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
I am a neuroscientist who is fascinated by the ways in which peripheral and spinal neurons respond to
environmental changes. By understanding these responses, I hope to develop new ways to treat neural conditions
caused by injury, endocrine disturbances and inflammation.
Research achievements (from final report):
This research furthered our understanding of how peripheral nerves and spinal cord neurons respond to injury. In
the former case, the results are relevant to developing new approaches for improving recovery of damaged
peripheral nerves, either by promoting regrowth of the injured nerves or enhancing the function of residual
(spared) nerves. The studies on spinal cord injury revealed specific types of neuronal remodelling within the cord
that may be related to the development of persistent pain, a debilitating problem in many people with this injury.
Expected future outcomes:
Developed new concepts for potentially recovering function after damage to the autonomic nervous system after
surgically-induced injury and new strategies for understanding the basis central neuropathic pain.
Name of contact: Janet Keast
Email of contact: jkeast@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512179
Start Year: 2008
CIA Name: A/Pr Christopher Jackson
End Year: 2010
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $436,883
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: Activated protein C utilises protease activated receptors and epidermal growth factor
receptor to heal wounds
Lay Description (from application):
Chronic leg ulcers are a major burden to the individual sufferer and to the health system. We have discovered
that activated protein C (APC) potently stimulates wound healing in the laboratory and now have exciting positive
results from a small pilot clinical trial showing that applying APC solution to leg ulcers also helps healing in
patients. This study plans to discover how APC works at the molecular level.
Research achievements (from final report):
Skin ulcers occur in patients with peripheral arterial occlusive disease, deep vein thrombosis, diabetes, pressure
sores and burns or in the elderly. A recent Theta report has estimated that impaired wound healing costs A$60
billion per annum worldwide and the incidence is expected to increase at a rate of 14% per annum. The current
treatment regimes for chronic wounds have limited success. This study has elucidated the mechanisms of action of
APC as a wound healing agent and reveal details on the efficacy of APC as a therapy to promote wound healing.
Expected future outcomes:
Our research has provided the direct evidence required for testing APC in human clinical trials. Topical
application of APC is likely to provide an effective, valuable and economically attractive contribution to treatment
protocols for this difficult problem. This is the first step toward approaching the validation of the use of APC in
compromised wound states.
Name of contact: Chris Jackson
Email of contact: chris.jackson@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 352576
Start Year: 2005
CIA Name: Prof Christopher Maher
End Year: 2007
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $521,625
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: A clinical trial of manipulative therapy and/or NSAIDs for significant acute low back
pain
Lay Description (from application):
Acute low back pain is a disabling condition with many sufferers being unable to perform their family or work
duties due to severe pain. Treatment of acute LBP is also costly, this condition being one of the most frequent
problems managed by general practitioners. Guidelines about how to treat patients with acute low back pain have
suggested that advice and paracetamol should be the first line of treatment. In patients with insufficient pain relief
two of the most frequently used additional treatments are anti-inflammatory medication and manipulative
physiotherapy. However, to date it is not known whether the addition of one or both of these treatments results in
faster recovery for the patient. Our clinical trial will clarify whether the addition of (i) anti-inflammatory
medication and/or (ii) manipulative physiotherapy, to advice and paracetamol given by the doctor results in a
faster recovery for the patient with acute low back pain. This results of this study will make it possible for
general practitioners to manage acute low back pain in an evidence-based way.
Research achievements (from final report):
The study revealed the importance of simple treatments delivered well; in this case provision of simple analgesics
and advice as the first line of care for patients with recent onset back pain. The trial showed that adding spinal
manipulation and/or non-steroidal anti-inflammatory drug (NSAID) therapy to the first line of care does not
confer any advantage. The consequences of application of the results of this study to clinical practice will be
profound - avoiding the serious complications of NSAIDs therapy, the costs of both treatments and the
inconvenience of attending for spinal manipulation.
Expected future outcomes:
The results of the trial will be incorporated into updates of clinical practice guidelines for low back pain
Name of contact: Prof Chris Maher
Email of contact: cmaher@george.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457464
CIA Name: Dr Catherine Sherrington
Main RFCD: Preventive Medicine
Admin Inst: University of Sydney
Start Year: 2007
End Year: 2009
Total funding: $536,435
Grant Type: NHMRC Project Grants
Title of research award: Minimising disability and falls in older people through a post-hospital individualised
exercise program.
Lay Description (from application):
This study aims to implement and evaluate the "Functional Activities for Better Balance (FABB) program", a
tailored exercise program which is designed to minimise disability and falls, among older adults who have
recently had a hospital stay. A randomised controlled trial will be undertaken to determine the success of the
program in minimising disability and falls and improving balance, muscle strength, and reaction time, quality of
life and fear of falling. In addition, predictors of adoption of and adherence to the exercise program and the cost
effectiveness of the program will be established.
Research achievements (from final report):
We have designed a home-based exercise program and safely implemented this in 160 older people (those
randomised to the intervention group in this trial to date). We have gained additional funds for this trial and we are
still continuing recruitment and 12-month intervention period and follow-up so are not yet able to communicate
the results of the study. We have established a website which enables the exercise program manual to be
downloaded. This will to enable the details of our program to be disseminated to clinicians and policy makers
internationally if our approach is found to be effective.
Expected future outcomes:
Clear guidance for clinicians and policy makers about the effectiveness and cost effectiveness of home-based
exercise e for falls prevention and disability minimisation in older people after recent hospital stays.
Name of contact: Dr Catherine Sherrington
Email of contact: csherrington@george.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402679
Start Year: 2006
CIA Name: A/Pr Louise Ada
End Year: 2008
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $341,350
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: Supported treadmill training to establish walking in non-ambulatory patients early after
stroke
Lay Description (from application):
This project will improve the health and well being of people affected by stroke. Stroke is the most common
disabling neurological condition in adults and consumes up to 5% of health care expenditure in developed
countries, estimated by the National Stroke Foundation at $1-2 billion per year in Australia. Some 48,000 people
suffer a stroke each year in Australia, with approximately one third of these people requiring inpatient
rehabilitation and 70% of them are unable to walk on admission to rehabilitation. This randomised controlled trial
will investigate whether treadmill walking with partial weight support via an overhead harness is effective at
establishing independent walking (i) more often, (ii) earlier and (iii) with a better quality of walking, than current
treatment for stroke patients who cannot walk. We will measure (i) whether patients achieve independent walking
and (ii) the time taken to achieve independent walking. We will also measure parameters of walking such as
speed, step length and step width to evaluate the effect of treadmill training on the quality of walking.
Furthermore, by measuring participation in the community at 6 months, we will evaluate the long-term effect of
this innovative treatment. Given that independence in walking is a major factor in the decision to discharge
patients from inpatient care, earlier independent walking should result in a reduction in length of hospital stay
which will save about $800 per patient per day in a teaching hospital setting. Identifying rehabilitation strategies
which enhance walking outcome will not only improve quality of life of both stroke patients and their carers by
reducing disability and handicap but also reduce the cost of rehabilitation.
Research achievements (from final report):
In non-abulatory people early after stroke, we found that treadmill training with body weight support resulted in
more people walking compared with assisted overground walking. Specifically, 71% of the experimental group
walked independently at six months compared with 60% of the control group, although this difference was not
statistically significant. In addition we found the experimental group walked 2 weeks earlier with 50% attaining
independent walking by 5 weeks compared to 7 weeks for the control group. Furthermore, with very few adverse
events, we have demonstrated that treadmill waling with body weight support can be safely provided for nonambulatory stroke patients.
Expected future outcomes:
Given independence in walking is a major consideration in discharge planning this earlier attainment of
independent walking after treadmill walking with body weight support has the potential to reduce the cost of
rehabilitation. Thus it is hoped the results of this trial will help increase the use of weight supported treadmill
training in the clinic.
Name of contact: Louise Ada
Email of contact: louise.ada@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211254
Start Year: 2002
CIA Name: Dr Anne Moseley
End Year: 2003
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $55,220
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: Randomised controlled trial of stretching for contracture after ankle fracture
Lay Description (from application):
Restricted ankle motion (contracture) commonly occurs after cast immobilisation following ankle fracture. The
prevalence of contracture could be as high as 77% immediately following cast removal. This interferes with tasks
such as walking and stair climbing, and can result in significant disability. While physiotherapists regularly treat
contracture after ankle fracture, the efficacy of specific treatment programs has not been established. This project
aims to determine the effectiveness of two commonly used stretching programs for contracture after ankle fracture
initially treated with cast immobilisation. Stretches of short and long duration will be compared to a no stretch
condition. The study will determine the effects of these interventions on ankle flexibility, ability to perform
everyday tasks (eg, walking), self-ratings of disability and pain.
Research achievements (from final report):
A common sequel of cast immobilisation for ankle fracture is loss of ankle joint range of motion. This is often
treated by a program of stretching, but it is not known how much stretch is required or if, for that matter, stretch is
effective. The aim of this study was to compare the effects of short (6 minutes) and long (30 minutes) duration
stretches with a control condition for the treatment of contracture after ankle fracture. Our multi-centre, assessor
blinded randomised controlled trial revealed that the addition of a program of passive stretches confers no benefit
over exercise alone for the treatment of plantarflexion contracture after cast immobilisation for ankle fracture.
Expected future outcomes:
Now that it has been shown that a clinical stretching protocol does not increase joint range of motion or reduce
disability in people with contracture following cast immobilisation for ankle fracture, physiotherapists can
discontinue prescription of stretching programs as part of the routine management of ankle fractures.
Name of contact: Dr Anne Moseley
Email of contact: amoseley@mail.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302013
Start Year: 2004
CIA Name: A/Pr Glen Davis
End Year: 2006
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $244,900
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: Orthostatic Tolerance during FES-evoked Stepping in Paraplegia: A Safety and
Viability Study
Lay Description (from application):
In the past 30 years, there has been growing interest in the potential benefits of functional electrical stimulation
(FES) of the paralysed leg muscles as a means of restoring movement in the lower limbs. FES uses electrical
impulses generated by a stimulator to elicit purposeful muscle contractions via skin-surface electrodes placed over
the muscles. Although traditionally limited to health-related activities such as stationary cycling exercise, recent
bioengineering advances in the area of FES present the SCI person with a means of restoring upright mobility and
reinstating functional tasks. Yet, while this technological innovation remains promising for optimising functional
outcomes after SCI, there remains a distinct lack of knowledge of the physiological stresses placed upon the
individual. In this preliminary safety and viability study, the physiological implications central to enhanced
upright mobility will be investigated during FES-evoked prolonged stepping. The responses during FES-stepping
will be contrasted with the responses observed during stepping performed without FES. The study will investigate
the blood pressure responses during FES-gait, but also address possible physiological mechanisms underlying
those blood pressure responses. The findings from this study will identify whether there is a phsiological
limitation to the performance of FES-evoked functional mobility. Current physiotherapy practice recognises
blood pressure control and orthostatic hypotension as a significant barrier to functional standing and stepping, yet
little is known about the physiology underpinning the condition. If FES does present a limitation to the
performance of upright functional activities, this study will also assist in devising alternative physiotherapy gait
training regimens.
Research achievements (from final report):
We can report that for some of our participants, blood pressure during functional electrical stimulation evokedwalking was well maintained within normal limits for an upright posture. However, we have had one participant
who has suffered severe orthostatic hypotension during FES gait, and for these individuals (~25-30% of the SCI
population) upright walking poses hazards due to possible syncope, fainting or other orthostatic sequelae.
As an original aim of the project, this study has also led to the development of 'best practice' physiotherapy-led
training programs that develop lower limb muscle strength and walking ability in the paralysed legs of spinal
cord-injured patients.
Expected future outcomes:
As a precurssor to individuals with spinal cord injury (SCI) who might wish to undertake functional electrical
stimulation-evoked walking, all SCI will be clinically assessed for the presentation of orthostatic hyptension,
including symptoms of nausea, fainting or pre-syncope.
Name of contact: Associate Professor Glen Davis
Email of contact: G.Davis@usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 253792
CIA Name: Prof Ronald Grunstein
Main RFCD: Respiratory Diseases
Admin Inst: University of Sydney
Start Year: 2003
End Year: 2005
Total funding: $320,438
Grant Type: NHMRC Project Grants
Title of research award: Neurobiological Effects of Sleep Apnea and Sleepiness
Lay Description (from application):
Sleep apnea affects over one million Australians. It not only affects the quality of a persons sleep and the oxygen
supply to their brain, but can cause sleepiness during the day which can in turn affect the ability of the person to
conduct their normal activities. Over 30,000 sleep studies are conducted annually in Australia and current
therapies result in significant improvements in the quality of life of the patient. However, the data analysis during
these studies does not give a clear indication of the degree to which individual patients may have problems with
performing their normal tasks during the day. Tasks like driving vehicles are of particular interest due to the
potential for accidents through fatigue or a lack of concentration.This research is designed to investigate the
impact of sleep apnea on brain function and daytime performance using certain new techniques - more
sophisticated analysis of the brain's activity, detection of brain chemicals and metabolism using a specific form of
brain scan called MR spectroscopy, a special monotonous computer based driving simulator, an other tests of
performance. We will assess a large group of patients with sleep apnea to determine how the impact of sleep
apnea on performance may be differ throughout the population and how this may be affected by the current
standard treatment for sleep apnea. We will examine the impact on brain function and performance of removing
the current standard therapy in a group of patients previously diagnosed with sleep apnea (as this is a common
occurrence in the community). We will also repeat some specific measurements on a control group without any
symptoms of sleep apnea for the purpose of comparison. We plan to show a relationship between the effects of
sleep apnea and the ability of a person to carry out activities such as driving and thinking. We will then be able to
better assess the risk a patient may face and the most appropriate way to treat them.
Research achievements (from final report):
The scope of daytime functional impairment in sufferers of obstructive sleep apnea was characterized using an
extensive assessment including questionnaires, computerized cognitive tests, and MRI scanning. The impact of
treatment of obstructive sleep apnea, and short-term withdrawal of treatment was also evaluated . A new method
of electroencephalogram (brain-wave) analysis was developed and tested in this study, and found to predict
aspects of performance known in previous studies to be vulnerable to the effects of sleep apnea. New methods in
magnetic resonance spectroscopy (MRS) to non-invasively measure the supply and consumption of brain energy
during sleep were developed to measure what occurred during sleep apnea events.
Expected future outcomes:
The brainwave analysis will be studied further in studies of sleep deprivation and simulated jet lag. If confirmed
on other studies, this analysis method may provide insights into the processes underlying brain electrical activity,
and provide a new method to measure sleepiness.
Name of contact: Delwyn Bartlett
Email of contact: delwynb@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1000507
Start Year: 2010
CIA Name: Prof Anthony Weiss
End Year: 2011
Main RFCD: Regenerative Medicine (incl. Stem Cells and Tissue Engineering) Total funding: $326,316
Admin Inst: University of Sydney
Grant Type: NHMRC Development Grants
Title of research award: Elastaderm: an improved human skin substitute for treating burns
Lay Description (from application):
We will focus on proof of concept needed for the commercialisation of improved dermal replacements designed
to repair severe skin burns. These novel dermal replacements are a substantial development of and improvement
beyond existing technology because they are intended to reduce wound contraction and increase elasticity.
Research achievements (from final report):
We generated proof of concept data supporting the improved function of skin substitutes following the inclusion
of synthetic human elastin. A commercial dermal substitute was modified by either including tropoelastin in the
material or supplementing it with a tropoelastin-enriched formulation. The effects of elastin were titrated &
distinguished. On the basis of efficacy we obtained two preferred formulations. The skin substitute constructs
displayed improved healing times, including improved take rates and improved rates of cellular infiltration. The
presence of elastic fibres in the resulting dermal tissue was due to the increased presence of tropoelastin. Potential
benefits of these constructs include the repair of damaged human skin that encompasses loss of the dermis due to
trauma and surgery.
Expected future outcomes:
Refined product formulation and continued in vivo testing for commercial translation. Subsequent human trials
leading to wound repair.
Name of contact: Professor Tony Weiss
Email of contact: tony.weiss@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457092
Start Year: 2007
CIA Name: Prof Leanne Togher
End Year: 2011
Main RFCD: Rehabilitation and Therapy: Hearing and Speech
Total funding: $634,830
Admin Inst: University of Sydney
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
I am a speech pathologist working to improve psychosocial outcomes
for adults with traumatic brain injury by improving their communication
and social skills.
Research achievements (from final report):
The communication problems that arise following traumatic brain injury (TBI) can lead to social breakdown,
family isolation and a burden on families. This fellowship produced the first effective communication training
program called TBI Express which provides strategies and guidance for families and carers of people with
TBI.The program is now published and is being used by all brain injury units in NSW. A TBI Express website has
been launched which provides families and clinicans free access to video demonstrations and treatment materials.
This website is being accessed nationally and internationally. Capacity building goals were achieved during the
Fellowship with 8 higher degree research completions, the employment of 3 postdoctoral fellows and 8 first class
Honours completions. Three of these Honours students are now enrolled in funded PhD programs at The
University of Sydney.
Expected future outcomes:
Future outcomes include the development of telehealth applications to assess and treat people with TBI and their
families, thus improving access to rural and remote patients. The newly developed website for people with TBI
will be expanded to include a range of evidence based treatment options and information to facilitate recovery.
Name of contact: Leanne Togher
Email of contact: leanne.togher@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402687
Start Year: 2006
CIA Name: A/Pr Leanne Togher
End Year: 2008
Main RFCD: Rehabilitation and Therapy: Hearing and Speech
Total funding: $448,293
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: Improving the communication of people with severe traumatic brain injury: A clinical
trial
Lay Description (from application):
Traumatic brain injury is the leading cause of disability in young Australians, and is particularly prevalent in
young men. The condition disturbs thinking and problem solving. Ultimately, these problems manifest in impaired
verbal communication. Communication problems following traumatic brain injury can make critical relationshipssuch as father, husband, and employee-impossible to sustain. Those affected are socially inappropriate and
uncomfortable to be around, which causes a lifetime of lost friendships, unemployability, and social isolation.
Minimisation of these lifelong effects is of the utmost importance to the health of those affected, and is critical to
reducing the economic burden of the condition. Two approaches have been shown to improve the
communication of those with traumatic brain injury. Training in social skills is helpful, as is training partners to
deal with difficult communication behaviours. However, to date, no research has concurrently studied these two
approaches to rehabilitation. Consequently, it is unknown whether best results are achieved with either one of the
two methods, or both. The present project uses a clinical trials approach in an innovative evaluation of three
methods of treating those with traumatic brain injury compared with a control group. The trial involves the
conceptual advances of including cost effectiveness of treatment as an outcome measure, and inclusion of
advanced methods to measure the intricacies of verbal communication. The multidisciplinary team of Chief
Investigators has international track records in the requisite disciplines for the study of traumatic brain injury and
its rehabilitation.
Research achievements (from final report):
This research has led to the finding that families and everyday communication partners, when appropriately
trained, are able to improve the communication of people with brain injury, even in the chronic phases of
recovery. The multi-media training program, called TBI Express, that was developed for use with families has
now been published and is available on www.assbi.com. The package includes a 420 page training manual and
DVD including examples of how to interact with people with brain injury. The results of this study have resulted
in significant interest from clinicians and researchers nationally and internationally. There are plans for this
project to be expanded to the Canadian context, with TBI Express being translated into French in 2012. The
videos made for the instructional DVD are being uploaded onto The University of Sydney website so that these
resources are freely available to people with brain injury, and their families, friends and carers.
Expected future outcomes:
Further research is planned in collaboration with rehabilitation researchers at The University of Montreal, Canada.
It is also expected that the future outcome of this training program is the widespread use of communication partner
training for people with severe traumatic brain injury. The training may also be applicable to the families of other
communicatively impaired populations.
Name of contact: Assoc. Professor Leanne Togher
Email of contact: leanne.togher@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402823
Start Year: 2006
CIA Name: Prof Chris Maher
End Year: 2010
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $607,101
Admin Inst: University of Sydney
Grant Type: Established Career Fellowships
Title of research award: Uncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The research fellowship allowed Professor Maher to enhance his competitive edge in research evaluating the
management of back pain in primary care. He has dramatically increased the number and quality of his
publications eg since the award he has published in leading medical journals such as Lancet, JAMA, Annals of
Internal Medicine and BMJ and his work is now much more widely cited. He has built research capacity by
establishing a multi-disciplinary group of ~35 researchers, The Musculoskeletal Division, at the George Institute
for Global Health; and by supervising to completion 12 PhD students. He has made important contributions to
knowledge translation eg as a Director of the Centre for Evidence-Based Physiotherapy he has developed novel
technologies to bring high quality research to the point of clinical decision making for clinicians and consumers.
He has worked with his Institute's communications department to disseminate his research in the media.
Expected future outcomes:
Prof Maher will expand his research and that of the Division he leads. He has submitted applications to the
NHMRC for a Centre of Research Excellence (Disability Trialists' Collaboration) and also to the Australian
Primary Health Care Research Institute (Musculoskeletal Primary Care Network).
Name of contact: Prof Chris Maher
Email of contact: cmaher@georgeinstitute.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211046
CIA Name: Prof Robyn Norton
Main RFCD: Epidemiology
Admin Inst: University of Sydney
Start Year: 2002
End Year: 2004
Total funding: $689,830
Grant Type: NHMRC Project Grants
Title of research award: Cohort study of risk factors for young driver injuries
Lay Description (from application):
Injuries impose a substantial burden on young people, both in Australia and internationally. In 1998, 70% of all
deaths among young men, and 57% of deaths among young women, aged 15-24 years in Australia were due to
injuries. The single largest cause of injury-related fatalities, hospital admissions and emergency department
presentations among this age group is transport-related incidents. Technological advances in motor vehicle
engineering and road design, and the implementation of various road safety measures, such as random breath
testing, have led to an overall decline in the incidence of motor vehicle-related injuries in Australia in the past
three decades. However, young people still have substantially higher rates of motor vehicle-related mortality than
older people. This suggests that if the burden of injuries among young drivers is to be reduced to levels that are at
least as comparable with those in other age-groups, then the identification of factors that are specifically
associated with an increased risk of motor vehicle injury among young people, must be a priority. The current
study aims to determine the role of several postulated risk factors in the incidence of young driver injuries. The
specific risk factors to be examined include pre-licence road and driving exposure/experience; type, quality and
quantity of driver training; and road risk perceptions and engagement in sensation seeking behaviours. The study
also seeks to determine whether factors associated with increased risk of driver injury are the same for different
socio-economic groups and for different ethnic and cultural groups. Information obtained in this study should
provide reliable evidence about causal factors for motor vehicle crash injury among young drivers. Such
information should be useful to licensing and road safety professionals, in the design of practical road safety
strategies aimed at reducing the burden of young driver injuries.
Research achievements (from final report):
With the successful recruitment of over 20,000 drivers aged 17-24 years, the DRIVE Study is one of the largest
cohort studies examining risk factors for young driver injury in Australia and internationally. The use of a robust
cohort methodology and linkage to routinely collected data sources for outcome measures, allows minimal
opportunity for bias. As a result, the DRIVE Study will provide results that will have significant road safety policy
implications for Australian and other jurisdictions. The success of baseline data collection aided by use of webbased data collection techniques has provided investigators with a valuable set of indicators for road traffic injury
in young people. Future use of the data by policy makers and road safety jurisdictional authorities is expected to
be significant. Planned linkages to resurvey data and outcome data, expected to occur in mid 2006, will allow the
provision of valuable data in the field of young driver injury in years to come.
Expected future outcomes:
The DRIVE Study will provide high quality evidence about the strength and direction of risk factors for young
driver serious injury and death, including driver training, risk perception, driver behaviour and mental health. This
information will contribute significantly to the improved management of young driver safety in Australia, and
internationally.
Name of contact: Dr Rebecca Ivers
Email of contact: rivers@thegeorgeinstitute.org
NHMRC Research Achievements - SUMMARY
Grant ID: 512326
CIA Name: A/Pr Colleen Canning
Main RFCD: Preventive Medicine
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2012
Total funding: $598,820
Grant Type: NHMRC Project Grants
Title of research award: Exercise therapy for prevention of falls in people with Parkinsons disease: a
randomised controlled trial.
Lay Description (from application):
Despite optimal medication regimes, people with Parkinson's disease frequently and recurrently experience falls.
Up to 68% of the 100,000 people living in Australia with Parkinson's disease fall every year and fall-related
injuries are the most common reason why people with Parkinson's disease are admitted to hospital. This project
will implement an exercise program targeting risk factors for falls and will determine the efficacy and the cost
effectiveness of the program.
Research achievements (from final report):
People with Parkinson's disease have a very high rate of falls. The aim of the project was to determine whether a
6 month exercise program can reduce fall rates in people with Parkinson's disease. We recruited our target sample
size of 231 people with Parkinson's disease and delivered a specially-designed a exercise program which targets
potentially remediable fall risk factors (reduced leg strength, poor balance and freezing of gait) to the 115
participants randomly allocated to the exercise group. We have established a website which enables the exercise
program manual to be downloaded. This will enable the details of the program to be disseminated to clinicians
and policy maker internationally if our approach is found to be effective. Data analysis is currently underway to
determine the effectiveness of the program in reducing falls and its cost-effectiveness. If fall rates are decreased
there will be significant benefits for people with Parkinson's disease, their carers and the community.
Expected future outcomes:
Clear guidance for clinicians and policy makers about the effectiveness and cost-effectiveness of exercise for
preventing falls improving mobility in people with Parkinson's disease.
Name of contact: Colleen Canning
Email of contact: colleen.canning@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457594
Start Year: 2008
CIA Name: A/Pr Jane Latimer
End Year: 2009
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $516,618
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: Which exercise for chronic low back pain?
Lay Description (from application):
About 1 in 10 Australians have persisting or chronic low back pain. Most are managed in primary care and the
most frequently prescribed treatment is exercise. Chronic low back pain remains a major health problem because
not all patients respond to each treatment so on average treatment effects are small. At present there are no
guidelines to help clinicians select the best treatment for a patient. As a result a lot of time and money is wasted on
treatments which ultimately fail to help the patient. We have begun a research program to solve this primary
health care problem. We have focussed on exercise because the treatment is widely available in primary care and
of modest cost. The program includes basic research to understand the mechanism of action of exercise and
clinical trials testing the effectiveness of different types of exercise. The proposed study falls into the latter
category, and is a direct comparison of the two most promising types of exercise used in Australia. The study will
also identify clinical features that modify treatment effects, a finding that will allow clinicians to identify which
type of exercise is more likely to be effective for an individual patient. This study offers a potential solution to a
major health problem with enormous economic and social costs.
Research achievements (from final report):
Motor control exercises and graded activity are two commonly used exercise therapies, yet there is little evidence
to support the use of one intervention over another. The objective of this study was to compare the effectiveness of
motor control exercises and graded activity for patients with chronic non-specific low back pain. One hundred and
seventy two patients with chronic (>12 weeks) non-specific low back pain were randomised to receive either
motor control exercises or graded activity. Patients in both groups received 14 sessions of individualised
supervised exercise therapy. Outcomes were pain, function and quality of life measured at study entry and at 3, 6
and 12 months. Analysis of the outcomes showed that there were no significant difference between treatment
groups for any of the time points for any of the outcomes studied. The results of this study suggest that motor
control exercises and graded activity have similar effects for patients with chronic non-specific low back pain
seeking care for their low back pain.
Expected future outcomes:
Our next step is to disseminate this research result.
Name of contact: A/Prof Jane Latimer
Email of contact: jlatimer@georgeinstitute.org.au
.
NHMRC Research Achievements - SUMMARY
Grant ID: 512351
Start Year: 2008
CIA Name: A/Pr Jack Crosbie
End Year: 2011
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $412,707
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: A novel approach to the training of functional standing following spinal cord injury
Lay Description (from application):
The study will employ a new type of functional electrical stimulation (FES), strength-endurance muscle
conditioning and standing training to improve stance in SCI victims with incomplete paralysis. We will evaluate
an innovative combination of muscle training and novel FES protocols which allow paralysed people to stand and
perform upper limb functional tasks. The primary outcomes will be duration of standing, number of repetitions of
standing and sitting and upper limb function while standing.
Research achievements (from final report):
This project has investigated the effect of functional electrical stimulation (FES) on muscle activation in people
with partial paralysis due to spinal cord injury. We have found that, while the immediate effects of using this type
of stimulation is beneficial in assisting some functional activities, particularly standing, the use of this technology
as part of a training program appears to have little effect on muscle force production. The study has allowed us to
investigate the effect of FES on the quadriceps muscle in the thigh at various stages of innervation and
denervation and we find that muscle which is under sufficient voluntary control to extend the knee against the
weight of the lower leg tends to respond poorly to the addition of FES, indeed, there is an apparent inhibitory
effect. However, when FES is applied to muscle which is under no voluntary control or in which the weakness is
profound, the force produced is sufficiently increased. However, the magnitude of these contractions is usually
insufficient to elicit significant function.
Expected future outcomes:
Further investigation of the physiology of FES is justified. There is continuing uncertainty about the specificity of
this technology, particularly as part of a training program.
Name of contact: Jack Crosbie
Email of contact: Jack.Crosbie@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211278
CIA Name: Prof Philip Sambrook
Main RFCD: Geriatrics and Gerontology
Admin Inst: University of Sydney
Start Year: 2002
End Year: 2004
Total funding: $340,550
Grant Type: NHMRC Project Grants
Title of research award: Epidemiology of Osteoporotic Fractures in the Very Frail Elderly: Risk factors, Quality
of Life and Mortality
Lay Description (from application):
Osteoporosis, a disease characterised by skeletal fragility, is a major public health problem. The direct costs
alone of treating osteoporotic fractures have been estimated at more than $800 million in Australia. Hip fractures
are the most costly to treat and are due to a fall or injury in over 90% of cases. The frail elderly are at particular
risk of osteoporotic fractures but little is known about risk fractures in this 'at risk' group or the effect of fracture
on quality of life. This study is examining risk factors for fractures in the frail and institutionalised older person
by asessment of quantitative bone ultrasound, falls risk, vitamin D status and other biochemical markers of bone
in an attempt to identify predictors that can be modified to reduce fractures, improve quality of life and reduce
mortality due to osteoporotic fractures.
Research achievements (from final report):
In 1999, the NHMRC funded a 3 year Project Grant to assess the role of calcaneal ultrasound combined with falls
risk factors as a screening tool in a high risk population (the frail older person) for identifying those at risk of
osteoporotic fractures. This funding was extended between 2002 and 2004. Nursing homes and hostels in
northern Sydney were randomly selected from all such institutions within the Northern Sydney Area Health
Service and all residents over the age of 65 were asked to participate. The study, which recruited 2005 subjects.
Findings from the FREE Study include a very high prevalence of vitamin D deficiency as noted above, a very high
falls rate and a high fracture incidence. We observed 181 hip fractures with a rate of 367 per 10,000 person years
or 8.6 % over median 2.4 years followup. For total fractures, we observed 402 fractures during 3240 years of
follow-up with an overall rate of 1241 per 10,000 (compared with 295 per 10,000 for community dwelling women
in the Dubbo Osteoporosis Epidemiology Study) or 16.8% after 19.4 months of follow-up. Our study identfied
tools that can be used to predict future falls and fractures.
Expected future outcomes:
Further publications will refine these tools to allow prediction of those at high risk of fracture and falls and allow
preventive measures.
Name of contact: Philip Sambrook
Email of contact: sambrook@med..usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 307711
CIA Name: Dr Shameran Slewa-Younan
Main RFCD: Not Allocated
Admin Inst: University of Sydney
Start Year: 2004
End Year: 2008
Total funding: $274,225
Grant Type: Early Career Fellowships (Australia)
Title of research award: Investigating mechanisms of recovery following acute traumatic brain injury
Lay Description (from application):
Not Available
Research achievements (from final report):
Until the last decade there was little examination of sex differences in the recovery from clinical Traumatic Brain
Injury (TBI) . However, following the United States National Institutes of Health specific guidelines mandating
the inclusion of females in clinical studies and drug trials, and our increasing knowledge of brain sex differences,
the last decade has seen a surge in the number of such studies. This project represents the only systematic study of
sex differences following TBI in Australia to date. This project has demostrated that because clinical studies of
sex differences following TBI rarely produce the consistent results as reflected in the animal literature, greater
attention needs to be paid to factors such as the female patient's hormonal status at time of injury and other sources
of heterogeneity such as age and injury severity. Furthermore, this research award has resulted in published data
reporting clinical signifigant differences between men and women in their recovery and outcomes following TBI.
The potential importance of such information is that it may lead to improved clinical practice through more
appropriate rehabilitation interventions.
Expected future outcomes:
The importance of progesterone as a potential treatment for acute TBI is receiving increased attention world wide.
In 2009, a United States National Institutes of Health announced the funding of a phase III trial of progesterone
involving 17 centres and over 1000 patients. The data from this project may form the basis for future progesterone
treatment in Australia.
Name of contact: Dr Shameran Slewa-Younan
Email of contact: s.slewa-younan@uws.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 307710
CIA Name: Dr Catherine Sherrington
Main RFCD: Geriatrics and Gerontology
Admin Inst: University of Sydney
Start Year: 2004
End Year: 2008
Total funding: $133,900
Grant Type: Early Career Fellowships (Australia)
Title of research award: Physical ability and falls: addressing gaps in the evidence base
Lay Description (from application):
Not Available
Research achievements (from final report):
This work has enhanced understanding about risk factors for falls in older people and exercise interventions to
prevent falls and decrease disability levels in older people.
My cohort study of over 500 rehabilitation unit inpatients found that falls can be predicted by simple measures of
agitation, psychoactive medication use, continence, balance and gender (men were more likely to fall). This tool
will be implemented in clinical settings and its usefulness will be investigated in further studies.
My systematic review of 44 randomised trials found that ongoing exercise which targets balance can prevent up to
40% of falls. There has been much interested in this work from policy makers and clinicians.
This work has led to funding for further projects directly investigating the impact of exercise for on falls and
disability in older people. I am leading a large-scale NHMRC-funded trial of home-based exercise programs in
people who have had recent hospital stays. I was recently awarded NHMRC funding for a trial of a selfmanagement approach to exercise for people who have had a hip fracture. I am also a chief investigator on two
other NHMRC-funded trials looking at exercise in older people.
Expected future outcomes:
The current and future impact of falls and disability in older people and society is enormous and there is an urgent
need for evidence-based intervention strategies. These ongoing studies will provide evidence to guide practice and
so will have direct implications for clinical practice and health policy.
Name of contact: Dr Catherine Sherrington
Email of contact: csherrington@george.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301965
CIA Name: Prof Richard Taylor
Main RFCD: Epidemiology
Admin Inst: University of Sydney
Start Year: 2004
End Year: 2007
Total funding: $819,000
Grant Type: NHMRC Project Grants
Title of research award: Case-control studies of completed and attempted suicide in young people in NSW
Lay Description (from application):
Youth suicide rates have been increasing dramatically over the last three to four decades. The causes and
determinants of these suicide rate changes remain unclear, as do the causes and determinants of the suicides
themselves. Despite a range of risk factors being identified by researchers, predicting an individual suicide is
difficult due to the range of factors involved and the complex interactions between them. This study will
investigate associations between individual and environmental factors for both completed suicides and suicide
attempts in young people aged 18-34 years living in NSW. The study will be undertaken in Sydney, Newcastle
and in identified rural areas. The study is embedded in existing treatment, counselling and support services and
will aid their improvement and augmentation. Cases of suicide and attempted suicide will be compared with
community controls, and also completed suicides with attempted suicides, to identify potentially modifiable risk
factors associated with suicidal behaviour. This will provide more comprehensive information relating to how
various risk factors interact and influence suicidal behaviour, including in rural areas with significant Aboriginal
and Torres Strait Islander communities. Information from this study will improve prevention initiatives and
assist with community strategic development and provide evidence to enhance current health service and coronial
interventions.
Research achievements (from final report):
This study delineated major risk factors and population characteristics of both suicide and attempted suicide in
young people age 18-34 years from New South Wales across urban and rural areas and elucidated predictors for
completed suicide compared to attempted suicide. The project involved 3 case-control studies: suicides compared
to controls, attempted suicides compared to controls, and suicides compared to attempted suicides. By June 2010
data on 662 respondents had been collected, and interviews are continuing with other funding sources. The
suicide component has 68 male cases and 101 corresponding controls, and 12 female cases with 147 controls. The
attempted suicide component comprises 32 male cases with 85 controls, and 68 female cases with 143 controls.
Preliminary analysis indicates that hypotheses were largely confirmed (see below) with sufficient numbers for
statistical significance. These are the first case contol studies performed in Australia on this age group for suicide
and attempts and one of the few available internationally. The benefits are the potential effect of the results on
health service interventions and social and economic policy which affect this age group.
Expected future outcomes:
This study will assist in understanding the causes of suicide and attempts in young adults and thus contribute to
prevention through health service and social and economic policy.
Name of contact: Richard Taylor
Email of contact: r.taylor@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402639
CIA Name: Prof Philip Sambrook
Main RFCD: Preventive Medicine
Admin Inst: University of Sydney
Start Year: 2006
End Year: 2008
Total funding: $838,972
Grant Type: NHMRC Project Grants
Title of research award: The FREEDOM Study: a RCT of sunlight and calcium to reduce vitamin D deficiency
in older people in residential care
Lay Description (from application):
The proposed study emanates from a large ongoing epidemiological study on falls and fractures in the elderly (the
FREE study). Falls and fractures are major problems in the elderly. This is the genesis for the FREEDOM (Falls
Risk Epidemiology: Effect of vitamin D on skeletal Outcomes and other Measures) intervention study. The
FREEDOM study will evaluate the effect of a public health strategy to reduce falls and fractures in older people
living in residential care (namely appropriate sun light exposure and calcium supplementation) in a randomised
trial. The primary endpoints of this study will be reduction in falls and change in vitamin D levels. Other
endpoints will be change in motor function, mood, bone turnover and fracture incidence. The proposed public
health strategy to be examined is readily transferable to routine practice and would have very good feasibility for
easy implementation and are generally applicable to the residential care setting, where the study will be
conducted. Moreover the proposed approach would be low in cost and does not depend on other health system
input. Potentially large numbers of people would benefit from the better understanding of simple methods of
securing improved vitamin D status.
Research achievements (from final report):
The study found that it was difficult to get an elderly population living in hostel care to increase their sun
exposure.and that it did not increase vitamin D levels. It was concluded that giving Vitamin D supplements is
likely to be more effective at increasing blood vitamin D levels.
PhD research related to this research award has investigated the burden of medications on people in aged care
facilities, who take on average 6 medications per day. The relationship between this medication burden was
examined with respect to physical function and showed an increased risk of falls in this population who were
experiencing a measurable medication burden. These investigations provide great potential for future research
which could investigate associations with cognitive impairment, fractures and hospitalisation to see if medications
that are used to treat diseases are causing problems and whether decreasing the medication burden reduces the
incidence of these problems.
Other PhD research related to this award has identified barriers preventing residents in aged care facilities from
safe an appropriate sun exposure. These barriers include poor health, physical contraints and a sense of lack of
ownership of outdoor space.
Expected future outcomes:
Further PhD research will examine factors influencing adherence to therapeutic sun exposure. Also, analysis of
UV dose data will explore UV dose exposure and its relationship to changes in serum Vitamin D levels.
Name of contact: Professor Lyn March
Email of contact: lyn.march@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219307
CIA Name: Prof David Le Couteur
Main RFCD: Geriatrics and Gerontology
Admin Inst: University of Sydney
Start Year: 2003
End Year: 2006
Total funding: $162,750
Grant Type: SRDC - Research
Title of research award: Australian Ageing Alliance: Geriatric Pharmacology
Lay Description (from application):
Not Available
Research achievements (from final report):
We have published 15 papers and chapters including major reviews of prescribing in older people and evidence
based medicine in geriatric pharmacology. The relationship between drug classes and falls were investigated,
confirming the relationship between psychotropic agents and falling but excluding any association with
antihypertensive agents. We found that the relationship between falls and SSRIs might be mediated by
postprandial hypotension, an entirely novel finding. The relationship between benzodiazepines and falls was
found not to be mediated by sleep disturbances, which were found to be an independent risk factor for falling in
older people in residential care. The effects of age-related changes in liver metabolism on geriatric
pharmacokinetics was reviewed. We reported that the liver sinusoidal endothelium does impact on the transfer of
pharmaceuticals including liposomal preparations that are excluded by the steric relationship with fenestral
diameter. The funding supported the development of a post-doctoral biogerontologist facilitating a post doctoral
year in the National Institutes of Health (Bethesda MD) and her recent appointment as Lecturer in
Biogerontology, a new position created in the University of Sydney.
Expected future outcomes:
The reviews on geriatric pharmacology will improve prescribing in older people. Novel preventable mechanisms
for falls in older people have been identified related to sleep and post prandial hypotension. The implications of
age-related changes in hepatic drug metabolism will improve medication dosing in the elderly.
Name of contact: David Le Couteur
Email of contact: dlecouteur@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457247
CIA Name: Dr Rachael Murray
Main RFCD: Membrane Biology
Admin Inst: University of Sydney
Start Year: 2007
End Year: 2011
Total funding: $471,059
Grant Type: Career Development Fellowships
Title of research award: The cell biology and immunology of wound healing
Lay Description (from application):
Not Available
Research achievements (from final report):
With this grant I have looked at how macrophages are able to migrate into injured tissue and secrete factors that
regulate inflammation. We have identified a SNARE complex, VAMP3, Stx4 and SNAP23, that regulates
macrophage adhesion, migration and migration. This complex does so by regulating the recycling and delivery of
integrins to the cell surface at the leading edge through the long-loop recycling pathway (via recycling
endosomes). This same complex also regulates podosome formation in macrophages. The incorporation of
membrane from the recycling endosomes in the plasma membrane not only delivers these integrins to the cell
surface but also expands the membrane for lamellipodia formation. We have shown the SNARE protein, Stx11 in
macrophages, regulates fusion of late endosomes with lysosome and delivery of lysosomes to the cell surface
upon activation. Recently we have shown that the protein Flightless (Flii), a protein upregulated in response to
injury, is secreted via a lysosomal pathway in response to wounding. In macrophages Flii secretion is regulated by
the SNARE protein Stx11 and by Rab7. Importantly we found that the secreted form of Flightless has the
potential to regulate inflammation in response to wounding.
Expected future outcomes:
N/A
Name of contact: Rachael Murray
Email of contact: rachael.murray@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 253855
CIA Name: A/Pr Christopher Jackson
Main RFCD: Dermatology
Admin Inst: University of Sydney
Start Year: 2003
End Year: 2005
Total funding: $391,650
Grant Type: NHMRC Development Grants
Title of research award: Activated protein C as a promoter of wound healing
Lay Description (from application):
The healing of wounds is a complex process involving a number of stages, including coagulation, inflammation,
remodelling and finally development of full strength skin. Impaired wound healing and/or skin ulcers occur in
patients with peripheral arterial occlusive disease, deep vein thrombosis, diabetes, pressure sores and burns.
Despite intense investigation, the precise mechanisms associated with impaired healing are poorly understood.
APC is a serine protease that plays a central role in physiological anticoagulation. APC potently activates
gelatinase A, an enzyme that plays a prominent role during the remodelling phase of wound healing and
angiogenesis. Our preliminary experiments provide very strong evidence that APC accelerates wound healing
using both cultured cells and a rat skin wounding model. There are three aims to this study. The first will use cell
culture techniques to investigate the mechanisms of action of APC during wound healing. Secondly, we will
expand our pilot studies on the effect of APC as a promoter of wound healing in vivo. These studies will examine
the exact dosing and timing regime for APC, using a rat wound healing model. In addition, we will test the effect
of APC on slow healing wounds, present in diabetic rats. Thirdly, we will determine whether APC is
quantitatively or functionally deficient in human wound fluid derived from slow-healing wounds compared to
wounds that heal normally. This is the first time that APC has been implicated in wound healing. It is envisaged
that this work will ultimately lead to a novel topical treatment of APC to accelerate slow-healing wounds.
Research achievements (from final report):
Impaired dermal wound healing and/or dermal ulcers occur in patients with peripheral arterial occlusive disease,
deep vein thrombosis, diabetes, pressure sores and burns. In one two-year study at Heidelberg Repatriation
Hospital in Australia, leg ulcers accounted for 5259 inpatient bed days, a mean of 44.2 days per patient. Fewer
than 50% had documented improvement at discharge. Leg ulcers are costly due to their extended treatment on an
inpatient basis. A recent Theta report has estimated the global size of the wound healing market to be A$60
billion. As a consequence of an enlarging elderly population, the incidence is set to increase at a rate of 14% per
annum. Despite intense investigation, the precise molecular mechanisms associated with impaired healing are
poorly understood and current treatment regimes are unsatisfactory. This work provides the first evidence that
APC accelerates wound healing. Our experiments show promising results and have led to a number of basic
science papers in top world journals. Overall, our results elucidate mechanistic and efficacy data on APC's
potential as a wound healing agent. This work is likely to lead to topical application of APC as a novel treatment
for impaired wound healing abnormalities.
Expected future outcomes:
We anticipate that these results will lead to a multicentre, double blind human clinical trial to examine the efficacy
of APC in the healing of chronic skin wounds.
Name of contact: A/Prof Chris Jackson
Email of contact: cjackson@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402714
CIA Name: A/Pr David Little
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2006
End Year: 2008
Total funding: $310,137
Grant Type: NHMRC Project Grants
Title of research award: Role of the Osteoclast in Endochondral Fracture Repair
Lay Description (from application):
Failure of bone healing leads to significant pain and disability, such that augmentation of fracture repair is a
dynamic and important field of study. A full understanding of bone repair is necessary before we can hope to
introduce successful therapies. We theorise that by stimulating bone forming cells and inhibiting bone resorbing
cells we may be able to provide optimal results. Bone resorbing cells, or osteoclasts, have long been considered
essential to the initial stages of bone repair (endochondral ossification) during which the early soft cartilaginous
callus is replaced by hard mineralised callus. Our preliminary studies lead us to believe that endochondral
ossification can indeed proceed without osteoclast activity. If we can safely eliminate osteoclast function early in
the early stages of fracture repair, a number of therapeutic options open up for the augmentation of bone healing.
The return of osteoclast function is necessary in the long term, so our strategy will also need to take this into
account. This study will establish which systems are pivotal in endochondral ossification and therefore which
interventions we should explore.
Research achievements (from final report):
This study examined the role of the bone resorbing cell known as the osteoclast during the process of fractrue
repair. When a fracture heals it forms a soft cartilage callus which is then mineralised and replaced by a hard bony
callus. It is this process of replacing cartilage with bone that was the focus of this study. The osteoclast has a
pivotal role in bone tissue removal however has been considered necessary for cartilage tissue removal also. The
current work has shown in great detail that osteoclastic resorption is in fact not necessary to cartilage tissue
removal during bone repair. Instead we have shown that a group of enzymesknown as matrix metalloproteinases
(MMP's) are essential to proper cartilage tissue removal and hence bone repair. A number of cell types secrete
these enzymes including vascular endothelial cells, cells that line invading blood vessels.
The outcomes from this study carry high significance to the clinical management of osteoporosis. A number of
therapeutic agents used to treat this highly common disease target osteoclast acitivity. Hence concerns have
existed about the potential of these agents to interfere with bone repair. Our work suggests these agents will not
impair bone healing due to the elimination of osteoclastic cells from the process.
Expected future outcomes:
This group os studies will aide clinicians in decisions regarding the treatment of osteoporotic patients who sutain
or present with fractures. We will continue to work on a new line of investigation into discreet cellular processes
to provide supporting confirmation of the work we have completed in bone reapir models.
Name of contact: David Little
Email of contact: davidl3@chw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 253805
CIA Name: Dr Isabelle Leclercq
Main RFCD: Gastroenterology and Hepatology
Admin Inst: University of Sydney
Start Year: 2003
End Year: 2004
Total funding: $166,500
Grant Type: NHMRC Project Grants
Title of research award: Cellular and molecular mechanisms of the profibrogenic effect of leptin in the liver.
Lay Description (from application):
Cirrhosis of the liver in the 7th leading cause of death. Regardless of the underlying cause of liver injury (virus,
alcohol, or in affluent countries non-alcoholic steatohepatitis -NASH), the liver repairs damage by forming scar
tissue in a pocess similar to wound healing. All chronic liver diseases are associated with repeated rounds of
wound/healing leading inevitably to progressive fibrosis and cirrhosis of the liver. Obesity, in addition to being
linked to type II diabetes and cardiovascular diseases, is an independent risk factor for liver injury. It is the
clinical setting for NASH, the most common liver disorder in western countries. Also the severity of hepatic
fibrosis and the risk of progression to fibrosis in most forms of liver diseases (regardless of their cause) are
dramatically increased in overweight (>60%) and obese (20% of adult Australian) patients. Leptin is an hormone
that primarily controls food intake and energy balance in the body. In addition, leptin has many other functions.
It is a modulator of the immune and inflammatory system, it is involved in skin wound healing and increases
sclerosis in the kidney. We recently showed that leptin is necessary for fibrosis to develop in the liver and that
increased levels of leptin increases the severity of liver fibrosis. It appears that leptin is a fundamental player in
the biological processes of hepatic fibrosis. As increased serum levels of leptin is a feature of obesity, leptin is
likely to be the "missing link" between obesity and increased hepatic fibrosis. By understanding the mechanisms
by which leptin acts on liver cells to increase fibrosis, this work will lead to new strategies to prevent fibrosis in
obese patients and to reverse scarring in the liver. With the endemic "obesification" in developed countries,
prevention and treatment of obesity-associated liver disease will be the main challenge for the hepatologist in the
next decades.
Research achievements (from final report):
The major achievements of the project include the finding that leptin is an important profibrogenic mediator of
liver injury. This has an important bearing on hepatic fibrosis among patients with overweight and obesity who
comprise a majority of individuals in developed nations. In the absence of leptin, hepatic fibrosis is severely
retarded, while leptin replacement leads to an intact fibrogenic response in leptin deficient animals. In other
studies, we were able to demonstrate that there are leptin-specific mechanisms for impaired liver regeneration in
mice that are leptin-deficient. This leptin-specific effect appeared to be related to altered cytokine production.
Further studies which seek to examine the mechanisms of action of leptin on individual liver cell populations is
underway. This aspect of the project is being done under the auspices of the program grant obatined by the
investigators. In preliminary studies, the profibrogenic effect of leptin in the liver appears to be mediated by
actions on the hepatic Kupffer cell. Direct actions on the matrix producing hepatic stellate cell appear to be of
minor significance. In other published work, we have demonstrated that oxidative stress is a key mediator of
hepatic fibrosis in a rodent nutritional model of steatohepatitis.
Expected future outcomes:
This project has lead to an increased appreciation of the role of leptin in hepatic injury, inflammation and fibrosis.
More importantly, the role of adipokines (hormones secreted by adipocytes [fat cells]) to liver injury is being
appreciated, as is the role of metabolic factors as mediators of liver damage
Name of contact: Jacob George
Email of contact: jacob_george@wmi.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512245
CIA Name: Prof David Little
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2010
Total funding: $482,978
Grant Type: NHMRC Project Grants
Title of research award: Modelling the loss of NF1 heterozygosity in congenital pseudarthrosis of the tibia
(CPT).
Lay Description (from application):
Congenital pseudarthrosis of the tibia or CPT is a dibilitating orthopaedic condition that affects children. Healing
of a CPT is poor and, even with modern surgical techniques, amputation is a frequent outcome. As a group
experienced in animal models of bone healing, we are well positioned to develop advanced genetic models of CPT
in mice. With a better understanding of the underlying processes in CPT we will be able to develop treatments for
this severe childhood condition.
Research achievements (from final report):
Our primary aim was to develop a model of double activation of the neurofibromatosis type 1 (NF1) gene in
mouse fractures. Tibial bone healing in NF1 patients is highly problematic and amputation is not an uncommon
outcome. We hypothesized that NF1 double inactivation would severely impact on bone healing and that this
could be modeled in mice. This model would then be a valuable tool for testing putative therapies.
We successfully generated mice where double inactivation was locally induced using a Cre-expressing
adenovirus. A Cre-expressing lentivirus was used to mechanistically explore and evaluate the effects of NF1
double inactivation on bone cell commitment and differentiation on cultured primary osteoblasts in vitro. Double
inactivation in tibial fracture in vivo significantly impaired bone healing and showed significant fibrosis and
increased osteoclasts; this is consistent with clinical features of the disease. This model has been published in the
Journal of Bone and Mineral Research, which is the top journal in the field. We have explored the use of rhBMP-2
and bisphosphonate (BP) combination therapy in vitro and in vivo and this work has been published. In terms of
patient impact, we are now well placed to start evaluating therapies in this mouse model and in NF1 orthoapedic
patients.
Expected future outcomes:
We are now using this model to test novel therapeutic strategies as part of a new NHMRC funded intiative. We
already have promising results with new compounds. This work may also be translated to severe fractures in
genetically normal patients without NF1. We have also successfully, as part of an international consortium,
become involved in a rhBMP/BP clinical trial.
Name of contact: Aaron Schindeler
Email of contact: aaron.schindeler@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402627
CIA Name: A/Pr Janet Keast
Main RFCD: Autonomic Nervous System
Admin Inst: University of Sydney
Start Year: 2006
End Year: 2008
Total funding: $457,268
Grant Type: NHMRC Project Grants
Title of research award: Regeneration of pelvic autonomic axons after injury
Lay Description (from application):
This project is focused on the problem of erectile dysfunction, especially the common situation where this is
caused by injury to the penile nerves. These nerves are part of the parasympathetic nervous system . Nerve injuryinduced erectile dysfunction is a common problem for prostatectomy patients, with recovery of normal erections
occurring slowly, partially or not at all. There is currently no therapy to improve regeneration of these nerves, and
this is partly because very little is known about effects of injury on any parasympathetic neurons, and especially
for those that are essential for erection. The first aim of this study is to define the key structural and functional
changes occurring in penile parasympathetic neurons during regeneration after injury. This fundamental
neurobiological knowledge is essential to develop and optimise an future growth treatments. The second aim of
the study is to define the effects of a protein, neurturin, on axonal regeneration of penile pro-erectile neurons. Our
evidence so far strongly suggests that it is necessary for the early stages of injury responses. Our studies will be
performed in mice, where we also have colonies of knockout animals to study the effect of removing neurturin
from the regeneration process. Our experiments will include neuroanatomical studies of injured and growing
nerves, pharmacology studies on penile smooth muscle (corpus cavernosum) innervation and responsiveness, and
tissue culture studies. We will investigate not only the changes that occur following injury to penile nerves, but
also the way in which undamaged nerves may assist in returning erectile function.
Research achievements (from final report):
In this project we made a number of discoveries that provide important insights into how injury affects pelvic
autonomic neurons. These are neurons that give "motor" signals to organs of the urogenital system, such as the
bladder and reproductive organs. Injury of these neurons often occurs during surgery to remove tumours (e.g.
prostatectomy, hysterectomy). Using a rodent model of pelvic nerve injury we found that injured neurons that
normally control erectile function actually regrow connections quite successfully, but during the time that this
takes, the organ changes its responses to transmitters; therefore, when nerves finally return to their targets, they
are not very successful at controlling the organ. We also found that if some nerves are spared, the organs behave
quite differently during regrowth of the injured neurons. These observations have led us to consider new ways of
making the nerves grow back faster and also how to preserve the normal "responsiveness" of the organs during
this period. We also identified changes in a group of proteins called transcription factors that are likely to control
regrowth after injury. Finally, in a study on a transgenic rat model of metabolic syndrome, we found that pelvic
autonomic neurons are unable to regenerate adequately after injury. This may be relevant to conditions such as
diabetes, where pelvic autonomic nerves degenerate.
Expected future outcomes:
We hope that these outcomes will lead to the development of new therapeutic approaches to restore urogenital
reflexes after injury.
Name of contact: Janet Keast
Email of contact: janet.keast@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211023
CIA Name: Prof Paul Pilowsky
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Admin Inst: University of Sydney
Start Year: 2002
End Year: 2006
Total funding: $941,350
Grant Type: NHMRC Project Grants
Title of research award: Central control of blood pressure: neurotransmitters, receptors, signal transduction and
gene expression
Lay Description (from application):
The way that the brain controls blood pressure is of crucial significance to our day-to-day survival. Nerves in the
lower brain and spinal cord cause blood pressure to be maintained at appropriate levels for all types of daily
activities ranging from sleep, when blood pressure is very low, to exercise when blood pressure can be very high.
In hypertension, a disorder that afflicts around 10% of the community, blood pressure is elevated to an extent that
damages organs such as the brain, heart, kidney and eye. It now appears that most cases of hypertension have as
their basis a disorder of the way that the brain, through the sympathetic nervous system, controls the heart and
blood vessels. Many different brain systems need to change the way that blood is distributed in the body at
different times. For example, when we eat, blood goes preferentially to our gut; if we exercise, to our heart and
muscles; if we are cold, to our skin and when we think, to our brain. This specialised regulation of blood flow is
accomplished by the interaction of nerves in the lower brain and spinal cord. It involves a vast array of special
chemical messengers acting on specific receptors through different intracellular mechanisms and involving the
turning on or off of genes. Only a few of these neurotransmitter systems are well understood. At the core of our
proposal, we aim to determine which neurotransmitters systems are important for which cardiovascular functions.
We anticipate that this new information will permit the development of new approaches to the management of
hypertension. The reason for this is that since different pathways use different messenger systems, it should
become possible to tailor therapy to suit hypertension without causing undesirable side-effects.
Research achievements (from final report):
The major scientific achievements of our research program have been to increase understanding about the way
that the brain controls blood pressure and which chemicals are important in this regulation. Our work has a special
focus on a part of the brainstem called the rostral ventrolateral medulla since this area is known to be crucial for
maintaining normal blood pressure and in responding to reflexes such as low oxygen reflexes and high pressure.
The Funds awarded resulted in the publication of 30 peer-reviewed scholarly articles in major international
journals. Twelve PhD students received training during this period and worked on activities related to this grant,
and five of these candidates have completed their degrees. Thirteen students worked on Honours degrees
successfully during this period with twelve achieving a first class result. The potential benefit of our work can be
understood in terms of the acquisition of new knowledge about the central control of the cardiorespiratory system
which will likely lead to the development of novel forms of therapy for cardiovascular and respiratory diseases
which together are major causes of sickness and death in our society. Training is not to be underestimated. Our
successful students continue as medical doctors, dentists and specialists or combine these activities; others work in
high-technology industry, directly benefiting our economy.
Expected future outcomes:
We anticipate that the work conducted with funds from this grant will result in direct benefits in understanding
how the brain and heart work thereby leading to new treatment for disease. The importance of training young
graduates cannot be underestimated.
Name of contact: Professor P M Pilowsky
Email of contact: paul.pilowsky@mq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211279
CIA Name: A/Pr Lyn March
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2002
End Year: 2006
Total funding: $360,660
Grant Type: NHMRC Project Grants
Title of research award: Economic Evaluation and Health Outcomes of Arthritis and its Treatments
Lay Description (from application):
Musculoskeletal diseases are the most common single cause of chronic disability in Australia and total joint
replacement is rapidly becoming one of the most commonly performed operations. This burden of illness is
likely to increase with our ageing population and there is an urgent need to obtain data relating to the costs and
outcomes in the Australian context so that appropriate planning of health services and resources can be carried
out. The WHO (World Health Organisation) has declared 2000 to 2010 the Bone and Joint Decade,
recommending that research into musculoskeletal disorders be a priority. We have been recruiting and following
a unique cohort of osteoarthritis and rheumatoid arthritis patients, from both the public and private health sectors,
who have been carefully documenting their health outcomes, health care costs (including primary, revision and
bilateral hip and knee joint replacement surgery), out-of-pocket and indirect costs related to their arthritis. Longterm follow-up is now essential to obtain a clear picture of the impact of living with arthritis over time and the
cost-effectiveness and predictors of good and bad outcomes of joint replacement surgery. The information derived
from this study will be useful for patients and doctors in making their decisions about treatments, as well as for
health care providers in planning of health services for arthritis sufferers. Given that the cohorts are already
established, the study is in a unique position to provide ongoing important longer-term data for relatively low
cost.
Research achievements (from final report):
We have established a unique cohort of over 900 arthritis subjects (244 non-surgical and 687 surgical - including
revision and bilateral arthroplasty). A relatively high proportion of the cohort has been maintained considering
the age of the participants and the amount of commitment required from participants. This was done using regular
telephone contact, quarterly newsletters, birthday cards, certificates of appreciation and decorative magnets.
Analysis of costs and health outcomes over 9 years for the non-surgical cohort showed that disease progression in
the OA group was slow, with slight non-significant deterioration in health status measures. The health status of
the RA group deteriorated significantly over the 9 years. Out-of-pocket expenditure increased significantly for
OA subjects from $247 to $548 per 3 months, but remained relatively stable for the RA subjects, increasing from
$367 to $397 for each 3 month period.
Significant improvement from pre-surgery to 12 months post-surgery was shown. The OA group then showed no
deterioration in function or increase in pain over the following eight years, despite a worsening in general health
status which may be attributed to aging of the cohort. No increase was seen in out-of-pocket expenditure over the
eight year period. It appears that joint replacement sugery amongst this cohort is showing a sustained beneficial
impact in terms of costs and outcomes at 8 years post-surgery.
Expected future outcomes:
An assessment of pre-operative self-efficacy amongst the recently recruited patients has shown that higher selfefficacy was associated with better health status & lower costs to both the respondent & health system. Selfefficacy is amenable to change, so these preliminary cross-sectional results suggest that increasing patients' selfefficacy may improve post-operative outcome and reduce costs.
Name of contact: A/Prof Lyn March
Email of contact: lynmar@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302156
CIA Name: Dr Christopher Vaughan
Main RFCD: Basic Pharmacology
Admin Inst: University of Sydney
Start Year: 2004
End Year: 2006
Total funding: $432,750
Grant Type: NHMRC Project Grants
Title of research award: Cellular actions of cannabinoids within the spinal cord dorsal horn in a neuropathic
pain state
Lay Description (from application):
Morphine and other opioids are among the most important drugs used to treat moderate to severe pain. However,
some clinically important chronic pain states are relatively insensitive to opioid treatment, such as neuropathic
pain which is caused by injury to the nervous system. Human and animal studies indicate that the active ingredient
of the plant cannabis sativa, THC, and a number of synthetic cannabis-like drugs (cannabinoids) also have
analgesic, or pain relieving properties. Animal studies have shown that cannabinoids potentiate the analgesic
effects of opioids. Of particular interest is the finding that cannabinoids reduce the abnormal pain symptoms
associated with animal models of neuropathic pain, such as that caused by nerve injury. Several brain regions play
a pivotal role in the analgesic actions of both opioids and cannabinoids. In previous studies I have identified the
cellular mechanisms by which opioids and cannabinoids produce their analgesic effects in single cells within the
brain. In addition, the spinal cord is the initial relay point of painful stimuli entering the central nervous system
and is a major site of opioids and cannabinoid analgesic actions. However, the cellular mechanisms underlying
cannabinoid and opioid actions within the spinal cord, particularly in pathways which transmit ascending pain
information to the brain, are less well understood. In addition, the cellular actions of cannabinoids and opioids in
neuropathic pain states are unknown. The proposed study will determine the cellular mechanisms underlying the
analgesic actions of cannabinoids and opioids in single neurons identified as belonging to pain pathways within
the spinal cord in normal and nerve injured animals. These techniques have the potential to identify analgesic
combinations between cannabinoids, opioids and other agents with enhanced therapeutic activity and reduced side
effects.
Research achievements (from final report):
The spinal cord is the first relay point of pain inputs to the central nervous system. Animal studies have suggested
that pain is processed in a very specific manner within the spinal cord before the 'pain information' is sent to the
brain. The spinal cord is also a major site of action of pain-relieving drugs, such as morphine-like drugs (opioids)
which are one of the most important drugs used to treat moderate to severe pain. However, some clinically
important chronic pain states are relatively insensitive to opioid treatment, such as neuropathic pain which is
caused by injury to the nervous system. Animal studies indicate that the active ingredient of the plant cannabis
sativa, THC, and a number of synthetic cannabis-like drugs (cannabinoids) also have analgesic, or pain relieving
properties.
This study set out to identify (1) the manner in which different pain modalities are processed within the spinal, (2)
examine the effect of opioid and cannabinoid drugs modulate this pain processing and (3) identify novel
cannabinoids which alleviate animal models of significant chronic pain states. The present study has determined
the mechanisms by which potentially noxious cold sensation is processed within the spinal cord (aim 1) and the
effect of opioids and cannabinoids on this mode of pain sensation (aim 2). The study has also examined the effects
of novel cannabinoids in two important models of chronic pain, namely those caused by nerve injury and by
inflammation.
Expected future outcomes:
In the future we will examine the actions of the novel cannabinoids at the cellular level in an attempt to define
novel therapeutics. We will also examine their actions in clinically relevant chronic pain states. We will initate
further studies comparing the analegsic actions of THC and morphine-like drugs.
Name of contact: Chris Vaughan
Email of contact: chrisv@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512140
CIA Name: Prof Janet Keast
Main RFCD: Autonomic Nervous System
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2011
Total funding: $333,314
Grant Type: NHMRC Project Grants
Title of research award: Plasticity and regeneration of bladder motor nerve circuits after injury
Lay Description (from application):
Our goal is to determine ways of improving the recovery of bladder-controlling nerves after they are injured,
which has devastating effects on bladder function. This can happen because of lumbosacral spinal nerve damage
or pelvic surgery. We also expect to establish broad principles that may be tested in other neurological conditions
that affect bladder function, such as neurodegenerative disorders (e.g. diabetes) and spinal cord injury.
Research achievements (from final report):
This grant focused on how nerves that control bladder function recover from injury. These injuries commonly
occur during pelvic surgery procedures to remove cancer tissue and negatively impact on quality of life. Very little
is known about how these nerves respond to damage - e.g. if they can spontaneously recover or not, and if they
can be stimulated to recover more quickly and effectively. During this project we have developed a new and
detailed understanding of the connections that are made between the spinal cord and the bladder, and the chemical
changes that occur in the spinal neurons after their axons are damaged. We have also identified some unique
properties of these neurons that will allow us to identify them amongst the many other types of spinal neurons that
control other pelvic organs. This will be very important for future experiments aimed to promote their regrowth.
We have also mapped in great detail the connections that nerves normally make with bladder tissues, which will
allow us to track very precisely the impact of injury and growth treatments in the future. Finally, we have tested a
number of proteins and found some that are very effective at stimulating growth of bladder neurons. These new
findings provide important new information to show that nerves controlling bladder function are able to regrow
after injury but have properties that are different from nerves controlling other organs so will required 'tailored'
treatment to promote their recovery.
Expected future outcomes:
This new data is essential for designing and interpreting future studies on new regenerative therapies. The new
anatomical information we have obtained on the normal (i.e., un-injured) spinal cord and bladder nerves will be
very valuable for researchers trying to understand and treat other bladder health problems (e.g., overactive
bladder; bladder dysfunction after spinal cord injury).
Name of contact: Professor Janet Keast
Email of contact: jkeast@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512115
CIA Name: Dr Nicholas Henschke
Main RFCD: Primary Health Care
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2012
Total funding: $333,516
Grant Type: Early Career Fellowships (Overseas)
Title of research award: Derivation, transportability, and usefulness of clinical prediction rules for low back
pain
Lay Description (from application):
Low back pain (LBP) is a very common and expensive health condition worldwide. To help clinicians manage
LBP and other health conditions, clinical prediction rules can be used to identify patients at risk of prolonged
suffering and prescribe appropriate treatments. This research program will determine the best methods to develop
these rules and measure the effect they have on the burden of LBP. The findings will also contribute to improving
the management of many other health conditions.
Research achievements (from final report):
This research award allowed me the opportunity to develop my research skills at two leading international
research institutes. For the first two years at the EMGO Institute for Health and Care Research, Amsterdam, the
Netherlands, my focus was on developing my methodological and statistical skills with the available expertise
there. The award allowed me to work in collaboration with leading researchers in the Netherlands on providing the
best evidence for a number of treatments for low back pain, which is one of the most common and costly
musculoskeletal conditions. By contributing to the evidence around these treatments in a methodologically
rigorous way, my findings are able to inform policy and clinical recommendations for low back pain. In addition
to this, the international experience in research, teaching, and presentation of my findings was invaluable. Upon
my return to Australia in 2011, I completed the final two years of the award at The George Institute for Global
Health in Sydney. Working within the Musculoskeletal Division of the Institute, I was able to continue my work
in collaboration with international researchers while developing a line of research on sports injuries and
musculoskeletal conditions in children and adolescents. The lack of evidence around the epidemiology and
clinical implications of musculoskeletal conditions in children and adolescents, despite these conditions having
links to adult health complaints and disability, warranted a new perspective in this area.
Expected future outcomes:
The impact of this research in the future has the potential to change current best practice with regard to
management of these conditions, as well as recommendations about safe sport and physical activity for children
and adolescents.
Name of contact: Nicholas Henschke
Email of contact: henschke@uni-heidelberg.de
NHMRC Research Achievements - SUMMARY
Grant ID: 457142
Start Year: 2007
CIA Name: Dr Soufiane Boufous
End Year: 2011
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $283,336
Admin Inst: University of Sydney
Grant Type: Early Career Fellowships (Australia)
Title of research award: The prevention of road traffic injuries using linked data
Lay Description (from application):
Not Available
Research achievements (from final report):
As part of this fellowship, I led data linkage projects that investigated the burden and risk factors of traffic
crashes in collaboration with leading researchers in injury epidemiology. I played a major role in the Drive study
by linking data from one of the world's and Australia's largest cohort study of young drivers (20,822 provisional
drivers aged 17-24 in NSW) to administrative databases, including police and health data collections. The study
generated valuable new information about young driver safety and continues to inform policy and practice in this
area. Other data linkages projects I have led resulted provided new information about factors contributing to the
severity of traffic crashes in older drivers and added new knowledge on the burden and risk factors of workrelated traffic crashes, particularly the role of fatigue. All these projects resulted in a number of peer-reviewed
publications (see attached list).
During the period of my fellowship, I have also led and contributed to important policy research projects for
international agencies such as the United Nations Children's Fund and the World Health Organisation as well as
National and state government agencies in New South Wales, Victoria and the Northern Territory. I have also
been an active member of the International Collaborative Effort on Injury which undertakes research into the
comparability of international injury data and a member of a group of 20 international experts involved in the
Global Burden of Injury project (GBD).
Expected future outcomes:
My work as part of the GBD Injury expert group is expected to provide estimates of the injury burden that will
be used by national governments and international organisations, such as the World Health Organisation, for
policy development and resource allocation.
Name of contact: Soufiane Boufous
Email of contact: soufiane@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 153712
CIA Name: Prof Stephen MacMahon
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2001
End Year: 2003
Total funding: $364,218
Grant Type: NHMRC Project Grants
Title of research award: Randomised trial of ibuprofen for the prevention of ectopic bone-related pain and
disability after hip replacement
Lay Description (from application):
Joint replacement is a well-established treatment for severe osteoarthritis of the hip. While most patients benefit
substantially from the procedure, many still experience some pain and disability after surgery. New evidence
suggests that one important cause of this pain and disability may be abnormal bone deposits that form in the
muscles around the hip (ectopic bone formation) during the first few months after surgery. Ectopic bone formation
is seen in about 40% of all patients with hip replacements. If the formation is extensive, all movement of the hip is
lost and revision surgery is necessary. However, even when the formation is less severe, movement at the hip can
be restricted resulting in pain and disability. There is growing evidence that treatment with a non-steroidal antiinflammatory drug at the time of surgery may halve the risk of ectopic bone formation. While this would be
expected to decrease the risk and severity of post-operative pain and disability, there is little evidence available
about the long-term effects of these drugs after hip replacement. For this reason, together with concerns about
possible side-effect of these drugs, orthopaedic surgeons have generally been reluctant to prescribe these drugs
routinely for the prevention of ectopic bone formation. Ibuprofen appears to be the non-steroidal antiinflammatory drug with the lowest risk of side effects. If it was shown to be effective in reducing the incidence of
pain and disability associated with ectopic bone formation after hip replacement, it may well be considered
worthwhile by doctors and patients alike. If such benefits were realised, this preventive strategy is likely to be a
highly cost-effective way to improve long-term outcome among the rapidly growing numbers of patients that
receive hip replacements. This study will provide reliable evidence about the short and long-term effects of
ibuprofen among 1,000 patients receiving hip replacements in Australia.
Research achievements (from final report):
Worldwide, HIPAID is the largest randomised clinical trial conducted to date investigating the risks and overall
benefits of a perioperative course of a non-steroidal anti-inflammatory drug (ibuprofen) amongst people
undergoing elective hip replacement surgery. 902 patients were randomised from more than 20 orthopaedic
surgery centres throughout Australia and New Zealand. Bleeding and adverse events were closely monitored
during the study treatment period. Benefits were assessed 6 to 12 months after surgery and included a wide range
of both well-validated patient self-reported outcomes (pain, physical function, general health status and global
assessments of treatment effectiveness) as well as objective measures of physical performance (range of hip
flexion, walking speed). Loss to followup was minimal: less than 6% for the main outcome: self-reported
physical function. HIPAID confirmed that hip replacement surgery is extremely beneficial for most patients with
osteoarthritis, resulting in greatly reduced pain and improved physical function and mobility. HIPAID also
confirmed that more than 40% of patients will develop ectopic bone after elective hip replacement surgery and
that a short perioperative course of ibuprofen (1200mg for 14 days) will significantly reduce the risk of
developing ectopic bone without significantly increasing bleeding or the rate of adverse events. However, the
periooperative anti-inflammatory treatment did not appear to markedly improve the considerable long-term
benefits already achieved by the hip replacement surgery.
Expected future outcomes:
This unique data set will be further explored to analyse how closely ectopic bone is associated to poor outcome
and if any patient characteristics or peri-operative events increase the risk of developing ectopic bone or poor
outcomes to surgery (approximately 15% of this sample did not report that their hip was 'much better' after
surgery.
Name of contact: Dr Marlene Fransen
Email of contact: mfransen@thegeorgeinstitute.org
NHMRC Research Achievements - SUMMARY
Grant ID: 302175
CIA Name: Prof Robyn Tate
Main RFCD: Health, Clinical and Counselling Psychology
Admin Inst: University of Sydney
Start Year: 2004
End Year: 2006
Total funding: $365,700
Grant Type: NHMRC Project Grants
Title of research award: A clinical trial of the effect of neuropsychological treatments in increasing community
participation after brain injury
Lay Description (from application):
Traumatic brain injury is very common, with more than 2,000 people surviving serious brain injury in NSW each
year. The survivors are most commonly young adult males and many are left with permanent brain damage,
invariably affecting cognitive abilities. The impact of cognitive impairments on the person's capacity to resume
their premorbid lifestyle is enormous. In one of our studies we found that 40% did not work but nor did they have
any meaningful occupational activity to replace work. The current project targets this large group of people in
particular. The study aims to develop and test two alternative, intensive cognitive treatment programs that are
geared to increasing community participation, everyday activities and psychological well-being. To date, no such
therapies have been evaluated using powerful methodological designs. As a result of the study we will be able to
incorporate the standardised interventions into a format that can be easily applied to Brain Injury Rehabilitation
Services in Australia. The programs will not only improve the functioning of the individuals with brain injury, but
will have a flow-on effect for their families and the community at large.
Research achievements (from final report):
This project evaluated two therapy interventions for the treatment of neuropsychological impairments after
traumatic brain injury, with the aim of increasing community participation. People who have traumatic brain
injury are generally previously healthy young adults and the brain injury is a major contributor to morbidity; in
particular, a large proportion is unable to return to the workforce and many from this group do not have the skills
to establish and maintain alternative meaningful occupational activity in lieu of work. This project particularly
targetted this group of people and aimed to train them in skills and strategies to increase the number and variety of
avocational activities. To address this, we developed a therapy program that focused on one aspect of executive
impairment, disorder of drive. The therapy program involved developing awareness and problem-solving
strategies to improve goal achievement. A therapy manual was developed, that involved 20 sessions conducted
over 8 to 12 weeks (with a mix of individual and group sessions). This study used a randomized controlled trial
and recruited 49 participants who were allocated to either the executive therapy program (n = 17), a comparison
traditional community-based leisure education and recreational program (n = 17), or a no treatment, wait-list
control (n = 15). It was shown that after therapy the executive therapy group showed a larger increase in scores
on the Nottingham Leisure Questionnaire than did the other groups. Outcomes from the research have been
presented at conferences and prepared for publication.
Expected future outcomes:
This research provides a resource to conduct neuropsychological treatment for one aspect of executive impairment
(disorder of drive), with the aim of increasing community participation for people who are not able to return to
work. Further research needs to examine its applicability to other clinical groups.
Name of contact: Professor Robyn Tate
Email of contact: rtate@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402686
Start Year: 2006
CIA Name: Prof Kathryn Refshauge
End Year: 2008
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $393,975
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: The efficacy of manipulation for recent onset neck pain
Lay Description (from application):
Neck pain is extremely common, with a point prevalence of 46% in the general community. Neck pain can cause
significant disability, and is the second most common injury causing people to take time off work. Neck pain and
its associated disability clearly poses a substantial social and economic burden. Neck manipulation (high
velocity thrust of the joints, often associated with a "click") is widely used by physiotherapists for the
management of recent onset neck pain, but there is no clear evidence for its efficacy. In addition, the use of
manipulation is associated with serious, although rare, adverse events such as stroke or even death. The riskbenefit analysis, therefore, does not clearly favour manipulation because efficacy has not been established, while
the risks are serious, but infrequent. The findings of the proposed study will clearly and precisely determine the
efficacy of manipulation compared with the safer treatment technique of mobilisation (gentle oscillatory pressure
applied to the joints), information that is currently unavailable. This information is of vital importance to many
different disciplines, including health professionals, insurance companies, and to administrators for development
of health policy. Our findings will thus provide evidence-based guidelines for the use of manipulation, and will
ultimately lead to safer practice of physiotherapy for neck pain.
Research achievements (from final report):
Neck pain is extremely common in the Australian community. It is often treated with manipulation (a high
velocity thrust to the joints, usually accompanied by a "click"), but there are serious risks associated with
manipulation, such as stroke, or even death, although the frequency of complications is unclear. However, such
complications are particularly unacceptable because they arise from treatment of a simple, benign condition.
Despite the risk of these catastrophic complications, the efficacy of manipulation for recent onset neck pain is
unknown.
We therefore determine the efficacy of neck manipulation for recent onset neck pain in a randomised controlled
trial. We compared manipulation with the safer, gentler form of mobilisation for recent onset idiopathic neck
pain. The trial replicated authentic clinical practice, with clinician judgement included as part of the decisionmaking process.
We found that manipulation was not more beneficial than mobilisation for any outcome. In particular, neither
pain nor disability improved more rapidly or more completely. Although there were no serious adverse events
sustained in the trial, there were some minor adverse events, such as nausea, dizziness and increased neck pain
and these occurred more frequently in the manipulation group.
The greatest benefit to flow from this study is that we have shown definitively that neck manipulation confers no
better health outcomes than mobilization, a safer manual therapy procedure. This finding allows us to advocate
against the use of neck manipulation for recent onset idiopathic neck pain.
Expected future outcomes:
We expect that these findings will inform best-practice guidelines, teaching in tertiary institutions and the general
public, so that the use of manipulation for idiopathic neck pain will decline. There should be an attendant
decrease in serious health outcomes from manipulation, with consequent reduced cost to the health sector.
Name of contact: Kathryn Refshauge
Email of contact: Kathryn.Refshauge@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457245
CIA Name: A/Pr David Little
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2007
End Year: 2008
Total funding: $331,425
Grant Type: NHMRC Project Grants
Title of research award: The role of muscle cells in bone repair
Lay Description (from application):
Failure of bone healing leads to significant pain and disability, such that augmentation of fracture repair is a
dynamic and important field of study. A full understanding of bone repair is necessary before we can hope to
introduce novel successful therapies. We believe that a improved understanding of the origins of the cells involved
with bone healing may lead to new surgical, drug and cell-based therapies for the treatment of recalcitrant bone
repair. Stem cells originating from the bone marrow and periosteum are known to differentiate into mature bone
cells and produce bone. However, these tissues are damaged or have poor access to the site of bone injury in many
severe open fractures. In these cases, bone repair often initiates in a region adjacent to an opposing muscle. This
has led us to speculate that cells from the muscle may directly contribute to bone repair. Published studies,
which have be confirmed by our group, have demonstrated the strong potential for muscle-derived progenitor cells
(satellite cells) to become bone-like in response to stimuli such as bone morphogenic proteins. To put boneforming potential of muscle cells in perspective, we plan to expand on these studies and compare mouse satellite
cells with mouse bone marrow stem cells. In addition, we plan to use a transgenic mouse whose muscle cells
become permanently genetically transformed to stain blue. This mouse will allow us to assess the fate of muscle
cells and their contribution to bone formation in ectopic bone formation and fracture repair models. This study
will explore on the most basic level the cellular contribution of muscle to bone repair. The results of this research
project will significantly influence our therapeutic directions for improving fracture repair in the future.
Research achievements (from final report):
The goal of our research is to understand the different cell types that can contribute to bone repair. Delayed bone
union and non-union are significant complications associated with open fractures and most current interventions
do not target specific cell types. We speculated that progenitor cells from the muscle may be able to contribute to
orthopaedic repair.
We used cell culture models to show that muscle progenitors are particuarly sensitive to osteogenic stimulation in
the form of Bone Morphogenetic Proteins (BMPs). BMPs are used as an adjunctive treatment during open
fractures surgery. Mechanistically, we identified an association between expression of BMP Receptor-1A
(BMPR1A) and the sensitivity of progenitor cells. This receptor may be a new potential target for therapies aimed
at mobilizing progenitor cells for orthopaedic repair.
Next, we performed surgical experiments using a special strain of genetically modified mice. In this line, muscle
progenitor are permanently labelled with a reporter gene and can be identified by histological staining. Using open
fracture and traumatic ectopic bone formation models we have proven that muscle cells actively contribute to bone
formation. This is the first study of its kind to demonstrate that this can occur in a significant manner in vivo.
These studies will have the potential to influence orthpaedic surgical practice and suggest that improved muscle
access may provide additional benefits beyond vascularity. These finding also indicate that muscle progenitors
may be an important target for future cell-based therapies for orthopaedic healing.
Expected future outcomes:
We have achieved all of the key aims of the project. We have generated new aims based upon testing the
functional importance of muscle progenitors in orthopaedic repair, and developing new therapeutic strategies for
mobilizing muscle progenitors. These will be the focus of ongoing future studies.
Name of contact: Dr Aaron Schindeler
Email of contact: AaronS@chw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211266
CIA Name: Dr James Melrose
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2002
End Year: 2004
Total funding: $331,320
Grant Type: NHMRC Project Grants
Title of research award: INVESTIGATIONS ON THE REGULATION OF INTERVERTEBRAL DISC CELL
MATRIX METALLOPROTEINASES
Lay Description (from application):
Degeneration of the intervertebral disc is a painful disabling condition with major socioeconomic consequences.
Medical problems associated with disc degeneration and back-pain, of sufficient severity to warrant consultation
with a physician, are experienced by 90% of the population some time during their lives. In man, back pain
increases in incidence in the third and fourth decades of life, peaks in the fifties and declines thereafter. Changes
in population demographics indicate this problem will increase in severity over the next few decades. American
Bureau of Census data indicate that between 1990 to 2010 the number of people >45 years will increase from 82
to 124 million, the number of elderly in emerging countries will also increase between 200 to 400% in the next 30
years. In the United States, back-pain is the second most common reason that people visit a physician and medical
conditions related to back-pain account for more hospitalisations than any other musculoskeletal disorder. Despite
its high incidence, associated problems of incapacity and economic implications, costed at $100 million per
annum in Australia in 1992, and US$100 billion globally in 1999-2000 (Dorland Data Networks, PA, USA) the
causes of low back-pain are still poorly understood. Disc disease is responsible for 23-40% of all cases of low
back-pain. The management of discogenic low back-pain is currently empirical, directed either toward life-style
changes to minimise symptomatology or to surgical resection or spinal arthrodesis to restrict articulation. Based
on our recent findings and those of colleagues over the last 16 years, it is our strong conviction that it should be
possible with a better understanding of disease mechanisms and with the use of modern technologies to inhibit,
reverse or ideally prevent disc degeneration. Without such basic research there will be no scientific foundation
upon which prospective therapies may be based.
Research achievements (from final report):
Defects in the intervertebral disc are difficult to treat clinically and may be a source of intense low back pain,
furthermore overloading of a biomechanically compromised disc may exacerbate this condition and lead to
propogation of the defect to other neurological structures which may also be a source of intense pain. In dense
avascular connective tissues such as the intervertebral disc the normal healing response to a traumatic insult
leading to formation of a defect in this important weight bearing structure is to lay down a stabilising collagenous
scar tissue in the defect site. Unfortunately, such scar tissue is generally less compliant and less capable of acting
as a weight bearing structure than the native connective tissue of the disc. Replacement of scar tissue with new
functional weight bearing connective tissue is only possible if the endogenous connective tissue cells remodel the
scar tissue and replace it with new functional tissue. Intervertebral disc cells are not a particularly active metabolic
cell type thus agents have been sought which can increase their cellular metabolism to encourage them to remodel
connective tissue and reconstruct mechanically damaged regions of the disc. Such an approach has provided
encouraging results in-vitro with regard to the remodelling of major structural components of scar tissue, namely
collagen and its proteoglycans. On-going studies in animal models in which intervertebral disc defects are
reproduced surgically may provide significant insights as to how dense avascular connective tissues may be
remobilised to provide new functional weight bearing connective tissues.
Expected future outcomes:
Improvement in the recovery of trauma defects in dense avascular connective tissues such as intervertebral disc
and tendon would be expected to improve their functional status and aid in the rehabilitation of affected
individuals and the mobility of the general population.
Name of contact: James
NHMRC Research Achievements - SUMMARY
Email of contact: jmelrose@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570922
CIA Name: Prof Christopher Little
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2009
End Year: 2011
Total funding: $685,270
Grant Type: NHMRC Project Grants
Title of research award: Stem cell treatment for tendon degeneration
Lay Description (from application):
Degeneration and tearing of tendons such as the rotator cuff is a major health issue in working and ageing
Australians. Tendon ruptures are preceded by degenerartive change which contributes to the poor success with
surgical repair. There are very limited medical treatments available. We have developed an animal model
mimicing human tendon dgeneration and will determine the utility and mechanisms of action of using a novel new
therapy, stem cells in modulating degenerarion and aiding repair.
Research achievements (from final report):
There are currently no effective treatments for tendon disease, a major cause of pain and disability in society. This
study sought to determine the potential therapeutic effect of adult mesenchymal stem cells (MSCs).
MSCs injected directly into the site of tendon injury inhibited the early molecular and the highest doses of MSCs
that could be administered (25-50 million cells) gave the broadest improvement. We then detemined whether
injection acutely (2 weeks) or delayed (11 weeks) after tendon injury affected tednon disease in the long term
outcome (3, 6 and 12 months). We found that MSCs significantly modulated tendon degeneration, but
interestingly while both injection timepoints were initially effective (3 months), only the delayed MSC injection
was beneficial in the long term (12 months). Thus while potentially very beneficial, the timing of administration is
critical for the therapeutic potential of MSCs.
In order to understand how MSCs might be working, we studied their effects in a tissue culture model mimicking
the changes that occur in patients. MSCs significantly inhibited the expression of enzymes that degrade tendon
and the associated detrimental changes in tendon mechanicl properties. Importantly these beneficial effects did not
require contact between MSCs and the tendon, indicating that it was driven by soluble factors released from the
MSCs rather than their differeniatun into tendon cells. Furthermore, the scretion profile of the MSCs was affected
by time and exposure diseased tendon. This complex molecular dialogue between MSCs and tendon may expalin
the improved effect with delayed injection.
Sonnabend DH, Appleyard RC, Melrose J, Hunyor S
Expected future outcomes:
Future studies will deternine the exact time frame where MSCs are beneficial, and whether all MSC sources are
equally effective. These results can then be translated into human clinical trials to treat shoulder and other tendon
injuies and disease.
Name of contact: Christopher Little
Email of contact: christopher.litle@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402524
CIA Name: A/Pr Ann Sharpe
Main RFCD: Preventive Medicine
Admin Inst: University of Sydney
Start Year: 2006
End Year: 2008
Total funding: $244,878
Grant Type: NHMRC Project Grants
Title of research award: Hypervigilance in the development of chronic pain
Lay Description (from application):
Chronic pain is a common and debilitating condition. One in five people in the Australian community have been
found to experience chronic pain at any one time. Although there is no evidence of a consistent increase in rates of
chronic pain, the rate of permanent disability has increased dramatically in recent decades. This has contributed to
the growing cost of chronic pain. For example, back pain is the most common reason for filing workers'
compensation claims and leads to loss of 101.8 million workdays annually. The annual costs of medical care for
back pain alone have been estimated at $AUD50 billion in the US and $10 billion in Australia. Not only is
chronic pain a considerable economic burden, it is also a considerable personal burden to patients. Pain is one of
the strongest predictors of poor quality of life and has consistently been found to be associated with high rates of
depression. Although there is a large body of research that investigates what factors are associated with chronic
pain, there is surprisingly little research that investigates the mechanisms that cause chronicity. Theories of
chronic pain suggest that psychological characteristics increase the propensity for people to develop chronic pain.
Specifically, theories argue that those people who tend to be fearful of pain will over-attend to painful sensations
and avoid pain-provoking activities and as a result are at risk of developing chronic pain. This study will test those
theories. If it is found that over-attending to pain does predispose patients to develop chronic pain, this will have
important implications for preventing the development of chronic pain. These findings could help to devise early
interventions to prevent chronicity and thereby reduce the economic burden to health services and the emotional
burden to patients in terms of reduced quality of life.
Research achievements (from final report):
The primary aim of the present research was to investigate the role of biased attentional processes in chronic pain.
One of the leading theories of chronic pain implicates over-attention to pain-related information in the
development and maintenance of chronic pain. The present study therefore sought to establish whether attentional
processes are involved in the development of chronic pain and whether they could be used help to identify those
patients with acute back injuries who are at risk of chronic back pain.
Our research found attentional biases for words describing the sensory qualities of pain amongst both acute and
chronic pain patients, but not in healthy pain-free individuals. These biases were not, however, found to predict
which acute pain patients would go on to become chronic pain patients nor did they predict time off work or use
of health care services. Preliminary evidence was found for the role of attentional biases for words describing the
affective or emotional experience of pain. Importantly, biases for these types of words were predictive of the
development of chronic pain 6 months after the initial acute injury.
The findings of the present research have important theoretical and practical implications. Amongst other
things the findings of the present research suggest that attentional biases are important in the development of
chronic pain, but that this may only true of attentional biases for particular types of words. The findings of the
present study also highlight the possibility that clinical interventions aimed at reducing attentional biases for
affective words may be associated with positive treatment outcomes. This possibility, however, requires further
testing.
Expected future outcomes:
N/A
Name of contact: Assoc Prof Louise Sharpe
Email of contact: louises@psych.usyd.edu.ay
NHMRC Research Achievements - SUMMARY
Grant ID: 512167
CIA Name: Dr James Melrose
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2008
End Year: 2010
Total funding: $605,037
Grant Type: NHMRC Project Grants
Title of research award: The role of perlecan in tensional connective tissues
Lay Description (from application):
Musculoskeletal diseases affect tension and weight bearing connective tissues which have notoriously poor
repair capabilities. These conditions are difficult to treat clinically and surgical repair in many cases does not
provide a return to optimal joint function impinging on the quality of life of afflicted individuals and their carers.
Our project aims to better understand the structure and function of these tissues in health and disease with a view
to improving repair strategies.
Research achievements (from final report):
We have published reviews on the multifunctional properties of perlecan which stabilise connective tissues and
the diverse cell signalling events which perlecan regulates. We also demonstrated the prominent distribution of
perlecan in the development of human foetal spinal tissues and how it differed from other prominent intervertebral
disc matrix components such as the chondroitin sulphate rich proteoglycans versican and aggrecan. Perlecan
isolated from human foetal knee rudiment cartilage was shown to form complexes with FGF-2 and FGF-18 and
these induced cell proliferation in an engineered Baf 32 cell line expressing FGFR2IIIc and FGFR3IIIc. This cell
line does not produce endogenous heparan sulphate proteoglycans thus for the cells to remain viable and
proliferate an exogenous source of heparan sulphate proteoglycan (perlecan) or heparin must be supplied and the
specific effect of a given growth factor on cell proliferation can thus be examined in-vitro. FGF-2 and 18 both
induced cell proliferation when presented to Baf 32 cells when complexed with perlecan. The interaction between
FGF-2 and perlcan was totally dependant on interaction with perlecans HS side chains, removal of these with
heparanase ablated this cell proliferative effect. In contrast FGF-18 still ellicited a significant cell proliferative
response even in the absence of the perlecan HS chains, with ~ 70% of the response evident with perlecan
containing HS chains evident. These publications clearly show the importance of perlecan in the assembly,
maintenance and stabilisation of tensional and weight bearing connective tissues. Its growth factor binding and
regulatory properties may also be of application in regenerative medicine.
Expected future outcomes:
In on-going studies we have shown that perlecan displays interactive properties with tropoelastin, type VI collagen
and fibrillin-1. Thus perlecan is not just a proteoglycan of vascularised and basement membrane tissues but also
has novel roles to play in the elastic properties of tensional and weight bearing connective tissues.
Name of contact: James Melrose
Email of contact: james.melrose@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570942
CIA Name: A/Pr Hala Zreiqat
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2009
End Year: 2012
Total funding: $448,017
Grant Type: NHMRC Project Grants
Title of research award: Novel coatings for orthopaedic implants
Lay Description (from application):
At present the failure rate of joint replacement is unacceptably high and will continue to rise due to the ageing
and active life styles of the baby-boomer generation, placing an increasing burden on the health budget. We have
developed a new bioactive material with improved mechanical/biological properties for bone regeneration. We
will modify the surface of the currently used orthopaedic implants with this bioactive material to promote
permanent fixation of the prosthesis to the bone.
Research achievements (from final report):
This project has provided new important information on the role surface chemistry modification of commonly
used orthopaedic implants on bone remodelling. The major finding of this study is that we describe for the first
time the development of plasma sprayed novel calcium silicate materials coated onto commonly used orthopaedic
implants (titanium alloy-Ti-6Al-4V). We found that the developed coatings possess significantly improved
bonding strength, chemical stability and cellular bioactivity compared to the currently clinically used
hydroxyapatite (HAp) coating. The chemical stability of the ceramic is an important factor influencing the longterm stability of the coating. In this study, we found that our novel ceramics when plasma-sprayed coated has a
decreased dissolution rate compared to HAp coating, indicating that our developed novel material possesses an
improved chemical stability, compared to clinically available coatings (HAp). A major finding of our research
was that our developed material is highly bioactive inducing bone cells proliferation and differentiation, compared
to plasma-sprayed HAp coating and uncoated Ti-6Al-4V. Moreover, in vivo we demonstrated that the novel
coating induce bone formation at the skeletal tissue device interface indicating its potential application as a
coating for orthopaedic implants.
This project has the potential of developing new implant materials with improved osseous integration. With the
current rate of prosthetic failures in orthopaedic patients unacceptably high, and with implant use growing at
~10% per annum, our new biocompatible coating for implants will make a timely contribution to reducing patient
morbidity, benefiting quality of life, and making significant health care savings.
Expected future outcomes:
With the current rate of prosthetic failures in orthopaedic patients unacceptably high, and with implant use
growing at ~10% per annum, our new biocompatible coating for implants will make a timely contribution to
reducing patient morbidity, benefiting quality of life, and making significant health care savings.
Name of contact: A/Prof Hala Zreiqat
Email of contact: hala.zreiqat@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302161
CIA Name: A/Pr Deborah Marsh
Main RFCD: Medical Genetics
Admin Inst: University of Sydney
Start Year: 2004
End Year: 2006
Total funding: $432,750
Grant Type: NHMRC Project Grants
Title of research award: Parathyroid tumorigenesis - a role for the newly identified putative tumour suppressor
HRPT2
Lay Description (from application):
Primary hyperparathyroidism is one of the most common tumour associated diseases of hormone secreting glands
affecting 0.1-0.5% of adults and up to 3.4% of post-menopausal women. It can occur in family members, either
alone or with other tumours, and can also occur with no family history (sporadic). Hyperparathyroidism is caused
by secretion of excessive levels of parathyroid hormone. Amongst other problems, this causes significant bone
disease that can lead to fracture. What is going wrong at the genetic level to cause this disease is, in most cases,
poorly understood. In Hyperparathyroidism Jaw Tumour Syndrome (HPT-JT), one form of familial
hyperparathyroidism, we and our international collaborators have recently identified mutations in the gene HRPT2
predicted to lead to loss of function of this gene. HRPT2 has no known similarities to other genes that may give
hints as to its function.The overall aim of this project is to test our theory that HRPT2 has an important role in
abnormal growth of parathyroid tissue that, in some cases, will lead to cancer. Further, we hypothesise that this
gene will have a role in both familial and sporadic presentations of parathyroid disease. We will investigate this
gene in parathyroid tumour specimens from patients with familial and sporadic disease for gene mutations and
also different levels of gene expression. We will also explore a mechanism for how these mutations may function
to cause disease and look at the effect of reduced HRPT2 expression on expression of thousands of other genes
using a technique known as microarray analysis. The expected outcomes of this study include the identification of
individuals at risk of developing cancer whose treatment will be tailored to their genetic profile. Characterisation
of HRPT2, and the genes its expression influence, may lead to the identification of suitable targets for future
treatment of hyperparathyroidism and its effects on bone disease.
Research achievements (from final report):
We completed a microarray study of 54 parathyroid tumour specimens and identified a strong cluster of genes
associated with mutation in the tumour suppressor linked to parathyroid tumorigenesis, HRPT2 / parafibromin
(Cancer Research). We are currently exploring a role for a number of the differentially regulated genes identified
by microarray as diagnostic markers for specific parathyroid tumours. We've worked closely with pathologists
developing a test for parafibromin immunoreactivity that we've established as diagnostic of parathyroid carcinoma
(American Journal of Surgical Pathology). This work has been complementary to our extensive mutation analysis
studies of HRPT2 published prior to and as part of the current grant (Journal of Paediatrics, Human Mutation) and
has included denaturing high performance liquid chromatography (DHPLC) scanning of genes involved in
parathyroid tumorigenesis, specifically HRPT2 and MEN1 (Journal of Molecular Diagnostics). We've also
completed localisation studies of parafibromin and have been the first to identify its nuclear localisation signal, as
well as report nucleolar localisation and the core sequences responsible (Oncogene and FEBS Letters). These
studies have also included analysis of the cellular localisation of specific HRPT2 mutants. As a result of these
studies, we were invited to write a review on familial hyperparathyroidism for a newly established journal (Expert
Opinion on Medical Diagnostics). In sum, a number of our findings have had direct translation to the clinic,
directly facilitating improved diagnostics. Further, our findings of the cellular localisation of parafibromin are
important to future work characterising the function of this tumour suppressor in healthy and cancer cells.
Expected future outcomes:
Our centre is becoming a reference centre for the diagnosis of parathyroid carcinoma based on this grant's
outcomes. Additional markers of parathyroid cancer will also likely be incorported into clinical diagnostics. Our
work on the cellular localisation of parafibromin will be important to understanding the function of this protein.
Name of contact: Deborah Marsh
Email of contact: dmarsh@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300487
CIA Name: Dr Hala Zreiqat
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2004
End Year: 2006
Total funding: $489,375
Grant Type: NHMRC Project Grants
Title of research award: Mechanisms of bone formation at the device/tissue interface: Role of Biomaterial
Surface chemistry modification
Lay Description (from application):
In 1992 300,000 prosthetic devices, artificial hips and knees were implanted into patients in a global market
worth $2.1 billion. Growth in this field of medicine has been exceptional with now more than 1 million implants
carried out each year. In 1998/99, 38,512 artificial hips and knees were implanted in Australia alone, with
approximately 10% of these replacing older, failed implants. Since joint replacements provide great benefits for
the patient considerable health funding is required for joint replacements. However, failure of the implants is a
major concern to the patient and financially to our health system, especially with the ever increasing life
expectancy of our population. The long-and short-term success of an implant depends on the healthy support of
the surrounding bone. This study aims to find ways of improving the attachment of healthy bone to the implant by
modifying the surface characteristics of the implant. We will modify the surface chemistry of biomaterials with
divalent cations, such as magnesium, which is known to play a critical role in bone remodelling and skeletal
development. Our goal is to improve the formation of healthy bone that will promote a rapid and permanent
fixation of implant into skeletons. This study goes further to study the factors, inside the cell, on the cell surface
and secreted by the cell, which promote this attachment. Once these factors are identified, it should be possible to
alter implant surfaces in ways to improve stability. In this proposal we will use novel bioceramic coatings and ion
beam technologies. This study will not only improve our understanding of the interactions of bone and implant but
also identify ways of improving implants to benefit the patient's quality of life and reduce costs in this important
heath area
Research achievements (from final report):
This project has provided new important information on the role surface chemistry modification of commonly
used orthopaedic implants on bone remodelling. The major finding of this study is that we describe for the first
time the development of plasma sprayed novel calcium silicate materials coated onto commonly used orthopaedic
implants (titanium alloy-Ti-6Al-4V). We found that the developed coatings possess significantly improved
bonding strength, chemical stability and cellular bioactivity compared to the currently clinically used
hydroxyapatite (HAp) coating. The chemical stability of the ceramic is an important factor influencing the longterm stability of the coating. In this study, we found that our novel ceramics when plasma-sprayed coated has a
decreased dissolution rate compared to HAp coating, indicating that our developed novel material possesses an
improved chemical stability, compared to clinically available coatings (HAp). A major finding of our research
was that our developed material is highly bioactive inducing bone cells proliferation and differentiation, compared
to plasma-sprayed HAp coating and uncoated Ti-6Al-4V. Moreover, in vivo we demonstrated that the novel
coating induce bone formation at the skeletal tissue device interface indicating its potential application as a
coating for orthopaedic implants.
This project has the potential of developing new implant materials with improved osseous integration. With the
current rate of prosthetic failures in orthopaedic patients unacceptably high, and with implant use growing at
~10% per annum, our new biocompatible coating for implants will make a timely contribution to reducing patient
morbidity, benefiting quality of life, and making significant health care savings.
Expected future outcomes:
With the current rate of prosthetic failures in orthopaedic patients unacceptably high, and with implant use
growing at ~10% per annum, our new biocompatible coating for implants will make a timely contribution to
reducing patient morbidity, benefiting quality of life, and making significant health care savings.
Name of contact: Hala Zreiqat
Email of contact: hzreiqat@usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457490
CIA Name: A/Pr Kevin Keay
Main RFCD: Central Nervous System
Admin Inst: University of Sydney
Start Year: 2007
End Year: 2009
Total funding: $429,360
Grant Type: NHMRC Project Grants
Title of research award: Supraspinal Neural Adaptations in the Transition from Acute Injury to Chronic Pain
and Disability
Lay Description (from application):
Although there have been significant clinical advances in the management of injury and the control of acute pain
following tauma, many people still develop disabling conditions of chronic pain. Chronic pain and disability
occurs even though the acute signs of trauma have subsided and injuries have healed. People with chronic pain
conditions not only experience ongoing changes in sensation (ie., most commonly lowered thresholds for pain,
touch evoked pain and spontaneous pain), they also endure a number of disabilities for example disrupted family
and social relations, disturbed sleep, loss of appetite, weight changes, loss of sex drive, changes in menstrual
cycle, the inability to cope with stressors, and often moderate to severe anxiety and depression. The proposed
research aims to (i) identify changes in brain circuits which are responsible for producing these patterns of pain
and disability following injury and (ii) attempts to selectively reverse some of these disabilities by reversing the
brain changes. The results of this study will offer for the first time a rational basis for improving the outcomes of
injury and pain management in the acute phase of trauma, by identifying and reversing the critical changes which
predict the advent of the state state of chronic pain and disability.
Research achievements (from final report):
Our research has identified the specific neural networks which undergo (mal)adaptation following nerve injury
and lead to the behavioural and physiological changes which characterise Persistent Disability, in chronic
neuropathic pain conditions. We have characterised using molecular biological and functional-anatomical
techniques unique sets of neural adaptations in the brain likely to underlie the behavioural and physiological
components of disability following injury. 1. Disability is characterised by decreased plasma ACTH and increased
plasma corticosterone due to increased adrenocortical sensitivity to ACTH; decreased CRF levels in the
hypothalamus; (iii) decreased Cort mediated negative feedback of CRF neurons of the hypothalamus; and
increased Cort mediated negative feedback on medullary catecholaminergic neurons. 2. Disability is characterised
by decreased sleep and increased wakefulness. Wakefulness is regulated by dopaminergic neurons in the
midbrain. We have shown increased numbers of tyrosine hydroxylase containing neurons in the midbrain of
disabled rats; regulated by the neuropeptide CCK. 3. Disability is associated with increased CCK in the midbrain
of rats due to increased expression in spinal cord neurons, which project to the midbrain. CCK is known to
provoke anxiety when administered to this brain region and may underlie the enhanced anxiety observed in
individuals with pain and disability following injury. 4. Nerve injury evokes a significant reduction in the volume
and length of the dentate gyrus of the hippocampus in all rats. Significant asymmetry between left and right
hippocampal volumes was found in disabled rats. These observations may underlie the diminished memory and
cognitive capacities of individuals disabled by chronic pain.
Expected future outcomes:
This research will contribute to a better understanding of the transition from acute injury to chronic pain and
disability. These experiments will determine whether therapies based on cholecystokinin antagonists may provide
new avenues for clinical management of chronic neuropathic pain conditions by enhancing the coping style of
individuals with pain and disability.
Name of contact: Kevin Keay
Email of contact: keay@anatomy.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 358457
CIA Name: Prof Jonathan Craig
Main RFCD: Indigenous Health
Admin Inst: University of Sydney
Start Year: 2005
End Year: 2010
Total funding: $2,043,110
Grant Type: NHMRC Strategic Awards
Title of research award: SEARCH - Study of environment on Aboriginal Resilience and child health
Lay Description (from application):
The SEARCH program of research investigates the relationship between environmental determinants of health in
a cohort study with five year follow up involving 800 urban NSW Aboriginal families with approximately 2000
children aged 0-17. A subset of 480 families will be recruited to participate in a randomised controlled trial of the
impact of a health broker on (i) improving treatment of otitis media, and (ii) a feasibility study of an intervention
to improve housing in 50 households. These two studies will form the basis of an urban Aboriginal cohort study
spanning 20 years with funding from alternate sources.
Research achievements (from final report):
SEARCH (the Study of Environment on Aboriginal Resilience and Child Health) is a large scale and long term
study designed to decribe the health and disease trajectories of urban Aboriginal children, to identify precursors of
health and disease and critical periods for intervention. SEARCH is being implemented in partnership with
Aboriginal Communtiy Controlled Health Services (ACCHSs) across NSW in Mt Druitt, Campbelltown, Wagga
Wagga and Newcastle. At the end of December 2010, over 1600 Aboriginal children aged 0-17 years have been
recruited to the study.
We have collected detailed information about the health of participating children and the broad range of factors
likely to contribute to their health, inlcuding: ear health (1133 children have received audiology assessments and
examination for middle ear fluid, tympanic membrane abnormalities and hearing impairment); speech and
language development (600 of the children aged 1 to 7 years have received assessment by a speech pathologist);
social and emptional wellbeing, mental health and resilience; and cardiovascular and metabolic disease including
assessments of obesity, diet and exercise.
SEARCH is already impacting on policy and practice. For example: 1. SEARCH is building capacity in
Aboriginal health reserach. Training has been provided for 7 Aboriginal people employed on the study and 3 PhD
students and 3 post-doctoral fellows are using the SEARCH data for their work; 2. Government and nonGovernment agencies are using data from SEARCH to understand health needs and service provision; 3. The
ACCHSs are using information from SEARCH to identify opportunitities for service improvement; 4. Children
are benefitting from participating in SEARCH. Feedback from clinical tests is provided to families to enable early
identification of problems; and 5. SEARCH is providing infrastructure that enables the testing of new programs.
Expected future outcomes:
The value of SEARCH will increase over time as the children grow older and more information is collected. This
will be used to inform policy and practice through: peer review publications; feeding data back to ACCHSs;
working with health agencies; increasing Aboriginal health research capacity; and importantly, directly improving
the health and longer term wellbeing of Aboriginal children.
Name of contact: Gabrielle Williams
Email of contact: gabrielle.williams@saxinstitute.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 352562
CIA Name: Dr James Melrose
Main RFCD: Orthopaedics
Admin Inst: University of Sydney
Start Year: 2005
End Year: 2007
Total funding: $516,625
Grant Type: NHMRC Project Grants
Title of research award: Pathobiology of the small leucine rich repeat proteoglycans in cartilage, intervertebral
disc and tendon degeneration
Lay Description (from application):
Back problems (M$700), OA (M$600), muscle and tendon disorders (M$500) accounted for 60% of
musculoskeletal (MSK) health care expenditure in Australia in 1993-1994, were the second most common cause
of presentations to a general practitioner, the third leading contributor to health system expenditure (>$3 billion)
and accounted for ~300,000 hospital admissions, ~15 million medical services and over 13 million prescriptions.
Significant disability due to MSK disease were noted in ~50% of people aged 65 years. Australian census data
indicates that ageing trends will result in an increased incidence of MSK conditions as the longevity of the
Australian population rises, exerting an ever increasing burden on the healthcare budget. Extreme levels of
sporting or physical activity from traumatic loading of joints can lead to excessive loading of collagen fibres in
MSK tissues leading to their failure and loss of tissue function. Common end stages of collagen fibre breakdown
are preceded by matrix changes which may predispose MSK tissues to enzymatic and mechanical damage. One
such change is an increased degradation of a family of small leucine-rich proteoglycans (SLRPs) which modulate
the diameter, strength and assembly of collagen fibrils and bind and modify the effects of reparative growth
factors and degradative cytokines within connective tissues. Altered synthesis of SLRPs and SLRP fragments
have been identified in abnormal intervertebral disc, cartilage and tendon. Very little is known however about
how these fragments are generated within these tissues and how they affect growth factor binding or collagen
fibril formation. This deficiency will be addressed in our proposed study which will provide novel information
on mechanisms of cartilage, intervertebral disc and tendon degeneration and potential therapeutic and diagnostic
targets which may be exploited in future studies on the treatment of these musculoskeletal conditions.
Research achievements (from final report):
Musculoskeletal disorders affecting the knee and hip represent a major cause of disability and morbidity in
Western societies, exert a severe socio-economic impact on the afflicted individuals and cause a heavy burden on
healthcare resources. Disruption of collagen fibres in musculoskletal tissues through the action of collagenolytic
matrix metalloproteinases (MMPs) and mechanical forces represent a common end stage of disease. Identifying
changes in these tissues that not only precede collagen destruction, but also predispose them to disease
progression, may provide important targets for diagnosis, disease monitoring and facilitate early intervention
strategies when the likelihood of therapeutic repair is enhanced. The small leucine rich proteoglycans (SLRPs)
including biglycan, decorin, fibromodulin, lumican and keratocan, have important linking, shape determining and
matrix organising roles which are essential for the correct functioning of musculoskeletal tissues. In the present
study we demonstrated in two publications that the SLRPs were extensively fragmented in a number of
pathological human connective tissues and in an ovine model of IVD degeneration. A further manuscript which is
currently under review showed that fragmentation of fibromodulin was dissimilar to other SLRP members in that
it was more extensively C-terminally processed. Two define MMPs (MMP-13 and ADAMTS-4) could reproduce
similar fragmentation patterns for fibromodulin to that evident in pathological cartilages. A final mauscript which
we are currently writing has determined a novel cleavage site in lumican duye to the action of ADAMTS-4 . We
have also developed and validated an ovine model to determine the changes in shoulder tendons which was
published in the top clinical arthritis journal Arthrits Rheum. This model will allow us to determine therapeutic
intervention strategies to prevent further degenerative changes in the tendon and improve tendon repair.
Expected future outcomes:
Improvements in tendon repair/prevention of further degeneration. Improvements in post surgical rehabilitation
for tendon injuries. Identification/characterisation of SLRP core protein fragments may identify them as valuable
biomarkers of joint disease progression. Identification of the enzymes responsible for their generation may
uncover useful therapeutic targets.
NHMRC Research Achievements - SUMMARY
Name of contact: James Melrose
Email of contact: jmelrose@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211226
Start Year: 2002
CIA Name: Prof Maria Fiatarone Singh
End Year: 2006
Main RFCD: Rehabilitation and Therapy: Occupational and Physical
Total funding: $819,180
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Title of research award: Hip Fracture Intervention Trial (HIPFIT)
Lay Description (from application):
Hip fracture secondary to falling in the elderly represents a large and rising health care problem in Australia. At
least 12,000 such hip fractures occur in the elderly in Australia each year and this number is expected to increase
substantially over the next several decades. Long term disability, nursing home placement, reduced quality of life,
and excess mortality are known sequelae of hip fracture despite successful surgical repair. Factors have been
previous identified in epidemiological research which predict poor recovery of function and the most prominent of
these are advanced age, pre-exiting mental or functional impairment, malnutrition, depression, poor social support
networks, and poor gait, balance and muscle function. Current treatment paradigms for hip fracture do not
uniformly screen for or appropriately address potentially reversible factors such as poor nutrition, neuromuscular
dysfunction, depression, strength of social supports, or risk factors for recurrent injurious falls. It is unlikely that a
unidimensional treatment will ever optimize long term functional independence in such a multifactorial syndrome.
Therefore, we propose to apply a multifaceted targeted experimental treatment package (HIPFIT) to elderly
patients admitted to hospital for repair of a fractured hip secondary to a fall. HIPFIT would begin in hospital and
continue throughout the 12 months of follow up, using individualized treatment strategies based on periodic
reassessments in these vital domains over time. The goal of the study is to reduce the number of patients requiring
nursing home care at the end of 12 months, as well as to improve independence in a range of activities of daily
living among experimental subjects. This would have significance not only in terms of large economic savings for
the health care system but reduced personal suffering and dependency on the part of the affected individuals.
Research achievements (from final report):
Between February 2003 & April 2007 we identified 1748 individuals (60% women) admitted to RPA Hospital
with potential hip fractures (median age 80 y). A total of 262 patients were found eligible for the study and
approached for their consent which was obtained from 124 patients (47% of eligible). Three assessments were
completed per participant: a total of 111 post hip fracture, 98 after 4 months & 87 after 12 months. The 12 months
intervention was implemented for 85% of the participants randomised to intervention. Drop-out rate was 10%,
lower than we conservatively anticipated, and death rate was also 10%.
This is the first study to target all major remediable contributions to recovery of function after hip fracture,
including a multi-component intervention directed at fall risk in the home, bone health, sarcopenia, muscle
weakness, gait and balance impairment, depression, cognitive impairment, nutritional deficiencies, low selfefficacy, low social support, polypharmacy, and visual impairment. The robust RCT design, supervised 12 month
intervention, and long-term followup of functional status and place of residence/death over 5 years make this
study completely unique internationally, and a critical addition to clinical practice in this area. If the intervention
proves successful as we complete our analyses of primary and secondary outcomes, we will have demonstrated an
approach that can be implemented directly into existing health care infrastructure in Australia, as this study was
carried out in the outpatient clinic of a hospital using a variety of health care professionals who typically work in
such a setting. However, the approach we took to proactively identifying and aggressively treating etiological
factors in hip fracture-related incidence and recovery is not currently the standard of care in Australia or
elsewhere, and translation of this approach to the community will require substantive and vitally-needed
educational and implementation strategies.
Expected future outcomes:
Training of health care professionals to implement this intervention in health care settings throughout Australia
and internationally.
Development of multi-medial training materials to allow translational research and dissemination into community
settings.
NHMRC Research Achievements - SUMMARY
Name of contact: Maria A. Fiatarone Singh
Email of contact: m.singh@usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570853
CIA Name: Prof Rebecca Ivers
Main RFCD: Epidemiology
Admin Inst: University of Sydney
Start Year: 2009
End Year: 2012
Total funding: $731,552
Grant Type: NHMRC Project Grants
Title of research award: Buckle up safely: pre-school based interventions for appropriate use of child restraints.
Lay Description (from application):
Despite overwhelming evidence that child restraints dramatically reduce the risk of death and injury there are
currently a large number of children globally who either do not use appropriate child restraints, or misuse them,
contributing to the overwhelming burden of road traffic injury in children. This project, using rigorous
methodology, will assess the efficacy of feasible, evidence based interventions aimed at increased use of
appropriate restraints, and decreasing misuse.
Research achievements (from final report):
We conducted a comprehensive evaluation of an education based program to promote use of child restraints. This
is an important measure to protect child passengers from injury in road crashes. The study was timely as the
National Road Rules were updated in 2009 to reflect best practice child restraint use. We worked with community
pre-schools and long daycare centres from South-West and Western Sydney where restraint use is traditionally
low. The program was delivered to 13 centres and comprised several components. Firstly a 2 hour workshop with
a theme of safe travel in cars was delivered to centre staff and ongoing curriculum development and policy
support provided. Posters in English and 5 community languages were made available to each centre and other
educational materials. The second component of the program involved a parent interactive session 6-8 weeks
after the staff training where parents were informed about the safety benefits of appropriate child restraints and
given hands on demonstrations (19 sessions held). An educational DVD was produced for the program and
screened at these sessions. Booster seats and forward facing child restraints were made available to parents from
participating centres at subsidised cost. Free restraint fitting vouchers were also given to each family.
Observations were conducted at each of the 27 centres actively enrolled in the trial. More children attending
intervention centers (43%) were optimally restrained (31%) (P=0.01, allowing for clustering by center).
Education, subsidized restraint distribution and fitting were effective in reducing errors in use and increasing use
of age-appropriate restraints in low income areas of Sydney, particularly in linguistically isolated families.
Expected future outcomes:
The main study results have now been accepted by the American Journal of Public Health. Once these results are
published a media campaign is planned to disseminate the study findings. The results will also be discussed with
stakeholders particularly government road agencies. All study materials have been made available and several
groups have already made use of the educational resources.
Name of contact: Professor Rebecca Ivers
Email of contact: rivers@georgeinstitute.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302203
CIA Name: Prof Graeme Jones
Main RFCD: Paediatrics
Admin Inst: University of Tasmania
Start Year: 2004
End Year: 2005
Total funding: $144,750
Grant Type: NHMRC Project Grants
Title of research award: A longitudinal study of bone development in children
Lay Description (from application):
Osteoporosis is a major public health problem resulting in 50-75,000 fractures each year in Australia costing the
community about 800 million dollars per annum. Bone strength is a risk factor for fractures in both childhood and
in later life. Relatively little is known about bone development with the exception of calcium intake and physical
activity. This study will follow 500 children from birth in 1988 to 2004 with the aim of understanding the
contribution of lifestyle factors to bone development in this time period.
Research achievements (from final report):
This study followed 415 children from birth to age 16 years observing the development of healthy bones in
children. At age 8, we found that breastfeeding, smoking during pregnancy, diet during pregnancy, birthweight,
physical activity, sun exposure, asthma medication and fruit and vegetables were all associated with bone mass.
By age 16, smoking during pregnancy was no longer associated but both breastfeeding and birthweight were
suggesting an effect on peak bone mass. Diet is still being analysed. Vitamin D deficiency was common (40%)
and was associated with bone mass. Fractures were common in these children (179/415) and were predicted by
bone mass (heel ultrasound and DXA), breastfeeding, asthma medication and physical fitness at age 8. Bone
density also tracks from age 8 to age 16. This study has provided novel data on the role of lifestyle factors in bone
development in children which should lead to the development of programs to prevent fractures in both younger
and later life.
Expected future outcomes:
This work is likely to lead to prgrams which increase peak bone mass and decrease fracture risk in both early and
later life
Name of contact: Graeme Jones
Email of contact: g.jones@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 106915
CIA Name: Prof James Vickers
Main RFCD: Neurosciences not elsewhere classified
Admin Inst: University of Tasmania
Start Year: 2000
End Year: 2004
Total funding: $390,326
Grant Type: NHMRC Project Grants
Title of research award: The neural reaction to injury: Clues to the cause and prevention of acquired brain
damage and Alzheimer's disease.
Lay Description (from application):
The cellular mechanism underlying neuronal degeneration following head trauma and Alzheimer?s disease is not
known and represents the major impediment to developing therapeutic strategies to protect nerve cells. This grant
application will utilise a variety of modern research methods to determine the key changes in the brain that are
associated with the response of nerve cells to physical trauma. These include not only the structural alterations that
immediately follow such injury, but the complex cellular and gene expression changes that determine the ultimate
fate of the cell. Both acquired brain injury and degenerative conditions such as Alzheimer?s disease represent an
enormous health, social and economic burden. Furthermore, with predictions that Alzheimer?s disease will
increase by 3-4 times by the middle of the next century due to the Oaging? of the population, it is becoming even
more crucial to establish effective therapeutic interventions. The animal models investigated in this project can be
used to unravel the crucial neuronal alterations associated with head trauma and the early stages of Alzheimer?s
disease and, more importantly, may be the key to discovering novel strategies to prevent neuronal degeneration in
these conditions.
Research achievements (from final report):
This project focussed on understanding how nerve cells and the mature brain respond to injury. We determined
that mature nerve cells undergo a series of cellular changes in response to damage, from initial reactive alterations
through to an attempt at regeneration. This demonstrated that nerve cells do not respond passively to injury, but
actively adapt to damage and seek to re-establish contact with other nerve cells. This indicates that there is a
window of opportunity to seek new approaches to protect nerve cells from injury and promote appropriate
regeneration. In this regard, we developed new culture models to test the effectiveness of drugs to manipulate the
nerve cell response to injury to promote the regeneration of damaged neurons. We determined that filamentous
proteins within nerve cells were crucial to this adaptive property of nerve cells and that agents that promote or
inhibit the stability of these proteins can affect the regenerative response following injury. Furthermore, we
determined that a class of metal-binding proteins has dramatic effects on nerve cell regeneration and the
University of Tasmania is currently seeking international patent protection for this discovery. Finally, this project
also examined how nerve cells and non-neuronal cells interact in the brain healing response to damage. We
recently determined that neural stem and progenitor cells are stimulated by cortical injury but that these
subsequently contribute to the glial response to injury and do not result in the generation of new nerve cells.
Expected future outcomes:
These studies have indicated the cellular processes underlying appropriate and inappropriate forms of nerve cell
regeneration following injury. We have identified new potential therapeutic agents for the brain and the platform
technologies developed will be useful for further drug development.
Name of contact: James Vickers
Email of contact: James.Vickers@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 491130
CIA Name: A/Pr Cynthia Whitchurch
Main RFCD: Infectious Diseases
Admin Inst: University of Technology Sydney
Start Year: 2008
End Year: 2011
Total funding: $418,517
Grant Type: NHMRC Project Grants
Title of research award: Characterisation of extracellular DNases of Pseudomonas aeruginosa and their
contribution to disease
Lay Description (from application):
The bacterium Pseudomonas aeruginosa causes a number of serious diseases of humans particularly of
immunocompromised patients. We have found that this bacterium secretes enzymes that have the ability to digest
DNA. This proposal aims to work out how this bacterium uses these enzymes to infect human tissues and escape
killing by immune cells. The results from this study will help to determine if these proteins may be used as targets
for the development of new anti-infective drugs.
Research achievements (from final report):
P. aeruginosa is an important pathogen of immunocompromised and hospitalised patients as well as those afflicted
with burns, cystic fibrosis or HIV. P. aeruginosa is also commonly associated with infections of the eye, ear and
skin. Many P. aeruginosa clinical isolates are insensitive to most or all antibiotics. Thus, the identification of new
targets for diagnosis, therapy, and prevention is essential for our ability to control this important nosocomial
pathogen. In recent years it has become evident that secreted extracellular nucleases are important virulence
determinants of some bacterial pathogens. This project has identified the gene which encodes the major secreted
nuclease of P. aeruginosa and has examine its involvement in various biological processes including escape from
neutrophils. This project has made a significant contribution toward unravelling the complex interactions between
P. aeruginosa and the host and has led to novel insights into how these bacteria attack host cells and outmanoeuvre
the immune system. The knowledge obtained from these studies may reveal new ways to improve the prevention
and management of diseases caused by P. aeruginosa and related bacteria.
Expected future outcomes:
Expected future outcomes are a greater understanding of pathogenesis processes of P. aeruginosa. At least 2
manuscripts describing the outcomes will be published.
Name of contact: Cynthia Whitchurch
Email of contact: Cynthia.Whitchurch@uts.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353569
CIA Name: Prof Osvaldo Almeida
Main RFCD: Mental Health
Admin Inst: University of Western Australia
Start Year: 2005
End Year: 2007
Total funding: $765,050
Grant Type: NHMRC Project Grants
Title of research award: Reducing depression and suicide amongst older Australians: a clustered randomised
clinical trial in primary health care
Lay Description (from application):
Like many industrialised nations, Australia's population is ageing. By the year 2051, the population aged 65 years
and over is projected to triple in size, while those over 85 will increase five-fold. The social, financial, and health
consequences of a rapidly ageing society cannot be ignored. Accompanying this population explosion will be
greater numbers of individuals experiencing age-related physical disorders and disabilities that give rise to social
and psychological problems, including depression and suicide. Suicide rates are very high in later life, with the
ratio of men who kill themselves in late old age greater than that found in their youthful counterparts. Depression
is most often linked to suicidal behaviour in this age group, with research suggesting that the treatment of this
mental disorder may directly lead to a reduction in suicide in the aged. Approximately 80% of older adults will
visit their general practitioner at least once per year in Australia, while up to 70% of older people will consult their
GP in the month prior to their death by suicide. This suggests that GPs are in the best possible position to detect
and manage depression and suicide risk in later life. Unfortunately, depression is consistently reported to be
underdiagnosed and undertreated in this setting. The purpose of this study is to determine whether an educational
programme targeting Australian GPs can enhance doctors' detection rates of depression and suicide risk, thereby
leading to a reduction in depression and suicidal behaviour among those older patients visiting their surgeries.
Research achievements (from final report):
At the time of writing, 16 publications have arisen from this project, with another 4 planned for the upcoming
year.
Expected future outcomes:
The final results of the trial have not been analysed yet. Data collection was completed in January 2009 and this
last database is now being cleaned and prepared for merging with existing databases. As previously stated, we
plan to draft another 4 papers over the next 12 months.
Name of contact: Osvaldo P. Almeida
Email of contact: osvaldo.almeida@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 303265
CIA Name: Dr Giles Plant
Main RFCD: Central Nervous System
Admin Inst: University of Western Australia
Start Year: 2004
End Year: 2008
Total funding: $444,500
Grant Type: Career Development Fellowships
Title of research award: Gene therapy and cell transplantation to repair the mammalian spinal cord.
Lay Description (from application):
Not Available
Research achievements (from final report):
The achievements of this grant were excellent . The eileen Bond Spinal Cord Research Center which I direct is
internationally renowned for its work in gene therapy and transplantation to the injured spinal cord. I am asked
frequently to present data at national and international meetings.
Expected future outcomes:
Continue to direct the laboratory and collaborate with national and international colleagues in addition to
companies.
Name of contact: Giles Plant
Email of contact: gplant@anhb.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513724
CIA Name: Dr Ian Dick
Main RFCD: Endocrinology
Admin Inst: University of Western Australia
Start Year: 2008
End Year: 2011
Total funding: $237,708
Grant Type: NHMRC Project Grants
Title of research award: Functional effects of polymorphic variation of the aromatase (CYP19) gene on enzyme
activity:relationship to disease
Lay Description (from application):
After menopause, oestrogen synthesis changes from an ovarian to an adipose source by concersion of androgens
to estrogens, a process catalyzed by aromatase, the product of the CYP19 gene. We will generate mutants of the
CYP19 gene that we have previously found in humans by site-directed mutagenesis and observe the effects of
these mutants on aromatase function. This research will help with diagnosis and treatment of breast and other
cancers and osteoporosis in humans .
Research achievements (from final report):
The work conducted under this grant has involved deciphering the key components of variation responsible for
enzyme activity within the aromatase gene and applying it back to a well characterised population to examine the
phenotype/genotype relationship.
Initially studies showed that wild-type aromatase demonstrated substrate inhibition by androstenedione which,
although well recognised for other P450-mediated reactions has not previously been reported for CYP19A1.
Expected future outcomes:
N/A
Name of contact: Joshua Lewis
Email of contact: joshua.lewis@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572671
CIA Name: Prof Jiake Xu
Main RFCD: Orthopaedics
Admin Inst: University of Western Australia
Start Year: 2009
End Year: 2011
Total funding: $605,123
Grant Type: NHMRC Project Grants
Title of research award: The role of the secreted SVS7 protein in bone Homeostasis
Lay Description (from application):
Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue leading to
bone fragility and an increased susceptibility to fractures caused by imbalance between cells that are constantly
reabsorbing and reforming bone. The cost to society with our aging population and individuals who become
disabled by hip fractures could triple by the year 2040.The proposed project studies a novel factor that controls
bone mass. Its potential is for therapeutic treatment.
Research achievements (from final report):
1) The project increases our understanding in the regulation and function of SVS7 in bone biology, thus advancing
our scientific knowledge.
2) The information generated will assist future development of therapeutic agents to treat osteolytic bone diseases;
including osteoporosis.
3) The project helps to train up postdoctoral research fellows and graduate students.
4) The project has resulted in publications that help to disseminate the updated knowledge in bone biology.
Expected future outcomes:
The scientific knowledge regarding the role of SVS7 in bone biology will be advanced. The information gathered
will help to develop the potetnial use of SVS7 for treatment of osteolysis, including cancer-induced bone loss.
Name of contact: Jiake Xu
Email of contact: jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572734
CIA Name: Prof Fiona Wood
Main RFCD: Dermatology
Admin Inst: University of Western Australia
Start Year: 2009
End Year: 2009
Total funding: $188,600
Grant Type: NHMRC Development Grants
Title of research award: Pre-clinical evaluation of nano-membrane dressings to promote wound healing
Lay Description (from application):
This project will investigate whether a novel type of wound dressing can promote faster wound healing and
reduce scarring. Time taken to heal is one of the best predictors of whether a wound will heal with significant
scarring. The faster wounds heal the better. We have identified a new dressing with specific nano-scale pores that
may promote faster healing. This dressing will be tested in the best model of human wound healing with the
potential to progress to clinical trials if successful.
Research achievements (from final report):
We have gained understanding of how we might be able to use different shaped surfaces, created at a nanoscale
level, to speed up wound healing. This has the potential in time to allow us to design better wound dressings that
promote wound healing and reduce scarring, after any injury to the skin. This can impact not only on patients with
large burn or similar injuries, but also those with much smaller injuries that still have problems with scarring and
functional deficits for life.
Expected future outcomes:
Use of the knowledge of how to influence wound healing with nanosize structures to design better dressings for
patients with skin injuries.
Name of contact: Mark Fear
Email of contact: mark@mccomb.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513832
CIA Name: Prof Jiake Xu
Main RFCD: Orthopaedics
Admin Inst: University of Western Australia
Start Year: 2008
End Year: 2010
Total funding: $424,189
Grant Type: NHMRC Project Grants
Title of research award: Regulation of osteoclast differentiation and function by the PKC pathway.
Lay Description (from application):
Developing strategies to control the formation of osteoclasts which underlines many disorders such as
osteoporosis and osteoarthritis has been a major focus of bone research.The proposed research examines the
fundamental role of Protein Kinase C (PKC) in bone resorption.This work will help elucidate the role of PKC in
osteoclast formation;define the physiological role of PKC in bone structure and bone resorption in vivo and
develop the treatment of bone disorders.
Research achievements (from final report):
1) The project increases our understanding in the regulation and function of osteoclasts by PKC delta and its
signalling molecules, thus advancing our scientific knowledge.
2) The information generated will assist future development of anti-resorbing agents to treat osteolytic bone
diseases.
3) The project helps to train up postdoctoral research fellows and graduate students.
4) The project has resulted in publications that help to disseminate the updated knowledge in osteoclasts and bone
biology.
Expected future outcomes:
The scientific knowledge regarding the role of PKC delta in osteoclasts and bone biology will be advanced. The
information gathered will help to develop novel PKC delta inhibitors for the potential treatment of osteolysis,
including cancer-induced bone loss.
Name of contact: Jiake Xu
Email of contact: jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458608
CIA Name: Dr Gina Ambrosini
Main RFCD: Epidemiology
Admin Inst: University of Western Australia
Start Year: 2007
End Year: 2008
Total funding: $167,707
Grant Type: NHMRC Project Grants
Title of research award: Long Term Supplementation with Retinyl Palmitate (Vitamin A) and the Risk of Bone
Fractures: A population based study.
Lay Description (from application):
Osteoporosis is a major health problem in Australia and other western industrialised countries where populations
are increasingly ageing. In Australia, the number of hip fractures is expected to increase by 36% between 1996
and 2006, owing to the rise in elderly aged 85 years and over. This is in contrast to projections in Europe and
North America, where the number of hip fractures are expected to double by 2026 and then stabilise. Clarification
of the role of vitamin A in bone health is pertinent, given that the popularity of supplement use has increased
markedly in western industrialised countries over the past two decades. Around 37% of the adult population in
Australia is thought to take a supplement regularly and figures range from 28% to 54% of adults in the US, with
women and adults aged over 49 years being more likely to use supplements. Furthermore, the fortification of food
with minerals and vitamins is increasing. For all of these reasons, is it imperative that the role of vitamin A in
inducing fractures be clarified. Results from this study will contribute to knowledge about the safety of retinol
and beta carotene supplements in relation to bone health, which is especially relevant to people at risk of
osteoporosis, and people who take vitamin A supplements. We will also be able to clarify the upper levels of
dietary retinol, beta carotene and vitamin A intake beyond which fracture risk increases. Because of the age range
of subjects in our study, our results should be applicable to the whole population, not only the elderly or post
menopausal. The results of our study will be useful to agencies such as Food Standards Australia and New
Zealand which regulates our food supply.
Research achievements (from final report):
Earlier studies have suggested that the risk of bone fractures is greater among people taking Vitamin A
supplementation. This project examined the risk of bone fractures among participants of a cancer prevention
program taking long term supplementation with Vitamin A. A strength of this study was that Vitamin A and
fracture risk was examined in two ways (1) the level of vitamin A in blood plasma and (2) the amount of Vitamin
A taken as a supplement. In summary, risk of any fracture or any osteoporotic fracture was not associated with
either the level of vitamin A in blood plasma or the amount of supplement taken.
Expected future outcomes:
N/A
Name of contact: Dr Gina Ambrosini
Email of contact: Gina.Ambrosini@mrc-hnr.cam.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 254743
CIA Name: Prof David Wood
Main RFCD: Orthopaedics
Admin Inst: University of Western Australia
Start Year: 2003
End Year: 2005
Total funding: $307,400
Grant Type: NHMRC Development Grants
Title of research award: Biological, functional and radiographic evaluation of autologous chondrocyte
implantation
Lay Description (from application):
We will test the hypothesis that autologous chondrocyte implantation (ACI) and extensor realignment produces
superior clinical, biological and radiographic results when compared with conventional treatment of realignment
and debridement. We will specifically address the following aims: 1. Quantify the clinical outcome of ACI
compared to the traditionally used treatment of debridement through the use of functional evaluation in a blinded
randomised controlled clinical trial; 2. Evaluate the radiographic changes in the patellofemoral joint that occur as
a result of ACI, using high resolution magnetic resonance imaging (MRI) to quantify the regeneration of hyaline
articular cartilage; 3. Using the new technique of confocal arthroscopy, we will compare the histologic
appearances of the ACI graft and its interface with adjacent articular cartilage; 4. Evaluate patient, surgical and
explant chondrocyte characteristics in relation to functional, radiographic and biological outcomes. With respect
to the matrix-induced autologous chondrocyte implantation (MACI) technique, we wish to clarify the clinical
practice as a definitive treatment for articular cartilage defects. This will be the first randomised, controlled
clinical trial of the MACI technique compared to that used by other groups. A positive clinical outcome from this
trial will help promote the three cornerstones of this procedure – successful cell culture, efficient surgical
procedures, and complimentary postoperative rehabilitation. Furthermore, this research will: a) Enhance the
expansion of the MACI technique; b) Encourage development of endoscopic techniques of implantation using a
combination of – • Preoperative defect registration with MRI • pre-cut custom patches, implanted with •
Computer-assisted navigation techniques: c) Increase the potential to cater for a larger number of patients
requiring articular cartilage repair; d) Confirm the long-term durability of regenerated cartilage in the 4th year and
beyond; e) Add further commercial value by demonstrating MACI may prevent the onset of osteoarthritis.
Research achievements (from final report):
1. The development of matrix induced autologous chondrocyte implantation as a recognised clinical technique in
the treatment of articular cartilage defects.
2.The reduction in invasivness surgery from a wide inscision to arthroscopic surgery.
3. A greater understanding of the histological appearances and outcomes following autologous chondrocyte
implantation.
4. Development of best practice rehabilitation protocols, in support of the cellular and surgical advances, to ensure
the best possible patient outcomes following this procedure.
5. A greater understanding of knee joint loading (and therefore, defect graft), during the post-surgery time course
with incremental increases in patient functioning.
Expected future outcomes:
Autologous chondrocyte implantation is now an established surgical procedure for articular cartilage defects
of the knee. Biologically about 80% of tissue develops into hyaline chondrocytes and the rest into fibrous tissue.
Further outcomes should be aimed at improving the hyaline chondrocyte diifferentiation.
Name of contact: David Wood
Email of contact:
david.wood@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 139021
CIA Name: Dr Robin Scaife
Main RFCD: Protein Targeting and Signal Transduction
Admin Inst: University of Western Australia
Start Year: 2001
End Year: 2003
Total funding: $256,528
Grant Type: NHMRC Project Grants
Title of research award: Regulation of signal transduction by Cbl: investigation of effects on the cytoskeleton,
cell adhesion and cell motility
Lay Description (from application):
Changes in cell adhesion and motility have been implicated in a wide range of human pathologies (e.g. immune,
reproductive, mental, and cancerous disorders) . Cell adhesion and motility are tightly regulated by a group of
proteins known as Rho-GTPases. Novel pharmacological agents that target signalling by Rho-GTPases have been
demonstrated to profoundly affect tumour metastasis, as well as central nervous system regeneration following
injury. Further exploitation of Rho-GTPase signal modulation, by detailed studies of the molecular mechanisms
involved, could lead to significant advances in medical sciences. In particular, treatment of cancer and spinal
injuries are likely to benefit from further development of Rho-signalling research.
Research achievements (from final report):
Neuronal cells have the capacity to become highly polarised by formation of long cytoplasmic extensions. Since
these extensions, known as neurites, are required for relaying information between neuronal cells, they are the
central component of the neuronal circuitry that underlies functioning of the nervous system. The cellular and
molecular mechanisms by which neuronal cells form neurites have, however, not been adequately defined. In this
study we determined that deregulation of specific signal transduction mechanisms can cause non-neuronal cells
(fibroblasts) to form neurite-like extensions. Our novel experimental system permitted us to identify a key role
for microtubule protein fibers in the formation of neurite-like extensions. Further, our results identified key
molecular signaling components involved in the assembly and organisation of microtubule and microfilament
protein fiber structures.
Expected future outcomes:
Our experimental system has the potential to yield further valuable insights into the mechanisms that regulate
microtubule organisation and neurite formation.
Name of contact: Robin Scaife
Email of contact: rscaife@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 212027
CIA Name: Prof Ming Hao Zheng
Main RFCD: Orthopaedics
Admin Inst: University of Western Australia
Start Year: 2002
End Year: 2004
Total funding: $226,320
Grant Type: NHMRC Project Grants
Title of research award: Structural and functional analyses of rat receptor activator of NF-kb ligand
Lay Description (from application):
Rat RANKL (Xu & Zheng, rat RANKL, AustraliaProvisional Patent PQ3147) has a variety of biological
activities including osteoclast differentiation and polarization, and dendritic cell function. Overproduction or
increased activity of RANKL can result in excessive osteoclast formation, activation, and bone resorption. This
process contributes to many common bone lytic disorders such as osteoporosis, Paget's disease, bone metastatic
diseases, arthritis, aseptic bone loosening and non-union of fractures. This proposal addresses the important and
fundamental issue of RANKL regarding the role of molecular structure on its biological function. We have
established that the TNF-like core domain is the functional domain, important for osteoclastogenesis, osteoclast
polarisation and protecting against Fas-triggered apoptosis. This proposal will further characterise the mutant
forms of the TNF-like core domain of RANKL using site directed mutagenesis and protein truncation analysis,
and assess their respective binding activities to OPG and RANK, and their biological activities both in vitro and in
vivo. It will lead us into better understanding of the structure-function relationship of RANKL. Ideally, we would
like to develop a relative agent for the suppression of osteolysis in orthopaedic related diseases including
osteoporosis. Such an optimized molecule could become a potent therapeutic agent that selectively inhibits
osteoclast formation and bone resorption.
Research achievements (from final report):
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone
tissue. Overproduction or activation of osteoclasts underlies many bone lytic disorders such as osteoporosis,
Paget’s disease, bone metastatic diseases, arthritis, aseptic bone loosening and non-union of fractures. The
receptor activator of NF-kB ligand (RANKL) is the “master cytokine” for the induction of osteoclastogenesis and
bone resorption. The binding of RANKL to its receptor RANK induces signal transduction pathways such as NFkB and NFAT. In this study, we have generated mutant forms of RANKL recombinant proteins and found that
they inhibit RANKL-induced osteocalstogenesis. In addition, modulation of RANKL signaling pathway also
disrupts osteoclastogenesis. Information gathered has a potential for the development of a range of therapeutics to
control bone lytic diseases such as osteoporosis and arthritis.
Expected future outcomes:
The results might be used to develop anti-resorptive agents for the treatment of osteoporosis.
Name of contact: Ming Hao Zheng
Email of contact: zheng@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353673
CIA Name: Prof Ming Hao Zheng
Main RFCD: Orthopaedics
Admin Inst: University of Western Australia
Start Year: 2005
End Year: 2007
Total funding: $276,000
Grant Type: NHMRC Project Grants
Title of research award: The Role of P62/A170 in Pathological Bone Destruction
Lay Description (from application):
Approximately up to 30% of patients are admitted to public hospitals in Australia for reasons related to skeletal
disorders, including trauma, osteoarthritis, osteoporosis, primary and secondary bone tumours, genetic and
metabolic disorders. Abnormal bone resorption contributes to most of these diseases and conditions. Based on
the clinical evidence of P62 mutation in patients with Paget's Disease of bone and our observation of the
involvement of P62 in RANKL-induced NF-Kb signaling, we propose that intracellular molecule P62/A172 may
play an important part in the switch off/on signals necessary for bone resorbing cells to resorb bone. To this end,
we will study the molecular mechanism of P62 in action, and the interaction with its possible partners for the
facilitation of abnormal bone resorption. The clinical significance of this project is to: 1) enhance understanding
of abnormal bone resorption in Orthopaedic related diseases and conditions. 2) provide a strategy of drug
development for the treatment of these disease and conditions.
Research achievements (from final report):
The aim of this project is to study the role of p62 and p62 UBA mutants in osteocalstogenesis, pathological bone
destruction and signaling pathways related to Paget's disease of bone.
Overproduction and activation of osteoclasts underlines many lytic bone disorders such as osteoporosis,
osteoarthritis and Paget's disease. Development of strategies to control the formation or activities of osteoclasts
has been a major focus of bone research. The RANKL-induced NF-kB pathway is critical for osteoclastogenesis
and osteoclastic bone resorption and, therefore might represent a potential molecular target for the discovery of
novel bone antiresorptive agents for the treatment of lytic bone disorders. The proposed research addresses the
fundamental role of the adapter molecule p62/A170 in RANKL-induced NF-kB activation and osteoclastogenesis.
Unraveling the molecular and cellular mechanisms by which p62 regulates osteoclast formation and activation
will significantly contribute to the field of knowledge and facilitate the development of novel and selective
inhibitors for the treatment of lytic bone disorders.
Expected future outcomes:
The outcomes of the work proposed will help us to
1.
Elucidate the role of adapter molecules p62/A170 in RANKL-induced activation of NF-kB and
osteoclastogenesis
2.
Understand the role of PKC isoforms in RANKL-induced activation of NF-kB and osteoclastogenesis,
either via p62 dependent or independent pathway.
Name of contact: Jiake Xu
Email of contact: Jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458765
CIA Name: Prof Ming Hao Zheng
Main RFCD: Orthopaedics
Admin Inst: University of Western Australia
Start Year: 2007
End Year: 2009
Total funding: $391,510
Grant Type: NHMRC Project Grants
Title of research award: Interaction of Rab3D and Tctex-1 is required for bone resorption through the regulation
of post-TGN vesicle trafficking
Lay Description (from application):
Osteoclasts are multinucleated cells responsible for the breakdown/resorption of bone tissue. Elevated osteoclast
numbers and/or activities is a major hallmark of a number of debilitating Orthopaedic-related diseases including
osteoporosis, arthritis, bone cancer and aseptic loosening. Among these, osteoporosis is endemic in Western
society with an estimated 1 in 2 women and 1 in 3 men sustaining a fracture in their lifetime. It is well accepted
that the transport of carrier vesicles containing bone destructive enzymes is critical for bone resorption by
osteoclasts. Although vesicle transport has been shown to be associated with microtubules (the cells skeleton), the
molecular mechanisms responsible for vesicle and microtubule interaction are largely unknown. We have
identified a novel interaction between Rab3D, a vesicle transport molecule, with Tctex-1, a microtubule-binding
protein. We propose that the binding of Rab3D to Tctex-1 in osteoclasts is essential for the interaction of vesicles
with microtubules and, hence, osteoclast function. The focus of this project is to further confirm our hypothesis
by analysing the importance of this interaction in osteoclast-mediated bone resorption. The anticpated outcomes
of the proposed project are: 1) Rab3D-mediated vesicle transport is directed via the microtubule network; 2)
Interaction between Rab3D and Tctex-1 is cruical for the coupling of Rab3D-mediated vesicle transport to the
microtubules; and 3)Disruption of the Rab3D-Tctex-1 interaction may impair bone resorption. Understanding the
molecular mechanisms which regulate osteoclastic vesicle trafficking might therefore enable us to develop new
strategies to specifically target and inhibit breakdown of bone tissue.
Research achievements (from final report):
Osteoclasts are large multinucleated cells responsible for the physiological resorption of bone. Excessive bone
resorption is a pathological hallmark of several debilitating bone diseases among which osteoporosis is endemic in
western society. The bone resorption process requires tight coordination between carrier vesicles and
microtubules, however, the molecular mechanisms involved remain unclear. The aims of this project were
therefore to characterise a novel interaction between Rab3D (a regulator of vesicle transport) and Tctex-1 (a
microtubule motor protein) and its contribution toward the function of bone resorption by osteoclasts. Our
findings indicate that interaction between Rab3D and Tctex-1 bridges the interface between carrier vesicles and
the microtubule network. Furthermore, disruption of Tctex-1 function impairs the ability of osteoclasts to resorb
bone, attesting to the notion that components of the Rab3D transport machinery are required for bone resorption.
Understanding the molecular mechanisms of intracellular transport in osteoclasts offers the exciting potential of
identifying new and specific therapeutic targets for the treatment and alleviation of bone loss.
Expected future outcomes:
It is anticipated that this work will provide the foundation to build future NHMRC projects exploring the precise
functional role of Tctex-1 in bone-resorbing osteoclasts through the generation of specific mouse knockout models
Name of contact: W/Prof. Ming-Hao Zheng
Email of contact: minghao.zheng@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 254662
CIA Name: A/Pr Jiake Xu
Main RFCD: Orthopaedics
Admin Inst: University of Western Australia
Start Year: 2003
End Year: 2005
Total funding: $235,500
Grant Type: NHMRC Project Grants
Title of research award: The role of V-ATPase accessory subunit Ac45 in osteoclasts
Lay Description (from application):
Osteoclasts are directly related to many lytic bone disorders including osteoporosis, osteoarthritis and Paget's
diseases. Development of strategies to control the formation or activities of osteoclasts has been a major focus of
bone research. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is
responsible for creating a low pH environment critical for bone resorption, and therefore a potential molecular
target for the discovery of novel bone antiresorptive agents useful for the treatment of lytic bone disorders. The
proposed research will give considerable insight into the role of the both V-ATPase accessory subunit Ac45 and
V-ATPase complex in osteoclasts. Understanding the molecular and cellular mechanisms by which V-ATPases
regulate osteoclast bone resorption will facilitate the development of novel and selective inhibitors for the
treatment of lytic bone disorders.
Research achievements (from final report):
Osteoclasts are the principal cells responsible for bone degradation. Overproduction and excessive activity of
osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone
loss. The critical condition for the removal crystals is the use of a specific low pH in a biological
microenvironment. The vacuolar proton pump H+-adenosine triphosphatases (V-ATPases) located on the boneapposed plasma membrane of the osteoclast, are imperative for osteoclastic bone resorption, and thus serve as a
potential molecular target for the development of novel anti-resorptive agents. Discovery of specific osteoclast VATPases subunits is an important and challenging area of bone research, might facilitate development of drugs for
the treatment of osteoporosis, Paget's disease, and various manifestations of skeletal cancer. The proposed project
addresses the fundamental role of the V-ATPase in osteoclast differentiation, acidification and bone resorption.
Understanding the molecular and cellular mechanisms by which V-ATPases subunits regulate osteoclast function
and bone resorption will facilitate the development of novel and selective inhibitors for the treatment of lytic bone
disorders.
Expected future outcomes:
Understanding the molecular and cellular mechanisms by which specific subunits of V-ATPase regulate osteoclast
function might facilitate the development of novel and selective inhibitors for the treatment of lytic bone
disorders, such as osteoporosis, Paget's disease, bone aseptic loosening and tumor-induced bone destruction.
Name of contact: Jiake Xu
Email of contact: jiake.xu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353638
CIA Name: A/Pr Richard Prince
Main RFCD: Motor Control
Admin Inst: University of Western Australia
Start Year: 2005
End Year: 2006
Total funding: $230,900
Grant Type: NHMRC Project Grants
Title of research award: Effects of vitamin D and calcium on bone strength, balance and falls in elderly women
Lay Description (from application):
Many osteoporotic fractures occur as a result of bone fragility and falls. Both falls and fractures are huge public
health problems in Australia. Falls are the leading cause of injury-related hospitalization and death in person older
than 65 years of age. During 1996 almost 36,000 people attended a hospital after a fall and 5% of these resulted in
fracturing a bone. The incidence of fall-related hospital admission increases exponentially with age, reaching 4%
per annum for men and 7% per annum for women aged 85 years and older. In the community approximately one
third of older people fall each year. Compared to men, women are three times more likely to be hospitalized or
one and half times more likely to die from a fall-related injury. Importantly women have an increased risk of
fracture and over 40% of women over the age of 50 will break a bone. Previous European and American studies
suggest that calcium replacement may improve bone strength while vitamin D may reduce falls. However, the
separation of these two effects has never been studied. We have previously studied elderly falling women who
attended the Emergency Department of large teaching hospitals in Perth and have shown that many are calcium
and vitamin D deficient. We are undertaking a short term randomized controlled trial of calcium alone or calcium
with vitamin D, to study the effects on bone strength as measured non-invasively, balance and falls in this high
risk group of subjects. We have already recruited 100 subjects and six subjects have completed their 6 months
assessment. We plan to recruit the remaining 200 subjects during the following 12 months and give all subjects
one year of treatment. At the end of this study we should be able to offer clear treatment guidelines for this high
risk group of patients.
Research achievements (from final report):
Both falls and fractures are huge public health problems in Australia. Falls are the leading cause of injury-related
hospitalization and death in person older than 65 years of age. In this one year study, we evaluated the effect of
vitamin D and calcium supplementation compared to calcium alone on falls risk in older women at high risk of
falling. The study participants were 302 community-dwelling ambulant women aged 70-90 living in Perth with
high risk of falling due to low vitamin D status and a history of falling in the previous year. Half of the
participants received vitamin D2 1000 IU per day for one year and the other half received identical placebo and all
of them received calcium 1000 mg per day. After one year, vitamin D supplementation is associated with 19%
reduction in the risk of falling. Vitamin D supplementation has no treatment benefit on falls reduction in
summer/autumn when better vitamin D status are achieved with increased incident solar radiation, but is
associated with 23% reduction of the risk of falling in winter/spring to the same level as in summer/autumn. Thus
it is proposed that in older women living in the community at high risk of falling it would be reasonable to aim to
achieve 25-hydroxy vitamin D levels of 60 nmol/L or above to prevent the risk of falling due to vitamin D
deficiency. This has resulted in a publication in a high impact journal - Achives of Internal Medicine ((Impact
factor: 7.92; in press).
Expected future outcomes:
The findings of this study are important for the development of falls prevention guidelines and strategies in
community-dewelling older women, and thus contribute to the reduction of the incidence of falls and fractures in
this population and the associated cost.
Name of contact: A Prof Richard Prince
Email of contact: rlprince@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 139017
CIA Name: A/Pr Soumya Ghosh
Main RFCD: Central Nervous System
Admin Inst: University of Western Australia
Start Year: 2001
End Year: 2003
Total funding: $196,415
Grant Type: NHMRC Project Grants
Title of research award: Neural mechanisms associated with recovery of function following motor cortical
lesions
Lay Description (from application):
Damage to movement control areas in the brain early in life (e.g. cerebral palsy) or in adulthood (e.g. stroke,
tumours) results in motor weakness and loss of skill; over a period of many months there is gradual recovery of
function. The neural mechanisms that are associated with functional reorganization of the brain and motor
recovery are not well understood. This project plans to use animal experiments to identify the location of regions
in the brain that undergo neural reorganization and compensate for lost function. Following brain lesions detailed
mapping of the motor areas of the brain and a careful study of movement disabilities will be performed. The study
will attempt to identify changes in motor maps that indicate neural reorganization and relate these changes to
motor recovery. The results of this study will be used in future projects to test training programs, drugs and neural
prosthesis on neural reorganization and recovery of function. Eventually the information may be used to direct
pharmacological and physiotherapeutic interventions, and motor rehabilitation programs for optimal recovery of
function.
Research achievements (from final report):
The study examined reorganization of motor areas of the brain and recovery of motor function in an animal model
of brain injury. We found that movement representation (reflected by minimal currents required to evoke
movements by brain stimulation and by movement related neural activity) in the motor areas of the cerebral cortex
was affected by motor skill training in normal animals, by lesions of the motor cortex in the same and opposite
hemisphere of the brain, and by rehabilitation procedures (constraint induced therapy). Following brain injury
there was an increase in the currents required to evoke movements by brain stimulation, not only in the cortical
regions surrounding the lesion, but also movement control regions further away in the same hemisphere and in the
opposite hemisphere. These changes were seen immediately after the lesion and appeared to progress for several
months afterwards. This was accompanied by a reluctance to use the affected limbs for skilled task performance,
and a greater frequency of use of the unaffected limbs. Constraint therapy (restraining the use of the unaffected
limb) in the acute stage of recovery was more effective in changing behavioural outcomes than in the chronic
stage. Training induced use of the limb was also associated with increased activity of neurons in the motor cortex
during task performance. These findings reveal the neurological basis for spontaneous and training induced
recovery of function following brain injury.
Expected future outcomes:
The study provides evidence for neuroplasticity induced by injury and by specific training programs. In the animal
model we found that constraint induced therapy (a retraining program for rehabilitation following stroke) was
more effective in the acute phase of recovery than in the chronic phase. These findings provide support for the use
of constraint induced therapy in stroke patients.
Name of contact: Soumya Ghosh
Email of contact: sghosh@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 303226
CIA Name: Prof Sarah Dunlop
Main RFCD: Sensory Systems
Admin Inst: University of Western Australia
Start Year: 2004
End Year: 2006
Total funding: $379,725
Grant Type: NHMRC Project Grants
Title of research award: Training-induced restoration of topographic maps and vision during opticnerve
regeneration
Lay Description (from application):
The mature brain and spinal cord, or central nervous system (CNS), are extremely complex. A consequence of
such complexity is that little if any spontaneous repair or regeneration occurs after damage. Brain injury and paraor quadriplegia thus inflict extremely high costs on the individual and to society, estimated at approximately $1
billion annually in Australia. One of the greatest medical challenges therefore is to restore function following
neurotrauma. One of the most exciting advances, however, over the last decade is the recognition that the adult
CNS, particularly after damage, does have a capacity for repair and that appropriate neural activity, produced
either via relevant experience or specific training, is essential in driving the repair process to produce useful
behavioural recovery. One of the clearest examples comes from our laboratory in which we have recently shown
that training animals on specific visual tasks during optic nerve regeneration allows useful vision to be restored;
untrained animals are blind via the experimental eye. The advantage of the visual system is that it is a relatively
simple part of the CNS with one major class of nerve cell projecting to well defined and accessible brain regions.
The significance of the project is that, for the first time, we are able pinpoint specific training-induced effects
within identified nerve cells and their connections, a task that is much harder within other CNS regions. In
particular, we will examine molecular, anatomical and functional changes that are induced via training and
explore whether intervention with blockers of inhibitory neurotransmission further improves the beneficial effects
of training. Understanding the changes in nerve cells that underlie the positive effects of training after
neurotrauma will have implications for the continuing development of rehabilitation strategies for improved
recovery after CNS injury.
Research achievements (from final report):
We have shown that behavioural training on a specific task can restore useful function following central nervous
system (CNS) injury. Sepcifically, in a lizard following optic nerve injury, nerve fibres regrow to the brain but do
not make connections in the right place and nor do they work properly and animals are blind via the experimental
eye. However, visual training induces accurate axon regrowth to brain centres, restores topographic maps by
reinstating appropriate molecular guidance cues, restores a normal balance of excitiation and inhibition and,
crucially, useful vision. However, if training is delayed, fibres grow to the wrong places and animals cannot see.
We have also shown that after a partial injury, in which some fibres remain intact, topography and therefore useful
is also restored. The significance of the work is that, once central nerve fibres can be encouraged to regrow
following injury in mammals, strategies will be necessary to induce fibres to regrow to the correct location and
reform functionally useful connections. In addition, our work suggests that such strategies will need to be applied
soon after the injury and also that partial injury will have better outcomes. The work is the clearest example yet of
the specific effects that behavioural training has on nerve cells. The potential benefits lie in elucidating the prerequisites which must be fulfilled to ensure successful repair following CNS injury in mammals which have been
overlooked because spontaneous regeneration does not occur. In addition, the potential lies in translation into
rehabilitation medicine.
Expected future outcomes:
The work has allowed an opportunity to reconsider rehabilitation strategies for spinal cord injury by a newly
formed multidisciplinary Move Again Program (MAP) research team which has recently received seed funding
from the State Government of Western Australia's Neurotrauma Research Program.
Name of contact: Professor Sarah Dunlop
Email of contact: sarah@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 303169
CIA Name: A/Pr Richard Prince
Main RFCD: Preventive Medicine
Admin Inst: University of Western Australia
Start Year: 2004
End Year: 2008
Total funding: $840,575
Grant Type: NHMRC Project Grants
Title of research award: Environmental and metabolic influences on musculoskeletal and other diseases in a
cohort of elderly women
Lay Description (from application):
Osteoporosis is a largely preventable disease yet 1 in 10 Australians have osteoporosis. Every year >64,000
osteoporotic fractures occur, which is one every 8.1 minutes and women are three times as likely to have the
disease than men. The Bone and Calcium Research Group at the University of Western Australia, has been
monitoring a cohort of elderly women for since 1998. This study is called the Calcium Intake Fracture Outcome
Study or CAIFOS. 1,500 women were recruited to study whether a daily calcium supplement for 5 years helps to
prevent fractures compared to a diet without a supplement. Each year the study participants are reviewed and
asked whether or not they have broken any bones and have other measurements to monitor their bone and
cardiovascular health and cognitive function. The subjects will end the treatment phase in 2003 and they will find
out the results of the study. More than 93% are interested in being followed for a further 5 years, where they will
be contacted every 6 months and asked questions about their general health including information on fracture,
hospital visits and changes in medication use. The subjects will have a clinic visits at 2 and 5 years post treatment.
With the ongoing collection of adverse event data and metabolic and environmental data from the first phase of
the study, we will be able to examine the metabolic and environmental factors that influence musculoskeletal,
cardiovascular and mental health. This is important to determine how we can prevent disease to maintain the
quality of life and independence in the elderly, a growing segment of the population.
Research achievements (from final report):
The aim of this project was to determine the importance of lifestyle, genetic and physiological factors as
determinants of the disease of ageing in a cohort of 1500 older Western Australian women, whose health has been
monitored since 1998. This aim has been realised through the publication of 27 peer-reviewed journal articles
since 2004 with majority of them in high impact journals.
In particular our studies have played a critical role in:
1. Proving the hypothesis that genetic factors predict disease outcomes in old age in the area of musculoskeletal
and cardiovascular health. We have examined the role OPG, Klotho, TTTA repeat, BMP4, LRP5 and calcium
sensing receptor gene polymorphisms on bone and cardiovascular diseases in our study.
2. Proving the hypothesis that physiological, nutritional and physical activity factors predict disease outcomes in
old age in the area of musculoskeletal and cardiovascular disease. We had 12 publications in this area and showd
the improtance of calcium, vitamin D, physical activity, protein, potassium, tea dreaking and free estradiol index
in maintaining bone health in older women and also that tea drinking is associated with lower plasma total
homocysteine in older women.
3. Proving the hypothesis that musculoskeletal symptoms predict deleterious outcomes in old age in the area of
musculoskeletal and cardiovascular disease. We have demonstrated that daily back pain is related to a higher risk
of mortality and coronary heart events. We also evaluated the clinical utility of measured kyphosis as a predictor
of vertebral deformities.
These outcomes will play a significant role in developing guidelines and policies for healthy ageing.
Expected future outcomes:
We obtained a 5-year NHMRC grant to follow the cohort for a further 5 years and we have obtained the data for
hospital morbidity, mortality, cancer registry and emergency department since 1980 for this cohort through the
WA data linkage system. This will enable us to further examine the role of lifestyle, genetic and physiological
factors as determinants of the disease of ageing in this cohort.
NHMRC Research Achievements - SUMMARY
Name of contact: Prof Richard Prince
Email of contact: richard.prince@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572550
CIA Name: Dr Melinda Fitzgerald
Main RFCD: Central Nervous System
Admin Inst: University of Western Australia
Start Year: 2009
End Year: 2011
Total funding: $409,148
Grant Type: NHMRC Project Grants
Title of research award: Understanding and preventing secondary degeneration following CNS injury
Lay Description (from application):
After neurotrauma, tissue escaping initial injury undergoes secondary degeneration; tissue loss spreads, function
worsens. In the complex brain and spinal cord it is difficult to distinguish vulnerable tissue. Using the visual
system as a model I will precisely identify cells and processes of secondary degeneration, determine if vulnerable
tissue can be rescued by drugs stopping toxic calcium influx and if rescued circuits work properly. The work has
implications for neurotrauma and glaucoma.
Research achievements (from final report):
Secondary degeneration is a serious consequence of neurotrauma, leading to further loss of nerve and supporting
cells outside the initial injury and progressive loss of function. However the way secondary degeneration
progresses is not well understood and no treatments exist to successfully prevent it. The Project exploited a model
of secondary degeneration in the visual system of rat, where a small precise cut was made in the optic nerve and
the remainder of the nerve became vulnerable to secondary degeneration. The model allows us to precisely define
the events associated with secondary degeneration, without the confounding influences of the initial injury.
Using this model we have demonstrated many features of secondary degeneration, including death of neurons,
infiltration of cells of the immune system, action of free radicals and structural degradation of the nerve.
Furthermore, we demonstrated that treatment with a calcium channel blocker called lomerizine was able to
prevent the death of neurons due to secondary degeneration in our model. However, lomerizine was not able to
maintain the structural integrity of the nerve and vision was only partially preserved.
The project has significantly enhanced our understanding of secondary degeneration. The valuable model of
secondary degeneration we have characterised is now being used as a first line screening tool for testing additional
potential therapeutic stratgegies. Of these strategies lomerizine, in combination with other agents designed to
preseve nerve integrity including nanotechnologies and photobiomodulation, may prove useful in preventing
further loss of function following traumatic injury to the central nervous system.
Expected future outcomes:
Testing combinations of treatments that include the calcium channel blocker lomerizine may result in strategies
that can be translated to the clinic for treatment of secondary degeneration following neurotrauma. Furthermore,
enhanced understanding of the importance of free radicals in progression of secondary degeneration may lead to
additional new treatments.
Name of contact: Melinda Fitzgerald
Email of contact: lindy.fitzgerald@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 403909
CIA Name: A/Pr David Preen
Main RFCD: Epidemiology
Admin Inst: University of Western Australia
Start Year: 2006
End Year: 2006
Total funding: $133,750
Grant Type: NHMRC Project Grants
Title of research award: Morbidity, Mortality and Health Service Use among Criminal Offenders: A Western
Australian Population-based Study
Lay Description (from application):
This study will focus on the health of criminal offenders, as a most likely marginalised and neglected section of
the community, in order to identify areas of need that if addressed will possess benefits for both offenders and the
general community. A research team will apply their public health, criminology and forensic psychology
expertise, in partnership with the WA Police Service, to provide information on the health outcomes and health
service use of adult offenders in WA. Four themes will be explored: (1) Health Status, to estimate the prevalence
of overall and cause-specific hospital-treated morbidity (2) Mortality, to estimate the prevalence of overall and
cause-specific mortality, (3) Health Service Use, focussing on both the rate of primary and secondary health
service use; and (4) Inequalities In Health Outcomes, firstly comparing the health outcomes of adult offenders
with the general WA population, and secondly, comparing the health outcomes of adult offenders based on
sanction severity and custodial setting. This investigation is one of only a few worldwide to study health among
criminal offenders. Offenders are a neglected section of the Australian health system. Responding to their needs
is not possible without an understanding of their health outcomes and the disparities that exist. An important
public health opportunity therefore exists to investigate the health of this socially disadvantaged group. This study
will provide more detailed data regarding offender-health than currently exists internationally or nationally.
Results can be used by health and/or justice administrators as indicators of program and service performance, and
potentially lead to improved collaboration between these sectors. The methods used for outcome evaluation can be
used readily for the routine evaluation of health performance indicators for offenders.
Research achievements (from final report):
This study used cross-jurisdictional/discipline data linkage to examine the health of adult offenders to identify
areas of health need, that if addressed would benefit both offenders and the wider population. In summary, the
significant research outcomes of this project were as follows:
1.
Aided in the establishment of routine linkage of data between the WA Departments of Health and
Corrective Services. This linkage (not available elsewhere in Australia) will facilitate future research to examine
critical issues regarding offender-health and implications for the wider health system.
2.
Development of research/statistical methodology for analysing cross-jurisdictional linked data, which
will aid future research in this area.
3.
Results identified vulnerable offender sub-populations in terms of morbidity and mortality based on
sanction severity, recidivism and Aboriginality.
4.
Findings demonstrated inequity between metropolitan and country-based offenders in terms of health
service provision and risk of hospitalisation and death.
5.
Results of work investigating the number and cost of hospital stays in the first 12 months post-prison
release found that >20% of offenders are admitted to hospital with preventable conditions resulting in substantial
health care costs.
o
A briefing paper is being prepared to be sent to the Department of Corrective Services to inform policy
relating to monitoring high risk offenders after prison release.
6.
Output from this project acted as preliminary work for further successful nationally-competitive research
grants including a multi-institutional NHMRC project grant.
7.
This project resulted in the commencement of a separately-funded PhD investigating the prevention and
treatment of psychiatric illness in offenders.
Expected future outcomes:
Three journal articles are currently under review and are expected to be published by mid-to-late 2009. This
research has laid the foundation for two other successful nationally-competitive research grants to further explore
NHMRC Research Achievements - SUMMARY
the major health issues/inequities for the marginalised offender population. It has led to a recently-commenced
PhD to investigate mental health in the offender population.
Name of contact: A/Prof David Preen
Email of contact: david.preen@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 403924
CIA Name: Prof Alan Harvey
Main RFCD: Central Nervous System
Admin Inst: University of Western Australia
Start Year: 2006
End Year: 2008
Total funding: $521,026
Grant Type: NHMRC Project Grants
Title of research award: The combined use of transplantation and gene therapy techniques to promote
regeneration after neurotrauma
Lay Description (from application):
Trauma in the adult mammalian central nervous system causes long-lasting functional deficits. The resulting
physical and financial burdens to the individual, to his or her family, and to the community at large, are immense.
When fibre tracts are damaged there is disruption of circuits and there may be death of associated nerve cells.
Interventions are therefore necessary to promote repair and to try to restore function. Highly modified, nonharmful viruses can be used as vectors to introduce genes into cells, a method that allows targeted s