NHMRC Research Achievements - SUMMARY
END OF GRANT REPORTS
OUTCOMES OF NHMRC FUNDED RESEARCH INTO ASTHMA
ENDING 2000 TO 2013
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Australian National University
Australian Stem Cell Centre Ltd
Curtin University of Technology
Flinders University
Garvan Institute of Medical Research
Griffith University
Institute for Breathing and Sleep
James Cook University
La Trobe University
Ludwig Institute for Cancer Research
Macfarlane Burnet Institute for Medical Research and Public Health
Menzies Research Institute
Monash University
Murdoch Childrens Research Institute
Murdoch University
Queensland Institute of Medical Research
RMIT University
Royal Prince Alfred Hospital
Sir Charles Gairdner Hospital
St Vincent's Institute of Medical Research
University of Adelaide
University of Canberra
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 Western Australia
Walter and Eliza Hall Institute
NHMRC Research Achievements - SUMMARY
Grant ID: 179811
Start Year: 2002
CIA Name: Prof Frances Shannon
End Year: 2004
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $452,310
Title of research award:
A functional proteomics approach to the study of inducible gene transcription in a chromatin context.A
functional proteomics approach to the study of inducible gene transcription in a chromatin context.
Lay Description (from application):
Cells of the immune system detect assaults on the body such as infection, inflammatory or allergy-causing
agents. Using a complex set of signaling pathways, the cells translate this information into a change in the
pattern of expressed genes in those cells. These changes in gene expression occur rapidly and are generally
transient. The changes that occur in gene expression pattern leads to functional changes in the cell that in turn
are critical for the downstream events of the immune response. One set of genes that is rapidly and transiently
switched on in response to immune stimuli in T cells (one important immune cell type) are those that encode
proteins known as cytokines. These cytokines function to send messages between cells thus activating
downstream events of the immune response. Thus understanding the mechanism of how these genes are
switched on and off is critical in understanding an immune response and in developing potential novel
therapeutics based on gene transcription. Genes exist in the nucleus of the cell in the context of a complex
structure known as chromatin. The process of RNA transcription from these genes, therefore, takes place in the
context of this complex structure. While there have been many studies defining the molecular mechanisms that
control the expression of cytokine genes, little attention has been paid to the role of chromatin in the inducible
and transient nature of this gene transcription. This proposal addresses the molecular mechanisms by which
inducible cytokine gene transcription occurs in a chromatin context. We will use both in vitro and in vivo
approaches to probe the structure of chromatin that overlies these genes and the mechanism by which this
structure is altered to allow the genes to be expressed.
Research achievements (from final report):
Activation of T cells by foreign antigens is one of the key events in an immune response. When T cells are
activated they produce a variety of cytokines that communicate with other cell types in the immune syatem or
act in an autocrine fashion to drive proliferation and differentiation of the T cells. Upon initial activation,
cytokines such as GM-CSF (a myeloid growth factor) and IL-2 (a T cell growth factor) are made in large
quantities. The mechanisms by which these genes are activated to express mRNA and hence protein is of great
interest in understanding how the immune syatem responds to foreigh or self antigens. , One important aspect
of gene activation is the changes that occur in the packaging of the DNA around the inducibal genes. In this
project we have shown that chromatin is remodelled across a very small promoter region, in the order of one
nucleosomes worth of DNA and that this remodelling involves the loss of histone proteins from this region. We
have charaterized the signaling needs for this histone loss and shown a specific need for the NF-kB but not the
NFAT familiy of transcription factors. In addition, we showed that the SWI/SNF chromatin remodelling
complexes may play an important role in the chromatin structure across these gene promoters. We have also
investigated the relationship between the SWI/SNF complexes and the NF-kB family of transcription factors.
Expected future outcomes:
Work from this project has underpinned further recent work on models of chromatin remodelling in T cells
which match models being proposed from yeast systems. Thus this work will lead to a better understanding of
gene transcription in eukaryotes in general.
Name of contact:
Prof Frances Shannon
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
frances.shannon@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 179841
CIA Name: Dr Dianne Webb
Admin Inst: Australian National University
Main RFCD: Allergy
Total funding: $259,016
Start Year: 2002
End Year: 2006
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Characterisation of the signalling pathways utilised by IL-13 independently of IL-4R chain to mediate aspects
of allergCharacterisation of the signalling pathways utilised by IL-13 independently of IL-4R chain to mediate
aspects of allerg
Lay Description (from application):
Not Available
Research achievements (from final report):
The development of asthma is associated with deviation of the immune response towards a Th2 phenotype.
Chronic exposure to factors secreted by Th2 cells is associated with damage to the airways that result in the
clinical symptoms of asthma. Signaling through the IL-4Ralpha receptor on these cells is thought to regulate
deviation of the immune response toward a Th2 phenotype and the secretion of Th2 factors , such as IL-13, that
cause airway damage. Using a mouse model of allergic airways disease, the research undertaken in this project
has shown that , 1) chronic exposure to allergens induces signalling that bypasses the dependence of Th2
responses on the usual downstream IL-4R alpha signally factor, STAT6. , 2) although attenuated, aspects of
allergic airways disease persist in the absence of IL-4Ralpha suggesting other receptor components may be
important in IL-13 mediated disease. , 3) discrete changes (polymorphisms) in IL-4R alpha modify the way in
which IL-13 and IL-4 interact to induce allergic airways disease., 4) that polymorphisms in IL-4R alpha can
alter the way in which IL-13 and IL-4 influence the function and maturation of antigen-presenting cells
(dendritic cells) and thus the strength of the Th2 response in the lung.
Expected future outcomes:
Considerable focus in contempory asthma research is the development of therapeutic antagonists of Th2
cytokines such as IL-4 and IL-13. Our work suggests that the efficacy of targeting either of these cytokines
would be dependent on polymorphisms in IL-4R alpha in individuals.
Name of contact:
Dianne Webb
Email/Phone no. of contact:
dianne.webb@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 366765
CIA Name: Dr Dianne Webb
Admin Inst: Australian National University
Main RFCD: Allergy
Total funding: $283,768
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Functional analysis of the Ym2 chitinase-like lectin in allergic airways diseaseFunctional analysis of the Ym2
chitinase-like lectin in allergic airways disease
Lay Description (from application):
The prevalence of asthma is widespread and nationally affects over two million Australians. Consequently, one
of the Country s National Health Priorities is to improve our understanding of this condition. Analyses of the
asthmatic lung reveal an airway wall that is thickened, an airway lumen that is obstructed and abnormal
spasmogenicity of the airway smooth muscle: processes that collectively contribute to both acute and chronic
respiratory dysfunction. Asthmatics develop an immune response that is biased toward production of allergyrelated T helper 2 cytokines of which interleukin (IL)-13 is a potent mediator of disease. However, the
molecular processes linking IL-13 with abnormal airway wall changes are unclear. To identify previously
uncharacterised IL-13-related molecules, we used a protein profiling approach that identified a novel lectin
(carbohydrate-binding protein) termed Ym2, which is secreted abundantly into the airway fluid of mice in
which allergic airways disease has been induced. Preliminary studies suggest that Ym2 is an intermediary of
IL-13 that is involved in respiratory dysfunction. This project aims to work out how Ym2 interacts with the
molecules and cells of the respiratory tract to regulate allergic disease. Specific inhibitors of Ym2 will be
developed to examine what happens to allergic responses when Ym2 can t function; transgenic mice will be
developed to determine if we see features of allergy when Ym2 is over-expressed in the normal lung, and
human samples will be screened to identify the human counterpart of Ym2 and whether this counterpart is
secreted into the lung fluid of asthmatics. Defining the mechanism by which Ym2 regulates the pathogenesis of
allergic disease will not only contribute to our basic understanding of the processes underlying asthma
pathology, but also generate new information for better design of therapeutics directed against specific
mediators of this debilitating and widespread disease.
Research achievements (from final report):
We have shown that the Ym lectin, which is highly expressed in the allergic airway, interacts and suppresses
the production of 12-hydroxytetraenoic acid (12-HETE). We have also identified a novel pathway by which
12-HETE negatively regulates the activation of immune cells in the allergic airway. When immune cells are
activated by allergens, their production of 12-HETE is reduced. However, when activated immune cells are
treated with 12-HETE, their production of pro-inflammatory mediators, which are known to induce the
damaging effects of asthma, is greatly reduced. We have also shown that treatment of male mice with 12HETE significantly attenuates allergic disease. In contrast, female mice do not respond to 12-HETE because its
effects are blocked by oestrogen.
Expected future outcomes:
12-HETE may have benefit as a novel therapeutic adjunct in the treatment of asthma. Because 12-HETE is also
produced endogenously, it may have benefit in supressing immune responses triggered by allergens in some
individuals. The observation that oestrogen interferes with 12-HETE may underlie the observation that
oestrogen potentiates allergic disease in women.
Name of contact:
Dr Dianne Webb
Email/Phone no. of contact:
dianne.webb@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471481
CIA Name: Prof Ian Young
Admin Inst: Australian National University
Main RFCD: Respiratory Diseases
Total funding: $495,381
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Role of IL-3 in allergic inflammation: modulation of basophils, mast cells, eosinophils and remodelling in
asthma.Role of IL-3 in allergic inflammation: modulation of basophils, mast cells, eosinophils and remodelling
in asthma.
Lay Description (from application):
Asthma is an important disease in the Australian community. We will investigate how the underlying
inflammation in this disease is controlled and will focus our studies on a hormone-like regulator of the immune
system called interleukin-3. Our hypothesis is that interleukin-3 regulates basophils, mast cells and remodelling
of the airways which are central features of asthma. This study will give a better understanding of how the
inflammation is caused and information for new drug targets.
Research achievements (from final report):
Asthma is an important disease in the Australian community. We have investigated how the underlying
inflammation in asthma is controlled with emphasis on the role of a hormone-like protein called interleukin-3
and using mouse models of allergic airways disease. Using house dust mite or ovalbumin to provoke allergic
inflammation we obtained increases in inflammatory cells such as eosinophils, mast cells and basophils.
Expansion of these inflammatory cells was reduced when mice were used which were unable to make
interleukin-3 demonstrating an important role for this cytokine in allergic inflammation of the airways. Viralinduced inflammation and stimulation of blood vessel formation is a contributing factor to asthma and we
showed that viral-induced inflammation was also reduced in the absence of interleukin-3. Expansion of the
inflammatory cells involves binding of interleukin-3 to its receptors on progenitor cells and the stimulation of
growth and maturation. We carried out detailed studies of how the interleukin-3 receptors are activated and
stimulate the growth and maturation of cells. We discovered a new variant form of the receptor which plays a
critical role in the generation of the inflammatory cells induced by interleukin-3. We have also carried out
preliminary work on the role of small regulatory ribonucleic acids called microRNAs in stimulating the
expansion of inflammatory cells induced by interleukin-3 and other cytokines. Targeting these powerful
regulators has great potential for treating a number of human diseases and we believe that microRNAs have
great promise as future drug targets for controlling allergic inflammation in asthma.
Expected future outcomes:
Our studies to date have provided an excellent foundation for further detailed studies on the process of the
expansion of inflammatory cells induced by cytokines and the specific roles of microRNAs in this process.
Such studies have great potential for devising new approaches to controlling allergic inflammation in asthma.
Name of contact:
Ian Young
Email/Phone no. of contact:
ig.young@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400323
Start Year: 2006
CIA Name: A/Pr Ivan Bertoncello
End Year: 2008
Admin Inst: Australian Stem Cell Centre Ltd
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $282,021
Title of research award:
Cell regeneration and repair in the adult lungCell regeneration and repair in the adult lung
Lay Description (from application):
Fibrtic lung diseases are a major health burden, and are a leading causes of mortality and morbidity worldwide.
These diseases are effectively incurable, and a considerable number eventually require lung transplants. As
such these diseases are prime candidates for stem cell therapies to regenerate and repair the lung. However, the
lack of knowledge about the precise identity, organisation and regulation of these cells; how to deliver them
effectively to the damaged lung; and how to pre-condition their site of lodgement to best harness their
potential. This project aims to address these issues. We have recently identified a rare population of cells in the
adult mouse lung which has a number of characteristics consistent with that of an adult stem cell. We are able
to grow these cells in tissue culture, and we have preliminary data suggesting that they can regenerate lung
tissue when transplanted. The aim of this project is to precisely identify these cells, develop methods for their
isolation and determine their location in the lung. The assays we will develop in this model will then be used to
identify stem cells in the bone marrow which have similar properties and which could potentially be used
clinically to alleviate lung disease. The project brings together a group of investigators with unique expertise
in the isolation and analysis of adult stem cells, and in clinical and experimental respiratory medicine to
develop preclinical models in the mouse which are prerequisite for the developement and implementation of
step cell based therapies for lung disease in humans.
Research achievements (from final report):
In this project, we have developed a cell separative method which has enabled us to isolate and characterize
regnerative stem and progenitor cells in the adult lung on the basis of the expression of a unique pattern of cell
surface markers. We have established a novel clonogenic assay which now enables us to quantify stem cells of
differing regenerative potential and to determine how they are affected in intractable lung disease, and how
they respond to injury. The clonogenic assay also provides a valuable tool for identifying factors which
regulate their growth and differentiation and ability to repair the epithelial cells lining the airways and gasexchange surfaces of the lung. Our cell separation studies have also enabled us to determine the properties of
stromal cells of the lung epithlelial stem cell microenvironment and play a key role in specifying their fate.
This work has placed us at the cutting edge of the lung stem cell field: best summarised in the words of the
reviewers of our recently submitted manuscript: "the field very much needs clarity and precision, including a
reliable and reproducible assay for multipotency and self renewal"….[the provision of strong evidence for the
existence of stem cells in the lung able to populate both proximal and distal compartments]….. "has the
potential to address an important missing element in studies on the identity and regulation of epithelial stem
cells in the mammalian lung. This work has culminated in the filing of a provisional patent covering the unique
marker signature of adult lung stem cells and applications of the assay used to ennumerate them.
Expected future outcomes:
Elucidation of the organisation and regulation of regenerative stem cells in the adult lung will ultimately enable
us to understand the pathophysiology of intractable lung diseases and identify stem cell targets around which
therapies can be tailored.
Name of contact:
A/Prof Ivan Bertoncello
Email/Phone no. of contact:
ivan.bertoncello@stemcellcentre.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 7090
Start Year: 2000
CIA Name: Dr Wendy Oddy
End Year: 2004
Admin Inst: Curtin University of Technology
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $260,018
Title of research award:
THE NUTRITIONAL EPIDEMIOLOGY OF CHILDHOOD ASTHMATHE NUTRITIONAL
EPIDEMIOLOGY OF CHILDHOOD ASTHMA
Lay Description (from application):
Not Available
Research achievements (from final report):
Dr Oddy completed her Ph.D. at the Faculty of Medicine, University of Western Australia prior to
commencing this award. Her thesis titled 'Breastfeeding and the development of asthma and atopic disease in
children' was an applied research project involving the analysis of a large epidemiological study based at the
Institute for Child Health Research in Perth. This work on breastfeeding and child health continued during six
months at the Arizona Respiratory Center, University of Arizona, Tucson, USA in 2002 studying the effects of
human milk cytokines on wheeze in infancy. Dr Oddy, with a commitment to the promotion of breastfeeding is
Chairperson of the Baby Friendly Hospital Initiative committee in Western Australia, and represents WA at the
national level as well as is an invited member of the International Society of Research into Human Milk and
Lactation. Dr Oddy was invited to speak at 3 international conferences, 7 national conferences and 19 local
conferences on the nutritional epidemiology of childhood asthma. She is an invited reviewer for 16 scientific
journals and on the Editorial Board for the Journal of Human Milk and Lactation. With 29 peer review papers
and 3 chapters published during the fellowship she has met her stated aims that include to investigate asthma in
children with a) the ratio of omega-6 to omega-3 fatty acids in the diet; b) exclusive breastfeeding; c) the
interactions of early infant feeding with: i) infections, other atopic outcomes and hospitalisation throughout
childhood; and d) to communicate these findings to the scientific community.
Expected future outcomes:
Future outcomes include leading infant, child and adolescent nutrition research at the Telethon Institute for
Child Health Research; increase knowledge of nutrition and health through scientific publication and
presentation; participation in the conceptualisation and conduct of original nutrition research; and building
public health nutrition research capacity in Australia and internationally.
Name of contact:
Dr Wendy Oddy
Email/Phone no. of contact:
wendyo@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 139113
CIA Name: Dr Andrew McWilliam
Admin Inst: Curtin University of Technology
Main RFCD: Allergy
Total funding: $452,546
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Initiating events in the development of allergic airway inflammationInitiating events in the development of
allergic airway inflammation
Lay Description (from application):
Despite recent advances we still do not understand the basic mechanisms which underlie the development of
allergic airway inflammatory diseases such as rhinitis and asthma. It has been previously shown that when
pollen are exposed to water they release a large number of very small starch granules which contain a number
of potent allergens as well as plant steroids. In addition house dust mite allergens which are strongly associated
with asthma are mostly located in small faecal pellets. Both these particles are ideally sized to enter the
respiratory tract and initiate inflammatory responses. We have shown that these responses appear to be of the
type that is needed to initiate allergic reactions. We intend to further study the interactions of these small
inhaled allergen containing particles with cells of the respiratory tract. In this proposal we will look at both
alveolar macrophages and respiratory epithelial cells. These approaches will not only provide new information
about the processes of airway inflammation caused by allergens but may also define new therapeutic
approaches to the treatment of these diseases.
Research achievements (from final report):
N/A
Expected future outcomes:
We will be able to identify those substances which start the inflammation which results in hay-fever and
asthma and look for inhibitors of this process. We may also be able to isolate hitherto unidentified allergens
from the house dust mite.
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 324733
CIA Name: Prof R. Douglas McEvoy
Admin Inst: Flinders University
Main RFCD: Respiratory Diseases
Total funding: $276,750
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Hypoxia-induced suppression of respiratory sensations and reflexesHypoxia-induced suppression of respiratory
sensations and reflexes
Lay Description (from application):
Many diseases that effect the respiratory system have their primary effect on the lungs and airway themselves
but in some conditions, such as obstructive sleep apnea (OSA) and asthma, increased breathing load can induce
periods of low blood oxygen which could further contribute to morbidity in these diseases. OSA is a disorder
associated with snoring. Patients experience periods of sleep fragmentation and oxygen deprivation due to
obstruction of the floppy portion of the upper airway (pharynx) during sleep. It affects 4% of men and 2% of
women and causes excessive daytime sleepiness leading to increased risk of accidents, high blood pressure and
premature cardiovascular disease.Asthma produces airway inflamation and narrowing and affects a wide range
of people. Both OSA and asthma are associated with episodes of impaired breathing and reduced levels of
oxygen in the blood. Low levels of oxygen in the blood (hypoxia) is well known to impair functioning of the
central nervous system. We have recently found that hypoxia blunts sensations of increased breathing load in
healthy people and in asthmatics. Hypoxia might therefore contribute to worsening of attacks in these diseases.
This study aims to investigate how changes in blood oxygen levels affect brain processing of respiratory
signals, how this translates to perception of sensations and the physiological adaptations that people make to
cope with increased breathing load. We will also investigate whether the inhibitory effects of hypoxia on
central nervous system function extend to other vital protective respiratory reflexes such as cough, awakening
from sleep to increased breathing load and upper airway reflexes that are important for maintaining an open
airway.
Research achievements (from final report):
This project showed that low blood oxygen levels (hypoxia) depress the perception of increased breathing load
as well as important protective respiratory reflexes, including cough, arousal responses to increased breathing
load in sleep and some respiratory muscle reflex responses to sudden changes in muscle load. These findings
show that respiratory sensations and reflexes are particularly vulnerable to central nervous system depressive
effects of hypoxia. In conditions such as asthma and disorders of breathing in sleep where hypoxia and
increased breathing load frequently co-exist, hypoxia may therefore play an important role in progressive
worsening in these disorders. Reliance on a perception of worsening symptoms may therefore be unreliable in
the presence of gradually progressive hypoxia (e.g. in exacerbations of asthma and, chronic obstructive
pulmonary disease). Knowledge of this risk, combined with early interventions to correct hypoxia will likely
reduce the risk of potentially serious adverse health outcomes with failure to recognise worsening symptoms in
these disorders.
Expected future outcomes:
Greater recognition of potential risks associated with hypoxic interference with respiratory sensations and
reflexes has the potential to translate into improved treatment outcomes in several disorders, including asthma,
chronic obstructive pulmonary disease and breathing disorders of sleep.
Name of contact:
Peter Catcheside
Email/Phone no. of contact:
peter.catcheside@rgh.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276411
Start Year: 2004
CIA Name: Prof Charles Mackay
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $465,750
Title of research award:
The role of PAC-1 in leukocyte activation and inflammatory responsesThe role of PAC-1 in leukocyte
activation and inflammatory responses
Lay Description (from application):
The MAP kinase pathway is fundamental for signalling a variety of cellular responses. This pathway is
particularly important for immune responses ie. cytokine signalling, chemotaxis, and proliferation. PAC-1, a
MAP kinase phosphatase, is an important regulator of this pathway. Extensive gene profiling of various
immune cells using Affymetrix GeneChips identified PAC-1 as a highly regulated molecule in activated mast
cells. Mast cells are important inflammatory cells, particularly for rheumatoid arthritis and asthma. We have
shown that PAC-1 deficient mice are highly protected from inflammation and disease in a mouse model of
rheumatoid arthritis. This grant aims to extend these exciting initial findings to other inflammatory diseases,
particularly asthma and type 1 Diabetes, and to establish the basis for PAC-1 inhibition of disease. This
research should establish PAC-1 as a new and important target for inflammatory disease, provide
understanding on inflammatory processes, and possibly lead to improved therapies for diseases such as
rheumatoid arthritis.
Research achievements (from final report):
Understanding of MAP kinase pathway regulation , identity of a potential new target for inflammatory
diseases. we also published 2 high profile papers, one in Nature Immunology and another review paper in
Nature Reviews Drug Discovery. We believe that Pac-1 is an exciting new drug target, and any drug that
inhibits Pac-1 function should be highly selective and effective for diseases such as rheumatoid arthritis. Based
on our work, Serono initiated a drug screening program for inhibitors of Pac-1.
Expected future outcomes:
This work has led to new knowledge on how phosphatases regulate the MAP kinase pathway, and their role in
inflammation. A major outcome would be drug targeting of Pac-1, to achieve better anti-inflammatory
therapeutics
Name of contact:
Charles Mackay
Email/Phone no. of contact:
c.mackay@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325610
Start Year: 2005
CIA Name: A/Pr Michael Rolph
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Allergy
Total funding: $226,500
Title of research award:
Expression and function of fatty acid binding proteins in asthmatic airway epitheliumExpression and function
of fatty acid binding proteins in asthmatic airway epithelium
Lay Description (from application):
Asthma is an inflammatory disease of the lungs that affects over 10% of all Australians. It ranges in severity
from mild to life-threatening. Although a number of drugs are currently available for the treatment of asthma,
there are many people whose asthma does not respond very well to treatment. We have recently identified a
gene called aP2 that is important in the development of asthma. Drugs targeted against this gene may be very
useful in the treatment of asthma. In this project, we aim to understand how aP2 is turned on during asthma,
and how it contributes to disease development. This information will be essential for designing optimal
strategies for drug targeting of the aP2 pathway in asthma.
Research achievements (from final report):
Asthma affects greater than 10% of Australian adults. There is a great need to improve our understanding of
the cause and clinical course of asthma, with the ultimate goal being to develop improved strategies for
prevention and treatment. Our lab has studied the cells lining the airways (the 'airway epithelium') and the role
they play in asthma. Using a technique called 'gene profiling' we discovered 2 genes, aP2 and mal1, that are
very active in asthmatic airway epithelium. In mouse models of asthma, the absence of these genes conferred
near-total protection from the development of asthma., , In this project we sought to understand how aP2 and
mal1 function in the airway epithelium during asthma. In tissue culture experiments we compared the functions
of normal mouse airway epithelial cells (MAEC) to those of MAEC that had been genetically modified to be
defiicient in aP2 and/or mal1. In the absence of aP2 and mal1, the allergic inflammatory responses of MAEC
were significantly reduced. Absence of aP2 and mal1 also affected the PPAR-gamma signalling pathway which
is known to play an important role in asthma. The results of this study help to explain how aP2 and mal1 could
control inflammatory responses in asthma, and demonstrate the potential value of aP2/mal1 inhibitors for
treatment of asthmatic inflammation.
Expected future outcomes:
The ultimate goal of these studies is to determine whether drugs that inhibit the function of aP2 and mal1 could
be beneficial in the treatment of asthma. Future studies will focus on extending our findings in the mouse
model of disease to human airway epithelial function.
Name of contact:
Dr. Michael Rolph
Email/Phone no. of contact:
michael.rolph@canberra.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376024
Start Year: 2006
CIA Name: Dr William Hughes
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $509,268
Title of research award:
The Role of Phospholipase D in Regulating Insulin SecretionThe Role of Phospholipase D in Regulating
Insulin Secretion
Lay Description (from application):
Insulin, secreted appropriately by the b-cell of the pancreatic islets of Langerhans, regulates blood glucose
levels through its effects on various tissues throughout the body. Precise control of insulin secretion from the
pancreatic b-cell into the blood is therefore vital for accurate glucose homeostasis. Type II Diabetes Mellitus is
caused by the inability of pancreatic b-cells to respond adequately to changes in blood glucose. In the last 18
months we have determined that the enzyme phospholipase D (PLD) plays an essential role in distally
coordinating signals leading to accurately regulated insulin secretion from the pancreatic b-cell. Through this
proposal we now aim to define the signalling pathways upstream of PLD and identify the mechanism
downstream that allows PLD activity to regulate insulin secretion. We aim to use a combination of established
and novel, biochemical and cell biological, approaches to characterize the role PKC alpha and beta isoforms
and the small GTPase cdc42 may have in controlling PLD mediated insulin release. We will also use a variety
of cell biological approaches to identify why, where, and when PLD activation is required for appropriate
insulin secretion. We will also correlate these observations with the role the cell cytoskeleton may have in
mediating PKC, cdc42 and/or PLD effects. In particular we aim to use a state-of-the-art microscope facility
recently established at the Garvan Institute to achieve these aims. In doing this we will gain new insights into
the pathways determining how insulin is released into the bloodstream, further define cellular processes
common to all vesicular trafficking events and also identify potential targets for pharmacological intervention
in the disease Diabetes.
Research achievements (from final report):
The study was aimed at better understanding the mechanisms controlling the secretion of insulin from
pancreatic beta cells. The major achievement from the work is a the development of novel reagents and
techniques to image the insulin secretion process in live pancreatic beta cells. I have then either genetically or
pharmacologically stimulated or inhibited molecules implicated in regulating insulin secretion and have
visualized precicely which process in the secretory mechanism is defective.
Expected future outcomes:
A better understanding of insulin secretion and which molecules regulate which precise step in the process.
Name of contact:
William E. Hughes
Email/Phone no. of contact:
w.hughes@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402724
Start Year: 2006
CIA Name: A/Pr Robert Brink
End Year: 2010
Admin Inst: Garvan Institute of Medical Research Grant Type: Established Career Fellowships
Main RFCD: Cellular Immunology
Total funding: $548,878
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The work undertaken in this project focussed on B lymphocytes (B cells), the white blood cells that produce
destructive antibodies in response to foreign substances including infectious pathogens. The most significant
results include the identification of molecules that control B cell survival and movement in the body and the
mechanism by which the body senses which B cells are best suited to rapidly produce the most effective
antibodies. These findings are of particular significance to vaccine design and strategies to circumvent
autoimmunity.
Expected future outcomes:
Deeper understanding of the moecular controls of B cell survival and responsiveness.
Name of contact:
Robert Brink
Email/Phone no. of contact:
r.brink@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481363
CIA Name: A/Pr Michael Rolph
Admin Inst: Griffith University
Main RFCD: Respiratory Diseases
Total funding: $446,935
Start Year: 2008
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Disovery of new airway epithelial genes regulating allergic inflammationDisovery of new airway epithelial
genes regulating allergic inflammation
Lay Description (from application):
Asthma is an inflammatory disease of the lungs that affects over 10% of all Australians. A number of drugs are
currently available for the treatment of asthma, but there are many people whose asthma does not respond well
to treatment. We have identified 2 genes, aP2 and mal1, that may be important in the development of asthma.
Drugs targeted against these genes may be useful in the treatment of asthma. In this project, we aim to
understand how aP2 and mal1 contribute to disease development.
Research achievements (from final report):
Research during this fellowship focused on inflammatory disease caused by virus infection. In particular, the
research focused on viruses that cause arthritis. Viral arthritis is becoming an increasingly serious health threat,
with the emergence of highly pathogenic viruses such as chikungunya virus (CHIKV) and Ross River virus
(RRV). Infections with these viruses, which are transmitted by mosquitoes, result in extensive muscle and joint
inflammation accompanied by severe pain. RRV affects up to 8,000 Australians each year and CHIKV has
affected millions worldwide in recent epidemics. Other than symptomatic pain relief, there are no specific
therapies for these infections, nor is there a vaccine available.We used mouse models of infection with RRV
and CHIKV to study the pathogenesis of infection and to test new therapies. In particular, we discovered a
drug, bindarit, that can markedly reduce the severity of viral arthritis resulting from infection with CHIKV or
RRV. Based on these findings, we have established a partnership with Angelini Pharmaceuticals to undertake a
clinical trial of the use of bindarit in viral arthritis. We also tested the drug etanercept in viral arthritis. This
drug has been used extensively to test rheumatoid arthritis and other inflammatory diseases. However,
etanercept treatment resulted in a dramatic exacerbation of disease in the mouse models of viral arthritis. The
significance of this finding is that it suggests that rheumatologists in RRV endemic areas need to give very
careful consideration to the possibility of RRV infection when prescribing TNF inhibitors for patients with
rheumatoid arthritis.
Expected future outcomes:
We have discovered that bindarit has very effective therapeutic activity for treatment of viral arthritis. This
work is now moving into clinical trials and we are optimistic that this drug will ultimately gain approval for
treatment of viral arthritis.
Name of contact:
Michael Rolph
Email/Phone no. of contact:
m.rolph@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508601
CIA Name: Prof Suresh Mahalingam
Admin Inst: Griffith University
Main RFCD: Respiratory Diseases
Total funding: $584,118
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
RNAi therapeutic intervention of human viral respiratory diseaseRNAi therapeutic intervention of human viral
respiratory disease
Lay Description (from application):
Human metapneumovirus (HMPV), causes clinical disease that is very similar to human respiratory syncytial
virus (RSV) and co-circulates with RSV. HMPV is emerging as a major cause of morbidity and life-threatening
respiratory tract disease in infants, young children and the elderly worldwide. No treatment is currently
available. The objectives of this proposal are to develop novel antiviral drugs that silence the expression of
viral genes and to examine protection against the disease.
Research achievements (from final report):
There is an urgent need for new drugs against a range of human virus infections. Our research has focused
specifically on a newly discovered virus that is a major cause of respiratory infection- human metapneumovirus
(HMPV). Although this virus was only discovered last decade, it is now known as a major causative agent of
respiratory infection in children and adults. We sought to develop new drugs against HMPV by exploiting a
newly developed molecular technology known as RNA interference (RNAi). Using RNAi, we aimed to target
and destroy specific parts of the viral molecular structure. We did not identify any specific RNAi-based
strategies that were effective against HMPV and we are currently attempting to modify our experimental
approach to improve delivery of the drugs to virus-infected cells.
Expected future outcomes:
We are currently working on improved strategies for delivery of drugs to virus-infected cells and are optimistic
that this will enable us to effectively target HMPV.
Name of contact:
Professor Suresh Mahalingam
Email/Phone no. of contact:
s.mahalingam@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 430300
CIA Name: Dr Fergal O'Donoghue
Admin Inst: Institute for Breathing and Sleep
Main RFCD: Respiratory Diseases
Total funding: $340,867
Start Year: 2007
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Role of load detection and compensation in pathogenesis of obstructive sleep apnea.Role of load detection and
compensation in pathogenesis of obstructive sleep apnea.
Lay Description (from application):
This proposal will use novel techniques to explore how defective responses to the threat posed by a collapsing
upper airway contribute to the Obstructive Sleep Apnea syndrome, a disease involving repetitive collapse of
the upper airway in sleep. Responses to small increases in the resistance to inspiratory airflow will be examined
by measuring the small electrcal responses in the brain to these loads, and the response of the muscles
responsible for maintaining airway patency to the collapsing forces induced by these loads, in both wakefulness
and sleep. The brain's response to resistive loads will also be evaluated using the techique of functional
magnetic resonance imaging, which demonstrates areas of the brain activated by a stimulus.
Research achievements (from final report):
This project has not produced any major research outcomes to date. Research continues despite grant cessation,
with one full-time PhD student, and other members of the research team remaining committed to the project.
Expected future outcomes:
It is expected that this project will provide significant new knowledge relating to defects in load perception and
compensation in Obstructive Sleep Apnea patients.
Name of contact:
Fergal O'Donoghue
Email/Phone no. of contact:
Fergal.odonoghue@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 496713
CIA Name: Dr Mark Pearson
Admin Inst: James Cook University
Main RFCD: Infectious Diseases
Total funding: $321,533
Start Year: 2008
End Year: 2013
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Immunomodulatory molecules of parasitic helminths as novel therapeutics for allergic
disorders.Immunomodulatory molecules of parasitic helminths as novel therapeutics for allergic disorders.
Lay Description (from application):
Australia has one of the highest rates of asthma in the world with almost 3 million Australians are affected by
this disease. Previous research has shown that infection with various types of parasitic worms lessens the
severity of asthma. The aim of this research is to find out why this happens and to isolate the ingredients from
the parasite that suppress asthma. Once found, these molecules can be used to create new drugs for the
prevention of asthma and allergies in children and adults.
Research achievements (from final report):
Australia has one of the highest rates of asthma in the world with almost 3 million Australians affected by this
disease. Previous research has shown that infection with various types of parasitic worms lessens the severity
of asthma and other allergic and inflammatory diseases as the worms produce proteins to suppress their host's
immune system in order to survive. To find out what these molecules are, we are using exciting new
technologies to produce these proteins in the laboratory in a high throughput manner which eliminates the need
to isolate them from the parasites themselves that are often hard to source. Once made, these proteins can be
tested for their capacity to supress the immune system and treat inflammation using assays we have developed
in the laboratory.
Expected future outcomes:
The development of new anti-inflmmatory drugs to treat asthma and other allergic and inflammatory diseases
that will become competitors in a global marketplace worth over $US 50 billion.
Name of contact:
Mark Pearson
Email/Phone no. of contact:
mark.pearson@jcu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 541934
CIA Name: A/Pr Bircan Erbas
Admin Inst: La Trobe University
Main RFCD: Epidemiology
Total funding: $473,925
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The impact of outdoor aeroallergen exposure on asthma exacerbations in children and adolescentsThe impact
of outdoor aeroallergen exposure on asthma exacerbations in children and adolescents
Lay Description (from application):
Asthma is a chronic condition usually diagnosed in childhood and an important public health concern. We do
not fully understand what triggers an asthma attack, although outdoor pollen and moulds may be important.
This project will establish the relative importance of pollen and moulds in triggering asthma attacks among
Australian children. It will fill gaps in our knowledge of environmental triggers of asthma. Such knowledge
will improve asthma management and ultimately public health.
Research achievements (from final report):
Australia's asthma occurrence is among the highest in the world. It is the most common chronic condition
diagnosed in childhood, and as a result, it is a national health priority. Asthma is a major cause of hospital
admissions among children and adolescents, with possible severe long-term health consequences if managed
poorly in childhood. Sudden-onset asthma attacks in children can be triggered by various environmental
factors. It was not known whether exposures to outdoor pollen triggered attacks separately from respiratory
viruses such as human rhinovirus (HRV). We investigated this via a hospital-based study of asthma incidence.
This research had a number of major achievements. None of the asthmatic children recruited during the peak
2010 season showed the H1N1 virus, suggesting no loss of asthma control during influenza epidemics, as
previously thought. Grass pollen was the main pollen which increased the risk of an attack requiring
hospitalisation in children and adolescents. This was particularly for boys exposed to high concentrations of
grass pollen, and independent of HRV, air pollution and allergic sensitisation. This research has expanded our
understanding of the influences of aeroallergens and viral exposure on asthma attacks in children. It provides a
platform for further studies of the causal mechanisms of grass pollen exposure on early life pathways that lead
to asthma. These findings can be used to minimise the impact of outdoor allergen exposure for children with
asthma by developing self management plans to prevent environmentally-triggered attacks.
Expected future outcomes:
The role of outdoor fungi for asthma exacerbations in children requiring hospitalisation is not well understood.
We plan to expand the understanding of this subject through scientific publications and presentations at
relevant national and international meetings, as well as to further expand research capacity in aeroallergen and
asthma research in Australia.
Name of contact:
Bircan Erbas
Email/Phone no. of contact:
b.erbas@latrobe.com.au
NHMRC Research Achievements - SUMMARY
Grant ID: 234705
Start Year: 2003
CIA Name: A/Pr Margaret Hibbs
End Year: 2004
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Respiratory Diseases
Total funding: $250,250
Title of research award:
Is Lyn tyrosine kinase a predictor of severe, persistent multi-trait asthma and allergy?Is Lyn tyrosine kinase a
predictor of severe, persistent multi-trait asthma and allergy?
Lay Description (from application):
Asthma is a major health problem in Australia affecting over 10% of the population at any time, and more than
25% of the population at one stage in their lives. Although the public perception is that asthma treatments have
improved management of the disease, more than 700 people die from severe asthma each year and
hospitalisation from exacerbation (sudden worsening) is one of the most costly components of the health care
burden in Australia and most developed countries. Currently there are no molecular markers that can predict
who will get severe asthma and there are no specific treatments to reverse severe exacerbations. This project
will use advanced molecular biology methods to examine whether a molecule called "Lyn" may be important.
The Lyn tyrosine kinase is a member of a family of genes that participate in transmitting information across the
cell membrane. This enzyme is expressed in blood cells, and is involved in mechanisms pertaining to
infection, immunity and allergic responses. To further our understanding of the role of this enzyme in the
context of the whole animal, we have generated mice that are unable to make Lyn protein (Lyn-deficient mice).
In animal models of asthma we know that if Lyn is not functioning, severe and persistent asthma develops. We
have also made preliminary studies that suggest that Lyn does not work properly in people who have been
admitted to the emergency ward with life threatenting asthma. In this study we will examine in detail the role
that Lyn plays in asthma and allergy, and we intend to identify the pathways that give rise to asthma in Lyndeficient mice. We will also investigate our hypothesis that Lyn activity may be reduced or disregulated in
patients with asthma and allergy. This research should lead to better predictive markers for severe asthma and
also to improved and specific treatments.
Research achievements (from final report):
The purpose of this grant was to establish the importance of the Lyn protein tyrosine kinase in the pathogenesis
of asthma, since our earlier studies had shown that Lyn-deficient mice, in response to antigen challenge,
develop an intense eosinophilic asthma-like inflammation that closely resembles human disease. Thus, in this
grant we sought to answer two critical questions: (1) the molecular mechanism that gives rise to the severe
airway inflammation in Lyn-deficient mice; and (2) the role of Lyn in human asthma., , To understand the
cellular basis for the exaggerated Th2 immune response in Lyn-deficient mice, we have now demonstrated that
Lyn is expressed in dendritic cells, key initiators of T cell-dependent immune responses through presentation of
antigen to T cells. Furthermore, we have shown that dendritic cells from Lyn-deficient mice have a more
immature phenotype, and exhibit defective inhibitory PIR-B receptor phosphorylation, a receptor linked to the
biasing of immune responses. Moreover, dendritic cells from Lyn-deficient mice are capable of polarizing T
cells towards a Th2 phenotype when adoptively transferred into wild type recipients. Our results show that Lyn
regulates the intensity and duration of multiple asthmatic traits, and indicate that Lyn is an important negative
regulator of Th2 immunity., , To understand the role of Lyn in human disease, we have been evaluating the
enzymatic activity of Lyn in control and asthmatic patients attending the Asthma & Allergy Unit at the Alfred
Hospital. We have developed a kinase assay to assess the activity of human Lyn, and have devised a strategy
that permits reliable PCR amplification of full length human Lyn cDNA from peripheral blood mononuclear
cells. To date, we have analyzed five donors with asthma and ten controls without asthma, with sequences
obtained from up to ten replicate clones per subject, however in this limited assessment, all subjects had wild
type Lyn genomic sequences.
Expected future outcomes:
Our studies have clearly shown that Lyn plays an important role in allergic inflammation, dendritic cell
maturation and function in the mouse, and suggest that Lyn, or components of Lyn-dependent signal
NHMRC Research Achievements - SUMMARY
transduction pathways, may prove to be valuable targets for therapeutic manipulation of DC-induced immune
responses. We are currently pursuing this avenue.
Name of contact:
Margaret Hibbs
Email/Phone no. of contact:
Margaret.Hibbs@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 280910
Start Year: 2004
CIA Name: A/Pr Matthias Ernst
End Year: 2006
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Respiratory Diseases
Total funding: $323,750
Title of research award:
Genetic dissection of the function of the Src family tyrosine kinase Hck in inflammatory lung diseaseGenetic
dissection of the function of the Src family tyrosine kinase Hck in inflammatory lung disease
Lay Description (from application):
This project aims to identify better and safer treatments for serious, life-threatening inflammatory lung
diseases, such as Chronic Obstructive Lung Disease (COPD), which affect over 600 million people worldwide
and are a major health problem in Australia. There are no effective treatments that can reverse or slow these
diseases. The research is based on our recent discovery that an enzyme called "Hck" might play a very
important role in lung disease. We used mice in which a genetic method had been used to change Hck into its
active form. The mice appeared normal when they were born but developed a progressive lung inflammation
that resembled serious human lung diseases. Surprisingly, the mice also displayed enhanced responses to
substances from bacteria that can infect the lung - a so-called "innate immune response". This led us to
conclude that the main problem in the mice was actually enhanced innate immunity - which is usually
protective - turning against the lung to cause disease. To understand exactly what controls this fine balance
between protection and lung damage, we will use new and sophisticated gene modification methods that allow
us to target changes in Hck activity to specific cells that we suspect are the main cause of the disease. In doing
so we will add special tags into these cells, so that we can isolate the controlling molecules in the disease
process. We are particularly interested in a cell called the "macrophage", a major defensive cell in the lung that
is also known to be capable of causing lung disease. Our aim is to find disease-controlling molecules that could
be blocked with new drugs that would suppress disease but spare defenses against lung infections.
Research achievements (from final report):
1) Molecular identification of a mechanism that results in COPD-like disease in a Tcell-independent manner, 2)
Establishment of a preclinical mouse model for the above disease, 3) Exploring commercial
collaborations/licensing agreement for the preclinical use of the above model
Expected future outcomes:
1) Further dissection of molecular machanism underlying the establishment and maintenance of disease in
Hck(F) mice, 2) Explore susceptibility of above mice to development of lung cancer, 3) Establish licensing
contract for Hck(F) mice with commercial partner
Name of contact:
Matthias Ernst
Email/Phone no. of contact:
matthias.ernst@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 315525
Start Year: 2005
CIA Name: Dr Bruce Wines
End Year: 2007
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $535,500
Grant Type:
Title of research award:
IgA mediated Activation of FcalphaRI, an Fc receptor and a Leukocyte Ig-like Receptor.IgA mediated
Activation of FcalphaRI, an Fc receptor and a Leukocyte Ig-like Receptor.
Lay Description (from application):
Our immune system exists to seek and destroy infections caused by bacteria and viruses (pathogens) that would
grow in us. B cells in the immune system make antibody tags which attach to pathogens marking them for
elimination. A special type of antibody is IgA. IgA occurs in two forms, the first is found at mucosal sites,
these are membranous passages in the body, such as the lung, the gut and the genital tract. These communicate
with the outside and are the major route of pathogen entry into the body. Here IgA forms a rather passive, but
pathogen specific, "sticky" barrier to prevent microbial pathogens attaching to these large surfaces. In an
everyday analogy this IgA behaves somewhat like fly-paper. This subdued response is appropriate as we are
constantly exposed to micro-organisms living in our gut, or breathed into our lungs, and our immune system
would make us ill if it aggressively attacked our innocuous microbial neighbours. The second type of IgA is
found in the blood where it attaches to pathogens that have breached the body's barriers. These IgA tags are
actively sought by white blood cells whose function is to protect the body from infection by recognising and
engulfing the tagged pathogens and destroying them with killer molecules, including bleach. The IgA-Fc
receptor is the sensor on the surface of white blood cells which seeks the IgA tags as they attach to pathogens.
In order to survive in this hostile environment some of our pathogens, such as Staphylococcus, have their own
strategies to make themselves invisible to the immune system. These strategies include cutting up the IgA tags
or blocking the sensors for IgA. In this project we will study how IgA tags turn on white blood cells to
destroy pathogens. We will also be looking at two Staphylococcal proteins which block up the sensor for IgA
tags. Finally we are endeavouring to understand how it is the mucosal type IgA does not activate the white cells
nearly as much as the IgA from the blood.
Research achievements (from final report):
Antibodies trigger receptors on white blood cells to defend us from infection but they may also promote
autoimmune diseases such as lupus, rheumatoid arthritis and allergy. IgA is a class of antibody which
participates in protection but which also can regulate immune responses. Understanding the actions of the IgA
class of antibody is thus important in developing ideas for manipulating our immune system for better
protection against microbial infections and for modulating inflammation in autoimmune disease. Our studies
have determined fundamental aspects of the biology of IgA and its receptor, FcalphaRI. Infectious
microorganisms such as Golden Staph (Staphylococcus aureus) target IgA in a strategy to evade immune
defenses. Staphylococcus aureus is a major health burden and increased antibiotic resistance and pathogenicity
has heightened the risk of life threatening infections by this pathogen. S. aureus modifies the host immune
system and the new family of proteins, the SSL family of exotoxins participate in immune evasion. The first
described member, SSL7, was found to bind and inhibit the function of human IgA and we have determined the
structure of SSL7 bound to the Fc region of IgA at 3.2 Å resolution. Our results provide the molecular basis for
SSL7 helping S. aureus to evade immunity mediated by IgA triggering its receptor on white blood cells.
Expected future outcomes:
This research may 1) lead to the future development of strategies of targeting the IgA receptor FcalphaRI or
related immunoreceptors (e.g. LIR7) to reduce inflammation in autoimmune disease and 2) will lead to a better
understanding of immune evasion by S. aureus, which is potentially important in the future management of
antibiotic resistant S. aureus.
Name of contact:
NHMRC Research Achievements - SUMMARY
Bruce Wines
Email/Phone no. of contact:
bwines@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490014
Start Year: 2008
CIA Name: Dr Adele Holloway
End Year: 2011
Admin Inst: Menzies Research Institute
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $521,961
Title of research award:
How does basal chromatic structure predict cytokine gene responses?How does basal chromatic structure
predict cytokine gene responses?
Lay Description (from application):
To recognise foreign pathogens and eradicate them from the body, immune cells need to quickly switch on
genes encoding factors which communicate between cells and drive the immune response. Incorrect expression
of these genes contributes to immune diseases such as asthma, arthritis and leukaemia. The aim of this project
is to study how the DNA environment of immune genes controls their ability to be switched on and off, and
how altering this environment leads to incorrect gene expression.
Research achievements (from final report):
To recognise foreign pathogens and eradicate them from the body, immune cells need to quickly switch on
genes encoding factors which communicate between cells and drive the immune response. Incorrect expression
of these genes contributes to immune diseases such as asthma, arthritis and leukaemia. , This research
investigated the DNA environment of one of these immune genes (called GM-CSF) to determine how this
environment controls the ability of the gene to be switched on and off. The research identified DNA-associated
factors that control the ability of the gene to respond to immune signals. Further, the study found that there is a
set of immune genes that have similar DNA environments in immune cells to the GM-CSF gene and this
allows them to respond to immune signals in a similar way. These genes have a particular DNA environment
which maintains them in a tightly repressed state in the absence of an immune signal. Finally the study found
that changes to the DNA environment of the GM-CSF gene occur in leukaemic cells, and that this contributes
to the dysregulated activity of the gene in these cells. These findings are significant because unlike changes to
the DNA sequence, changes to the DNA environment are reversible with pharmacological agents, and therefore
suggests a potential avenue for therapeutic intervention in disease states in which these immune genes are
aberrantly expressed.
Expected future outcomes:
Expected future outcomes are a better understanding of how DNA environment controls the response of genes
to immune signals, and how changes to these environments contribute to immune diseases.
Name of contact:
Dr Adele Holloway
Email/Phone no. of contact:
a.f.holloway@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194304
CIA Name: Prof Robyn O'Hehir
Admin Inst: Monash University
Main RFCD: Allergy
Total funding: $406,980
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Couch grass allergy: cellular and molecular studies directed at improved specific immunotherapyCouch grass
allergy: cellular and molecular studies directed at improved specific immunotherapy
Lay Description (from application):
Couch grass pollen is increasingly important in Australia and other temperate and subtropical regions as a
seasonal allergen causing asthma and hay fever. In our allergy clinic 85% of patients with seasonal asthma
and/or hay fever are allergic to both couch grass pollen and rye grass pollen. Standard allergy treatment shots
usually cover the rye grass pollen allergens but there is no cross-reactivity with couch grass pollen and
therefore symptoms due to couch grass pollen are not controlled. These shots are seldom used in asthmatic
patients because of the risk of severe asthma or generalised allergic reactions. We plan to examine human
blood cell responses to couch grass pollen allergens before and after allergy shots with a preparation that
includes couch grass pollen and rye grass pollen. A comparable control group of patients receiving only drug
therapy will also be investigated. This study will identify dominant sites of couch grass pollen allergen
immunoreactivity and reveal mechanisms of desensitisation. Based on this information, we will develop novel
couch grass pollen proteins that retain the positive features needed for a successful desensitising vaccine but
without the ability to bind to allergy antibodies and possibly cause severe adverse events such as asthma
attacks. These preparations could be used to provide safer and more effective allergy treatments that can be
used in hay fever sufferers and asthmatics.
Research achievements (from final report):
This grant has allowed us to characterise the changes in the immune system of allergic patients that occur
during successful treatment with allergy shots for seasonal hayfever and mild asthma due to couch grass pollen
allergy. As part of this study we have dissected the critical sites of the grass pollen where the allergenicity is
located. This information is important for inclusion in the final allergy vaccines that can be used more safely in
patients with hayfever and asthma than the currently available products.
Expected future outcomes:
Children and adults of the future may line up for a vaccine to prevent grass pollen hayfever and asthma just as
they now do for childhood common infections such as measles, mumps and chicken pox.
Name of contact:
Professor Robyn O'hehir
Email/Phone no. of contact:
robyn.ohehir@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236934
Start Year: 2003
CIA Name: Prof Michael Abramson
End Year: 2005
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Environmental and Occupational Health and Safety
Total funding: $315,498
Title of research award:
The relationship between airborne particle exposure, incident respiratory symptoms and decline in lung
functionThe relationship between airborne particle exposure, incident respiratory symptoms and decline in lung
function
Lay Description (from application):
Air pollution has been consistently identified as the environmental health problem of greatest concern to the
general public in Australia. Yet hard evidence of adverse health effects from air pollution in Australian cities
and towns is limited to date. It has been estimated that high levels of particles in urban air could be responsible
for as many as 2,400 deaths nationally, costing approximately $4,300 million each year. This study will follow
two groups of young Melbourne adults recruited some years ago for studies of respiratory health. They will be
a sent a questionnaire by mail and invited back to our laboratory for breathing tests. We will obtain routinely
collected air quality data and measure fine particles < 2.5 thousandths of a mm in outdoor air. A subgroup of
100 subjects will also participate in some measurements of indoor air pollution. The analysis will look for
relationships between particles in the air, new symptoms and changes in lung function over time. Comparisons
will also made with other centres doing a very similar study in Europe. Reviews commissioned by the
National Environment Protection Council have highlighted the lack of Australian data to assist in setting
standards for particulate air pollution. The proposed study would provide some of the necessary local data and
assist in the development of new health based environmental protection measures for fine particles. Once these
measures have been implemented, we would expect to see an improvement in the respiratory health of the
Australian population.
Research achievements (from final report):
Air pollution has been consistently identified as the environmental health problem of greatest concern to the
general public in Australia. Yet hard evidence of adverse health effects from air pollution in Australian cities
and towns was limited. It has been estimated that high levels of particles in urban air could be responsible for
as many as 2,400 deaths nationally, costing approximately $4,300 million each year. , This study followed two
groups of young and middle aged Melbourne adults recruited some years ago for studies of respiratory health.
They were sent a questionnaire by mail and invited back to our laboratory for breathing tests. We obtained
routinely collected air quality data and measured fine particles < 2.5 thousandths of a millimetre in outdoor air.
A subgroup of 100 subjects also participated in some measurements of indoor air pollution. The analysis was
unable to find any relationships between particles in the air, symptoms and changes in lung function over time.
The levels of fine particles were low in comparison with other centres doing a very similar study in Europe.,
Reviews commissioned by the National Environment Protection Council have highlighted the lack of
Australian data to assist in setting standards for particulate air pollution. The study provides some of the
necessary local data and suggests that the current advisory National Environmental Protection Measure for fine
particles might adequately protect the respiratory health of the Australian population.
Expected future outcomes:
Once published in scientific journals, the findings of this research will contribute to the planned revision of the
NEPM for fine particle air pollution. Additional research is being undertaken on the effects of smaller
(ultrafine) particles upon the heart and lungs.
Name of contact:
Michael Abramson
Email/Phone no. of contact:
Michael.Abramson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284400
CIA Name: Dr Hayat Dagher
Admin Inst: Monash University
Main RFCD: Respiratory Diseases
Total funding: $288,240
Start Year: 2004
End Year: 2008
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Epithelial neutrophil activating peptide-78 regulation in fibroblast cells in response to rhinovirus
infectionsEpithelial neutrophil activating peptide-78 regulation in fibroblast cells in response to rhinovirus
infections
Lay Description (from application):
Not Available
Research achievements (from final report):
Asthma is a lung disease characterised by airway obstruction and airway hyperresponsivness associated with
persistent inflammation and structural airway remodeling: 600,000 people in Victoria, 2 million in Australia
and 150 million people worldwide have asthma. Rhinovirus infection, the major cause of the common cold,
causes the majority of asthma exacerbations in children and adults resulting in 4 death/week in Victoria and
16/week nationally. The research project investigated a protein previously known for its important regulatory
roles in other systems but only discovered for its novel role in host defense to viruses in this study. The protein
was discovered using recent technological tools and its role was further validated using basic research tools.
Further investigation into the mechanism of action of this protein may prove it a potential target for future
therapeutic strategies.
Expected future outcomes:
This research finding is novel and provides a basis for future investigation into the mechanisms by which the
investigated protein may regulate host defense responses to viral infections and possible development of new
therapeutic strategies.
Name of contact:
Hayat Dagher
Email/Phone no. of contact:
hdagher@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 292900
CIA Name: Prof John Mills
Admin Inst: Monash University
Main RFCD: Medical Virology
Total funding: $239,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Assembly functions of respiratory syncytial virus matrix proteinAssembly functions of respiratory syncytial
virus matrix protein
Lay Description (from application):
Respiratory syncytial virus (RSV) is the single most important cause of lower respiratory infections
(pneumonia and bronchiolitis) in young infants. In addition to the morbidity of RSV infection itself, it is well
established that symptomatic RSV infection in infancy predisposes to asthma later in life. As all infants are
infected by RSV at least once by age 2 yrs, this virus represents a major public health problem. Additionally,
re-infection by RSV is increasingly being recognized as a cause of severe lower respiratory disease in the
elderly and in immunocompromised patients. The goal of this research is to understand better the mechanisms
used by RSV to replicate itself in mammalian cells. Information from this work could be used to design novel
antiviral drugs to treat RSV, and novel attenuating mutations that may assist in developing live RSV
vaccines.The research focuses on a key viral protein, the matrix (M) protein, which is involved in many steps
in virus replication. We aim to understand how M protein interacts with other components of the virus
(specifically, envelope proteins) to orchestrate virus assembly. To coordinate assembly of new virus particles,
M protein binds to portions of virus envelope glycoproteins and to RSV nucleocapsids (the internal machinery
of the virus), bringing them together at the cell membrane. The protein-protein interactions which are
responsible for these functions of RSV M protein will be determined.
Research achievements (from final report):
We have identified key interactions between the RSV matrix protein and the cytoplasmic domain of the
envelope protein; this work was published in J Gen Virol in 2005. Subsequently we have demonstrated an
interaction between RSV matrix protein and a so-called second matrix protein, M2-1, which is responsible for
bringing the matrix protein into intracytoplasmic inclusions noted during RSV replication. Further we have
identified key domains of the matrix protein responsible for this interaction. This work has been submitted for
publication. Considered together these studies have advanced our knowledge of how RSV virions are
assembled prior to release from cells, and may lead to improved attenuated strains of RSV (for vaccines) or
new targets for novel chemotherapeutics.
Expected future outcomes:
Potentially, new attenuating mutations for live,attenuated vaccines, and new targets for investigational antiviral
drugs
Name of contact:
John Mills
Email/Phone no. of contact:
mills@portsea.net
NHMRC Research Achievements - SUMMARY
Grant ID: 299888
Start Year: 2004
CIA Name: A/Pr Timothy Cole
End Year: 2006
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $447,000
Title of research award:
The role of glucocorticoids, retinol and cAMP signaling in lung development and neonatal respiratory
dysfunctionThe role of glucocorticoids, retinol and cAMP signaling in lung development and neonatal
respiratory dysfunction
Lay Description (from application):
Underdeveloped lungs at birth and adult lung diseases (ie emphysema, acute resipratory distress, and asthma)
are a major cause of hopitalization and death. The World Health Organization ranks resipratory diseases at
number 6 in the global burden of disease. Preterm birth with associated respiratory complications occurs in
about 10% of all human births and accounts for 75% of neonatal deaths not associated with congenital
abnormalities . Respiratory Distress Syndrome (RDS) is a major complication in preterm births and the routine
antenatal treatment of glucocorticoids has a major benefit in reducing incidence of RDS leading to decreased
neonatal mortality. Glucocorticoids improve lung maturation yet their exact detailed role is not fully
understood. Other systemic hormones and factors , such as vitamin A (precursor for retinoic acid) are also
important in regulating, completing and maintaining proper lung development and function. Vitamin A
deficiency alters lung structure and function, and is believed to be a causal factor in chronic lung diseases such
as bronchopulmonary dysplasia, frequently problematic to infants. Detailed understanding of how these
hormones work in the lung is critical to the future improvement of treatments for respiratory distress at birth
and other respiratory conditions (emphysema, asthma) during adult life. We have developed a number of
mouse models to study how these hormones work in the lung and allows us to perform investigations not
possible in the human system. Using these mouse models of hormone resistance for glucocorticoids, retinoic
acid (vitamin A) and cAMP signaling we will study in detail how these hormones work in the developing lung.
Outcomes will be detailed knowledge and mechanisms of action that are critical for the design and testing of
novel agents and therapies for immature lungs at birth and in adult lung dysfunction and disease
Research achievements (from final report):
This research project has investigated the detailed action of three systemic hormone signaling pathways on
fetal lung development before birth using three specific gene-targeted hormone-resistant mice. Glucocorticoid
steroids are used routinely to treat very preterm babies yet little is known of their mechanism of action in the
developing lung. Studies with glucocorticoid receptor-deficient mice (two papers now published) clearly show
a role for this steroid in cell differentiation as well as surfactant protein gene expression. Similar studies have
been udertaken with cAMP-signaling defective mice and retinoic acid receptor deficient mice and reveal roles
in lung progenitor cell specification . Understanding underlying mechanisms of respiratory alveolarization,
pulmonary surfactant control and alveoli epithelial cell differentiation will clarify causes of fetal lung
abnormalities and improve strategies of hormone treatment in preterm births.
Expected future outcomes:
Current clinical treatment with antenatal glucocorticoids is controversial with the potential for impact on later
adult disease, such as hypertension, type II diabetes and metabolic syndrome. Our results will allow the design
of better steroid treatments and other drugs to promote proper lung function.
Name of contact:
Timothy J. Cole
Email/Phone no. of contact:
tim.cole@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 310603
CIA Name: Dr Robert Bischof
Admin Inst: Monash University
Main RFCD: Respiratory Diseases
Total funding: $435,375
Start Year: 2004
End Year: 2008
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Development of antibodies to Il-13 receptor and their preclinical testing in a sheep model for human allergic
asthmaDevelopment of antibodies to Il-13 receptor and their preclinical testing in a sheep model for human
allergic asthma
Lay Description (from application):
The increasing prevalence and severity of asthma worldwide highlights the need for novel approaches to treat
this disease. This proposal will generate antibodies that can be used to specifically block the action of a key
molecule known to regulate many of the hallmark features of asthmatic disease. Preclinical evaluation of these
antibodies in an established sheep model of human asthma will allow their assessment as a specific therapy for
asthma.
Research achievements (from final report):
This project involved the generation of antibodies that can be used to specifically block the biological action of
a key molecule, interleukin-13 (IL-13), known to regulate many of the hallmark features of asthmatic disease.
A panel of antibodies was developed and these were shown to recognise the receptor for IL-13 (the IL-13
receptor), expressed on a variety of cell types. Several of the antibodies were shown to block the binding and
functional activity of IL-13. Blocking or neutralising activity was demonstrated in both in vitro assays and
tissue model systems developed during the course of the project. In vivo studies confirmed the role of IL-13 in
a validated large animal model of human allergic asthma. The ultimate benefits of this research will be seen
following further testing of candidate antibodies in the sheep model to determine their potential as a specific
therapy for asthma. Furthermore, these studies provide a valid pre-clinical platform for the development and
testing of novel, specific and efficacious anti-asthma therapies.
Expected future outcomes:
Neutralising antibodies generated in this project and tested for efficacy in vitro and in vivo in an experimental
sheep model of asthma represent candidates for further commercial development and assessment as a specific
therapy for human asthma.
Name of contact:
Dr Rob Bischof
Email/Phone no. of contact:
rob.bischof@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334000
CIA Name: Prof Robyn O'Hehir
Admin Inst: Monash University
Main RFCD: Allergy
Total funding: $4,905,420
Start Year: 2005
End Year: 2009
Grant Type: Programs
Title of research award:
THE INTERFACE BETWEEN INNATE AND ADAPTIVE IMMUNITYTHE INTERFACE BETWEEN
INNATE AND ADAPTIVE IMMUNITY
Lay Description (from application):
Allergic disorders including asthma are amongst the most prevalent diseases in Australia afflicting up to 25%
of the population and costing the Australian Government in excess of $600 million annually. This program
aims to understand the molecular and cellular mechanisms controlling airway inflammation, focusing on the
cross-talk between scavenger cells at airway surfaces and circulating cells of the immune system. These studies
will combine sophisticated mouse models of airway inflammation in the laboratory with clinical investigation
and analysis of human tissue. Understanding these processes will translate into better treatments for patients
suffering from life-threatening allergy and asthma.
Research achievements (from final report):
This project characterised, at the molecular level, the interface between innate and adaptive immune responses
in allergy and asthma, in particular testing the hypothesis that disease induction, exacerbations and chronicity
of allergic lung disease and asthma involve the innate immune system. Critical molecular control mechanisms
governing macrophage lineage development, activation and survival in models of lung inflammation were
identified and new mechanisms and molecules in the interaction of innate and adaptive immunity using murine
and human allergy and asthma model systems were determined providing potential novel therapeutic targets.
The influence of microbial components on development of allergic airway inflammation was analysed and a
potentially beneficial role of neutrophilic inflammation in protection from lung viral infection observed.
Finally, translational studies assessed the therapeutic potential and clinical application of our findings. Clinical
samples validated macrophage lineage studies and the asthma endotype concept to further sub-divide clinical
cohorts was advanced as an adjunct strategy in translational medicine. Induction of allergen-specific T cell
tolerance via TGF-beta and regulatory T cells were shown to be mechanisms underlying clinically effective
sublingual immunotherapy for allergic disease. Patients with asthma, inflammatory lung diseases and other
allergic diseases will benefit from this research by changes in knowledge and clinical governance.
Expected future outcomes:
International adoption of our blood biomarker; cell-based treatment for lung disease based on macrophage
progenitor findings; progression to early phase clinical trials of novel immunotherapy for the treatment of
patients with allergic rhinitis and allergic asthma.
Name of contact:
Professor Robyn O'hehir
Email/Phone no. of contact:
robyn.ohehir@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334207
CIA Name: Prof Michael Abramson
Admin Inst: Monash University
Main RFCD: Primary Health Care
Total funding: $487,427
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Strategic Awards
Title of research award:
The role of spirometry in managing chronic respiratory diseases in general practiceThe role of spirometry in
managing chronic respiratory diseases in general practice
Lay Description (from application):
This study will compare the use of spirometry (a lung function test) in general practice, with and without
feedback of results, against the delivery of usual medical care without spirometry. If positive, the trial will
result in better health outcomes for patients with chronic respiratory disease.
Research achievements (from final report):
A randomised controlled trial of spirometry (lung function testing) was successfully completed in general
practice. This involved 31 general practices that agreed to participate, including 124 general practitioners and
practice staff across metropolitan Melbourne. They recruited a total of 386 patients who agreed to participate,
of whom 325 patients completed the study. Patients were randomly allocated to one of 3 groups:, o Group A.
Intervention: Three monthly spirometry with reports returned to the practice and regular medical review
o
Group B. Spirometry only at baseline
and 12 months, with no report until after completion of the trial
o
Group C. Control: usual medical care
(which did not include regular spirometry), There were no significant differences between groups in the
primary outcome: quality of Life.
There was a significant improvement
in asthma control within the intervention group, but not the other groups. However there were no significant
differences between groups in secondary outcomes: respiratory symptoms, asthma attacks, written asthma
action plans, days lost from usual activities, emergency presentations, hospital admissions or lung function.,
Focus groups at baseline identified a
number of potentially reversible factors that limited the use of spirometry in general practice. Problems could
be improved through a review of the MBS rebate, more support with training of practice staff, quality
assurance, and calibration and as well GPs needing further training in the interpretation of spirometry results.
Focus groups and interviews following completion of the trial are still being analysed.
Expected future outcomes:
It is difficult to recommend more widespread use of spirometry in Australian general practices to guide the
management of respiratory patients. However there is a role for spirometry as a "gold standard" to establish the
diagnosis when patients first present to general practitioners with respiratory symptoms.
Name of contact:
Prof Michael Abramson
Professor Michael Abramson
Email/Phone no. of contact:
michael.abramson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427608
Start Year: 2007
CIA Name: Prof Fabienne Mackay
End Year: 2011
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Immunology not elsewhere classified
Total funding: $618,722
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am an Immunologist interested in the role of B-lymphocytes, their survival and expression of a novel
chemoreceptor in Autoimmunity. I also study the important role of Neuropeptide Y in modulating key immune
functions.
Research achievements (from final report):
, Fabienne Mackay's work relates to one of the most exciting new academic and clinical advances in the field of
immunology and autoimmunity - the discovery of B cell activating factor belonging to the TNF family named
BAFF. She was the first researcher in the world to associate BAFF production with the development of
Systemic Lupus Erythematosus (SLE) and publish this key observation in a number of very highly cited
research articles. Her work supported by this NHMRC fellowship showed that BAFF triggers a very particular
form of SLE and that autoantibodies and the innate immune system played a major role in tissue damage
occurring in BAFF-mediated SLE. Supporting these results, clinical trials using Belimumab, a BAFF inhibitor
to treat SLE, showed that this new treatment was particularly effective in SLE patients with autoantibodies.
The clinical trial was successful and, in March 2011, the US Food and Drug Adminstration approved
Belimumab, as the first new treatment for SLE in over 50 years. This exciting clinical outcome validates over
10 years of discoveries in the Mackay laboratory in Australia, in particular the up-regulation of BAFF in
human autoimmune diseases, and the prediction, based on mouse models that, that BAFF inhibitors would be
promising new therapeutics for human autoimmune disease. Through her studies on pathogenic B cells
Fabienne Mackay also discovered that the chemokine receptor CXCR7 is critical for heart development leading
to a highly cited article in PNAS. CXCR7 is a potential therapeutic target for the prevention of tissue fibrosis. ,
Expected future outcomes:
The research supported the outcome of a new treatment, Belimumab, approved by the FDA in 2011, as the first
new treatment for SLE in over 50 years. Belimumab treatment is steroid-sparing, a great advantage as steroids
are often poorly tolerated by many patients and the source of severe side effects.,
Name of contact:
Prof. Fabienne Mackay
Email/Phone no. of contact:
Fabienne.MACKAY@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436611
CIA Name: Prof David Jans
Admin Inst: Monash University
Main RFCD: Infectious Diseases
Total funding: $495,042
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Role of nucleocytoplasmic trafficking of Matrix protein in RSV infectionRole of nucleocytoplasmic trafficking
of Matrix protein in RSV infection
Lay Description (from application):
Respiratory syncytial virus (RSV) is the major cause of viral pneumonia in infants and young children
throughout the world. By the age of 3, virtually every child has been infected by RSV at least once. RSV is
also an important cause of pneumonia in the elderly and is estimated to cause more deaths each winter than
influenza. In Australia, an estimated 100,000 infants are infected by RSV every year. In Victoria, RSV is the
most common cause of all reported cases of respiratory tract disease, with an estimated annual cost of $1-4
million. Despite more than 40 years of research there is no vaccine to prevent RSV infection, and the only
drug (ribavirin) licenced for treatment of RSV infection is expensive, difficult to administer, toxic, and of
doubtful efficacy. We propose to examine one of the RSV proteins, the matrix protein (M). M is very
important for virus propagation and is responsible for resultant cell injury. We have observed that M enters
the cell nucleus (the location for all cellular DNA and RNA synthesis) where it appears to inhibit host cell
RNA synthesis early in infection; later, it exits the nucleus in a step required for virus production in the
cytoplasm. The signals that regulate transport of M into and out of the nucleus and the effect on the host cell
leading to pathogenesis, are the focus of this proposal. The results of this study will be beneficial in many
ways. Most importantly, we will gain knowledge about the processes underlying cell injury caused in RSV
disease, which may lead to the identification of novel targets for intervention strategies.
Research achievements (from final report):
Our work has shown that regulated, appropriate nuclear transport of respiratory syncytial virus (RSV) matrix
(M) protein in infected cells is crucial to optimal virus replication and growth and that regulated nuclear
transport of RSV is a viable target for therapeutic/vaccine development as RSV carrying a mutation in either
the nuclear import or the nuclear export motif of M has reduced replication fitness. , RSV is the major viral
cause of lower respiratory tract infections, and infects about 100,000 infants each year in Australia with
associated high economic burden associated with hospitalisations and lost working hours. There are no
effective antiviral drugs or vaccines available with an urgent need for identification of new targets for drug and
vaccine development. Our work has added significantly to the advancement of knowledge in this field as it has
identified a novel candidate within RSV that can be targeted for drug development and may also be useful for
vaccine strategies.
Expected future outcomes:
The nuclear transport motifs and mechanisms of RSV M present a defined target for future therapeutic
development as well as attenuation for vaccine strategies. Our work also has implications for nuclear transport
of protiens of other related viruses and antiviral/vaccine development for major human and veterinary diseases.
Name of contact:
David A. Jans
Email/Phone no. of contact:
David.Jans@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436713
CIA Name: Prof Roger Summers
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $306,843
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Understanding cell signalling mechanisms activated by relaxin family peptides: targets with therapeutic
potentialUnderstanding cell signalling mechanisms activated by relaxin family peptides: targets with
therapeutic potential
Lay Description (from application):
One of the most powerful ways that the activity of the cells that make up the tissues and organs of the body can
be changed is by the interaction of chemicals with proteins called receptors located at the cell surface. The
commonest type of receptor is called a G-protein coupled receptor as it is linked to mechanisms inside the cell
by the G-proteins. These receptors are the most commonly targeted by pharmaceutical companies that wish to
alter the responses of cells for therapeutic purposes and almost 2/3 of all drugs currently marketed work
through these proteins. This project will examine the mechanisms whereby certain types of G-protein coupled
receptor produce signals in cells and determine what are the critical areas of the receptor for these interactions.
The receptors involved have been discovered only in the last 4 years and little is known of the ways these
change the activity of cells. The substances acting on these receptors have potential for development as targets
for drugs that have the potential to treat fibrosis which is a feature of many diseases including cardiac failure,
kidney failure and lung disease.
Research achievements (from final report):
The project was aimed at achieving a better understanding of how the relaxin family peptides signal to cells.
This has helped to establish how human relaxin 2 produces its effects at RXFP1 receptors which is important
since this peptide has now undergone a successful phase II clinical trial for the treatment of cardiac failure with
phase III expected to begin this year. We have also identified for the first time that multiple isgnalling
pathways can be activated by different relaxin family peptides acting at RXFP3 which will be important for
drug development for the treatment of obesity and anxiety.
Expected future outcomes:
Relaxin has undergone a successful clinical trial for the treatment of cardiac failure and it is to be hoped that
this continues. RXFP3 - the receptor for relaxin 3 is an attractive target for drug development.
Name of contact:
Roger Summers
Email/Phone no. of contact:
roger.summers@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 465110
CIA Name: Dr Geza Benke
Admin Inst: Monash University
Main RFCD: Epidemiology
Total funding: $471,059
Start Year: 2007
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Occupational respiratory and new technology epidemiology.Occupational respiratory and new technology
epidemiology.
Lay Description (from application):
Not Available
Research achievements (from final report):
The achievements of the research include :, 1) In 2007 Dr Benke was a co-author of a Lancet publication which
provided estimates of the relative and attributable risks of new-onset asthma in relation to occupations, workrelated exposures, and inhalation accidents. This research was significant in providing an estimate of the
prevalence of new-onset occupational asthma across 13 countries in Europe, North America and Australia., 2)
In 2008, 2009 and 2010 Dr Benke was co-author on a number of publications from the Morpheus Mobile
phone study that investigated cognitive function and mobile phone exposure in adolescents. The research
which is ongoing in the EXPOSURE study, found that RF radiation is unlikely to affect cognitive function, but
that subjects that were heavy phone users, tended to have quicker response times but higher error rates in
cognitive function tests. , 3) In 2010 Dr Benke was lead author of a Safe Work Australia Report that reviewed
the British Standard on safe use of Nanomaterials in the workplace. Recommendations regarding exposure
levels for future ISO Standards and Australian regulators for safe use of Nanomaterials were described. , 4) In
2010 Dr Benke assisted in the formation of the new Australian Mesothelioma Registry, that will assess
occupational exposure to asbestos using OccIDEAS, a new exposure assessment expert system., 5) In 2010 Dr
Benke was co-author of a publication describing the development of an asbestos task exposure matrix by the
NSW Dust Diseases Board. This matrix will assist in the AMR exposure assessment over future years.
Expected future outcomes:
Future Outcomes from this research will include:, 1) Further information regarding the risk of Brain tumors
and mobile phone exposure., 2) Further information regarding the risk of cognitive function and mobile
exposure., 3) Further insights into the causes of Occupational Chronic Obstructive Pulmonary Disease and
asthma., 4) Further insights into occupational chemical exposures and Glioma.
Name of contact:
Professor Malcolm Sim
Email/Phone no. of contact:
malcolm.sim@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 481309
Start Year: 2008
CIA Name: Prof Charles Mackay
End Year: 2009
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Immunology not elsewhere classified
Total funding: $342,540
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am an immunologist working on the molecular basis of immune
responses, particularly inflammatory responses. My research also
focuses on mechanisms of cell migration, and cytokines and
chemokines for immune responses. My research also has considerable
re
Research achievements (from final report):
The two main achievements were progression of a new drug to human clinical trials, and identification of a
receptor, GPR43, as a major regulator of inflammatory responses.
Expected future outcomes:
I will progress our C5aR drug through human clinical trials, and identify mechanisms that connect diet with gut
microbiota, and immune responses.
Name of contact:
Charles Mackay
Email/Phone no. of contact:
c.mackay@me.com
NHMRC Research Achievements - SUMMARY
Grant ID: 490908
CIA Name: Prof Magdalena Plebanski
Admin Inst: Monash University
Main RFCD: Allergy
Total funding: $540,075
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Inhibition of allergic airway inflammation by nanoparticlesInhibition of allergic airway inflammation by
nanoparticles
Lay Description (from application):
Inhaled air pollution particulate matter causes asthma exacerbations, with 'ultrafine' nanoparticles thought to
play a major role. Unexpectedly, we recently found that, by contrast, administration of inert ultrafine
nanoparticles prevents allergic airway inflammation. We will identify the key particle physical and chemical
properties associated with this novel type of disease inhibition, study particle effects in clinically-relevant
disease models and identify mechanisms of action.
Research achievements (from final report):
In this project we defined the parameters and elucidated cellular pathways for our dogma-challenging finding
that lung instillation of inert nanoparticles inhibits allergic airway inflammation, maintaining lung homeostasis
in an otherwise inflammatory setting. Comparing different particle sizes, we showed that both 50 nm and 500
nm particles inhibited allergic inflammation, but that 50 nm particles were more effective, preventing local Th2
immunity as well. Optimal surface chemistry and charge were also established and absence of systemic toxic
effects demonstrated. The pathway via which our inert nanoparticles modulate immunity involves induction of
a novel immunological 'imprint' in the lung, associated with impaired dendritic cell function (T cell stimulatory
capacity, antigen uptake and migration) in the lung and lung-draining lymph node. Nanoparticles also induced
expansion of regulatory T cells, a subset which may further be involved in the maintenance of lung
homeostasis.
Expected future outcomes:
Deep understanding of lung immunobiology and development of synthetic nanoparticles as modulators of lung
function
Name of contact:
Magdalena Plebanski
Email/Phone no. of contact:
magdalena.plebanski@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490977
CIA Name: Prof Magdalena Plebanski
Admin Inst: Monash University
Main RFCD: Cellular Immunology
Total funding: $690,502
Start Year: 2008
End Year: 2013
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I study basic mechanisms of the interaction of pathogens and particles with the immune system, to gain insight
into mechanisms of adjuvanticity, immune evasion and generally immuno-modulation. With this specific
insight I further pursue the development of
Research achievements (from final report):
Defined the new ways in which tiny particles the size of viruses and bacteria interact with the immune system,
changing thus the dogma that breathing in particles is always bad for the health of the lung, and showing that it
is possible for nanotechnology to deliver new therapeutics to prevent asthma, as well as to enable the design of
outstanding vaccines (thus far proven in animal models) against major diseases such as cancer and malaria.
Expected future outcomes:
A clincial trial of our nanovaccines is planned to test their safety and potency in humans with cancer. We will
also define the specific molecular elements which have enabled ceratin nanoparticles to provide a new range of
beneficial lung effects, to further support practical tranlation of our findings.
Name of contact:
Prof. Magdalena Plebanski
Email/Phone no. of contact:
magdalena.plebanski@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 519510
CIA Name: Dr Natalie Borg
Admin Inst: Monash University
Main RFCD: Tumour Immunology
Total funding: $380,559
Start Year: 2008
End Year: 2012
Grant Type: Career Development Fellowships
Title of research award:
The structural basis of T cell recognition in the context of lipid presentation and the CD1 isoformsThe
structural basis of T cell recognition in the context of lipid presentation and the CD1 isoforms
Lay Description (from application):
CD1 molecules are critical in our host-defence against microbial pathogens. They survey our body for
microbial lipids and then present them to our immune system for surveillance by T cell receptors. We aim to
understand how a T cell receptor interacts with a CD1/lipid molecule. This interaction is crucial to the
activation of our immune response and hence the elimination of the microbe. Once understood, this interaction
can potentially be modified and has immunotherapeutic potential.
Research achievements (from final report):
NKT cells are a type of white blood cell that survey lipid fragments captured from within the cell by a
molecule called CD1d. If the lipid is foreign to the body then the NKT cell generates an appropriate immune
response to protect the body. Numerous research achievements were made during this research award. The
NKT/lipid/CD1d interaction was fully described visually (atomic resolution) and functionally. The results
generated were quite unexpected and monumentally transformed the research field. The research conducted
paves the way for the design of lipids that can potentially modulate the immune response and may be effective
towards diseases such as arthritis and atherosclerosis.
Expected future outcomes:
With additional studies of a similar nature, it is expected that we will understand how the precise structure of
the lipid captured by CD1d can dictate the immune response generated by NKT cells. This body of information
will enable us to design lipids of a precise structure to modulate the immune system.
Name of contact:
Natalie Borg
Email/Phone no. of contact:
natalie.borg@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606407
CIA Name: Prof David Jans
Admin Inst: Monash University
Main RFCD: Infectious Diseases
Total funding: $580,196
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of subcellular localisation of respiratory syncytial virus M protein: implications for
pathologyRegulation of subcellular localisation of respiratory syncytial virus M protein: implications for
pathology
Lay Description (from application):
Respiratory syncytial virus (RSV) is the major cause of viral pneumonia in infants and the elderly, causing
more deaths in winter than influenza. We have observed RSV M protein in the nucleus of infected host cells
where it inhibits host cell transcription. We propose to investigate the regulation of nuclear localisation of M by
phosphorylation and binding to cellular factors and its importance to RSV pathogenesis. The results will relate
strongly to future drug and vaccine development.
Research achievements (from final report):
Respiratory Syncytial Virus is the most common cause of lower respiratory tract illness and mortality in infants
worldwide with approximately 200 000 deaths per year. RSV replication occurs completely within the
cytoplasm of an infected cell, yet a single viral protein, Matrix can shuttle in (to modulate host-cell
transcription) and out of the nucleus (critical for viral assembly) at specific times during infection. This project
identified that phosphorylation of M may regulate its nucleocytoplasmic shuttling by modulating interaction
with the host cell microtubule network which acts as a cytoplasmic retention factor and aids viral assembly.
Additionally, we have identified key residues wthin M that modulate host cell transcription irrespective of
nuclear localisation. Understanding the role(s) that M plays in the RSV lifecycle allows us to target these
pathways/interactions specifically as abrogation of M nucleocytoplasmic shuttling significantly reduces viral
titres, thus making M an attractive target for antiviral intervention.
Expected future outcomes:
By understanding the relationship(s) bewteen RSV M protein and host cell proteins we are able to design and
tailor therapeutic strategies that specifically target these interactions and abolish viral replication, without
affecting natural host cell function(s).
Name of contact:
David Jans
Email/Phone no. of contact:
david.jans@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606952
CIA Name: Prof Charles Mackay
Admin Inst: Monash University
Main RFCD: Innate Immunity
Total funding: $549,093
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of immune and inflammatory responses by short chain fatty acids and GPR43Regulation of immune
and inflammatory responses by short chain fatty acids and GPR43
Lay Description (from application):
Innate immune mechanisms provide essential signals that determine the outcome of immune responses. The
identity of these innate mechanisms may provide opportunities for manipulating immune responses, or
controlling inflammatory responses. This proposal centers around a new and little-studied receptor, GPR43,
which binds products of bacterial metabolism. This molecular pathway may explain how diet affect immune
responses.
Research achievements (from final report):
GPR43 deficient mice showed increased inflammation in DSS-induced or TNBS-induced colitis models,
K/BxN serum-induced arthritis model and OVA-induced asthma model. We have dissected additional
mechanisms and, in addition to GPR43 mediated effects, we find a very potent effect of SCFAs operating
through another pathway for development of asthma. This involves promotion of Tregs.
Expected future outcomes:
This research has strengthened the case for the effects of diet on immune and inflammatory responses. we
expect to validate a diet hypothesis for the pathogenesis of numerous inflammatory diseases
Name of contact:
Charles Mackay
Email/Phone no. of contact:
charles.mackay@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1000609
CIA Name: Prof Charles Mackay
Admin Inst: Monash University
Main RFCD: 0
Total funding: $399,998
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Development Grants
Title of research award:
Development of anti-CXCR7 mAbs for the treatment of fibrosisDevelopment of anti-CXCR7 mAbs for the
treatment of fibrosis
Lay Description (from application):
Fibrosis is a serious biological process that occurs in many disease conditions, including cancer, inflammation
and infections. We have produced antibodies to CXCR7, and these antibodies completely inhibit fibrosis in a
mouse model. We plan to develop these antibodies in to a suitable drug for human clinical trials.
Research achievements (from final report):
The CXCR7 mAb was shown to have a clear role in liver fibrosis. However studies on lung fibrosis were
inconclusive as one study in Newcastle looked very encouraging, however this was not reproduced by our
industry collaborator Medimmune. However our skin wound healing showed a clear role for CXCR7 which we
believe is significant finding on the role of this receptor.
Expected future outcomes:
We would like to do more work on fibrosis models, other than lung, to sort out conflicting data. We still hold
some hope that our CXCR7 inhibitor will find a clinical use. We have made an ideal drug, is a matter of
finding the right indication.
Name of contact:
Charles Mackay
Email/Phone no. of contact:
charles.mackay@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1009354
CIA Name: Prof Magdalena Plebanski
Admin Inst: Monash University
Main RFCD: Nanomedicine
Total funding: $637,921
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms of nanoparticle-mediated inhibition of asthmaMechanisms of nanoparticle-mediated inhibition of
asthma
Lay Description (from application):
Ultrafine pollution particles may promote asthma, and there is concern that man-made 'nanoparticles' have a
similar effect. Surprisingly, we found that inert toxin-free nanoparticles inhibit asthma. We propose
nanoparticles do this by leaving a unique ‘imprint’ in the lung. We will explore how this imprint modifies lung
inflammatory and immune regulatory cell function, and investigate particles made from advanced
biodegradable polymers as potential therapeutics for inflammatory lung diseases such as asthma.
Research achievements (from final report):
Changed the dogma that breathing in particles is always bad for the health of the lung, by showing it is possible
for nanoparticles to be designed to affect the lung in ways which render it resistant to develop asthma.
Expected future outcomes:
The patent on the nanoparticles was assigned to the Asthma CRC for commercial development. We will also
define the specific molecular elements which have enabled certain nanoparticles to provide a new range of
beneficial lung effects, to further support practical translation of our findings.
Name of contact:
Prof. Magdalena Plebanski
Email/Phone no. of contact:
magdalena.plebanski@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384423
Start Year: 2006
CIA Name: Prof Colin Robertson
End Year: 2006
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Respiratory Diseases
Total funding: $139,250
Title of research award:
Parent initiated oral prednisolone for acute asthma in children aged 5-11 years: randomised controlled
trialParent initiated oral prednisolone for acute asthma in children aged 5-11 years: randomised controlled trial
Lay Description (from application):
The objective of this trial is to determine whether parents should commence prednisolone (a steroid antiinflammatory drug) for an asthma attack in their child without waiting to see a doctor first. This strategy could
be described as parent initiated prednisolone in asthma (PIPA). PIPA is an important consideration in every
child's asthma management plan, but because of a lack of research evidence the role of PIPA is not clarified in
any of the international asthma guidelines. Hence prednisolone is rarely commenced without waiting for a
preceding medical review. PIPA has the potential to significantly reduce the health and economic burden of the
disease by increasing the proportion of asthma exacerbations managed at home rather than in the emergency
department or hospital. Prednisolone has been shown to be an effective drug when it is given to children with
an asthma attack that is severe enough for them to attend hospital. Whilst it would seem logical that PIPA
should be an effective strategy it is important to recognise that mild attacks are far more common than severe
ones, and the promotion of PIPA as standard practice would be associated with a significant increase in the
frequency prednisolone administration. As such it is important to determine if prednisolone is safe and
effective when commenced in the home setting. The PIPA trial has many unique features: It is community
based, where the vast majority of asthmatic children are managed. The eligibility criteria and dosing schedule
have been chosen to mimic 'real world' management and it will be easy for clinicians and families to interpret
and apply the results. A very large number of children will be involved (308) which has been made feasible by
the trial setting and recruitment methods. Furthermore the protocol has been designed in accordance with the
highest standards specified by the international research community and has been submitted to 'The Lancet' for
pre-trial publication.
Research achievements (from final report):
1.
Recruiting greater than 65% of
eligible children within the entire Barwon region of Victoria.2.
Collecting data on 287 episodes of
acute asthma resulting in parent-initiated treatment with the study medication. By comparison, a previous
research group conducting a similar project in Leicester, England, collected data on 107 episodes of parentinitiated treatment over a three-year period.3.
Maintaining the active participation
of 223 of the 225 children enrolled in the study. 4.Three related publications in peer reviewed journals.
Expected future outcomes:
We expect to complete data collection in the PIPA trial by March 2008. The role of parent-initiated
prednisolone in the management of childhood asthma is an important research question and it is anticipated that
this trial will inform asthma management strategies internationally.
Name of contact:
Dr Peter Vuillermin
Email/Phone no. of contact:
peterv@barwonhealth.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 491233
Start Year: 2008
CIA Name: Prof Katrina Allen
End Year: 2010
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Allergy
Total funding: $551,642
Title of research award:
Population prevalence and environmental-genetic predictors of food allergy in an infant cohortPopulation
prevalence and environmental-genetic predictors of food allergy in an infant cohort
Lay Description (from application):
This study will measure which children are at greatest risk of food allergy. We plan to recruit 5000 children to
test for food allergies, as well as asking a range of questions on different lifestyle factors such as diet and
history of allergies . If positive, participants will be invited to a hospital clinic for tests and treatment. This
will allow us to describe the epidemiology of food allergy, and assist the development of better services for
those with food allergy in the community.
Research achievements (from final report):
The HealthNuts study has become a world-leading food allergy study. With 5,000 12-month-old infants
participating, the study is the largest single-centre food allergy study internationally. The study provided the
first accurate data regarding the prevalence of infant food allergy in Australia, with the results confirming that
food allergy is a serious issue and is more common than previously thought. We found that 8.9% of 12-monthold infants taking part in the study were egg allergic and 3.0% were peanut allergic. Investigation of risk
factors for food allergy is continuing. Early results show that timing of introduction of egg into the infant's diet
may be important in the development of egg allergy. Contrary to previous belief, early introduction of egg into
an infant's diet (between 4-6 months of age) did not increase the risk of egg allergy and even appeared to be
protective, while duration of breastfeeding and age at introduction of first solid foods did not appear to play a
role in the development of egg allergy. These findings are helping to inform the development of evidencebased infant feeding guidelines internationally.
Expected future outcomes:
Investigation of environmental and genetic risk factors for food allergy within the HealthNuts study is
continuing. The role of additional environmental factors such as parental smoking, exposure to pets and use of
antibiotics in the first year of life in the development of food allergy will be explored.
Name of contact:
A/Prof Katie Allen
Email/Phone no. of contact:
katie.allen@rch.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 491246
Start Year: 2008
CIA Name: Prof Lex Doyle
End Year: 2010
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $1,417,605
Title of research award:
Determinants of Health in Adolescence of Extremely Low Birth Weight or Extreme PrematurityDeterminants
of Health in Adolescence of Extremely Low Birth Weight or Extreme Prematurity
Lay Description (from application):
We will uniquely determine the health outcomes at age 16 years of 298 very tiny (birth weight <1000 g) or
preterm (<28 weeks' gestational age) children born in Victoria in 1991-92, compared with 262 normal
birthweight children. We will track the pathways to the various health outcomes from a combination of social,
biological, genetic and environmental influences, some of which have been obtained from detailed assessments
of the children earlier in life, at birth, 2, 5, and 8 years of age.
Research achievements (from final report):
As this study is not yet completed we cannot report any findings at this stage., We have all assessments running
according to protocols and the subjects and their families are enjoying the process overall. , There are no
publications or presentations so far, as we will have no data to analyse until all subjects have been assessed.
Expected future outcomes:
To have a clearer understanding of the problems confronted by those born very tiny (<1000 g) or very early
(<28 weeks' gestation) in the teenage years, and how these problems relate to prior exposures to various
biological and environmental influences.
Name of contact:
Prof Lex Doyle
Email/Phone no. of contact:
lwd@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 546428
Start Year: 2009
CIA Name: A/Pr Mimi Tang
End Year: 2011
Admin Inst: Murdoch Childrens Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Respiratory Diseases
Total funding: $581,893
Title of research award:
Novel Candidate Genes, Lung Function and Allergic Airways DiseaseNovel Candidate Genes, Lung Function
and Allergic Airways Disease
Lay Description (from application):
We propose to study airway remodelling (structural changes to the airway) and in asthma using human samples
and rodent models of asthma. We are particularly interested in investigating the role of trefoil peptide 2 and
relaxin, two genes identified as determining lung function. To do this we need to understand the mechanisms
of airway remodelling and its impact on disease severity in the patient. A strength of this study is availability of
samples from a large study of human asthma.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
Assoc Prof Mimi Tang
Email/Phone no. of contact:
Mimi.tang@rch.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 546498
Start Year: 2009
CIA Name: Dr Adrian Lowe
End Year: 2013
Admin Inst: Murdoch Childrens Research Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Respiratory Diseases
Total funding: $292,639
Title of research award:
Epidemiology of asthma and lung function in Australian teenagersEpidemiology of asthma and lung function
in Australian teenagers
Lay Description (from application):
Asthma is a major health issue, which cause long term illnesses. The causes of asthma are unclear. This is
possibly because asthma is not just one condition, but multiple conditions, each with separate risk factors. This
project will search for specific forms of asthma and their causes, using a group of children that has been
intensively studied since birth.
Research achievements (from final report):
During his training fellowship, Dr Lowe has actively examined the evidence that a range of early life risk
factors may cause asthma. Two highlights from this period are described here. A paper led by Dr Lowe,
published in 2011, examined the role of an infant formula for the prevention of allergic disease. In the second
largest study on this topic to date, he demonstrated that there was no evidence to support current guideline
recommendations that children with a family history of allergic disease should be given hydrolysed formula for
the prevention of eczema. This result was published in the leading international allergy journal, and has
generated both local and international attention, including radio, television and print media coverage. This
evidence is currently being integrated into the literature, and may result in changes to various guidelines.Early
life paracetamol exposure has been suggest as a causal factor for development of asthma, due to causing away
inflamation. A number of studies of limited quality have observed an increased risk. Dr. Lowe led a letter to the
editor, published in the Lancet, highlighting the methodological limitations of the previous studies on this
topic. Following on from this, Dr Lowe published a paper that that demonstrated that, although there is a crude
association between paracetamol and asthma, this association is due to confounding by indication paracetamol is used to treat respiratory tract infections, a known risk factor for asthma - rather than being a true
cause. This paper was published in the BMJ.?????
Expected future outcomes:
Dr Lowe continues his research to identify modifiable risk factors for the development of asthma and allergic
disease, that can reduce the burden of these conditions in our commuinity. He currently leads an intervention
trial to reduce the incidence of eczema by building skin barrier function in infancy.?????
Name of contact:
Adrian Lowe
Email/Phone no. of contact:
Lowe.adrian@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 546500
Start Year: 2009
CIA Name: A/Pr Peter Vuillermin
End Year: 2012
Admin Inst: Murdoch Childrens Research Institute Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Allergy
Total funding: $176,719
Title of research award:
A population based investigation of early life lung development and immune programmingA population based
investigation of early life lung development and immune programming
Lay Description (from application):
Asthma and allergic diseases cost Australia in excess of 7.8 billion per year. We are yet to identify any
substantially effective preventative strategies. The applicant is a highly successful early stage clinicianresearcher based in regional Victoria. This collaborative project will involve extending two existing NHMRC
projects, in addition to establishing a new unselected Australian birth cohort, in to investigate the early life
gene-environment determinants of asthma and allergic disease.
Research achievements (from final report):
As Principal Investigator A/Prof Peter Vuillermin driven the establishment and success of the Barwon Infant
Study (BIS). BIS comprises an unselected prebirth cohort with antenatal recruitment. In addition to detailed
questionnaire measures, the protocol includes collection of an internationally unique array of biological
samples, physiological and clinical outcomes measurements. The objective of BIS is to investigate the interplay
between the modern environment, the microbiome, the epigenome, abnormal immune development and the
early life origins of eczema, food allergy, asthma and atherosclerosis and adverse neurodevelopment. BIS has
thus far secured greater than 4 million AUD in competitive funding, (NHMRC ref 546500, 607370 ,10099044,
1029927 & 1030701).The 3 year reccruitment phase was completed in June 2013 on target (n = 1,155) and on
budget. Participant retention to 1 year is currently over 80% and biospecimens have been successfully collected
on greater than 90% of occasions for each timepoint/specimen. The success of the BIS fieldwork schedule is in
large part due to Peter's engagement with the Barwon community and health services as a local
paediatrician.Other achievements:Published the results of a major clinical trial regarding the role of parentinitiated treatment with oral corticosteroids in the treatment of asthma (British Medical Journal);Published the
first evidence of a cross-sectional association between low vitamin D status and food allergy - one of the first
modifiable risk factors for food allergy to be identified.Established the Child Health Research Unit at Barwon
Health (CHERUB).
Expected future outcomes:
A wide of range of publication regarding the determinants of adverse immune, respiratory, cardiovascular and
neurodevelopmental outcomes during early life. The modern exposures under investigation include
psychological stress, determinants of the human microbiome (e.g. antibiotic exposure and mode of delivery),
diet, activity, sun exposure and vitamin D status and exposure to modern chemicals.
Name of contact:
Peter Vuillermin
Email/Phone no. of contact:
peter.vuillermin@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 437200
CIA Name: Dr Phil Stumbles
Admin Inst: Murdoch University
Main RFCD: Cellular Immunology
Total funding: $491,065
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Cellular and Molecular Pathways Regulating Airway Mucosal Dendritic Cells During Onset of Allergic
Airways InflammationCellular and Molecular Pathways Regulating Airway Mucosal Dendritic Cells During
Onset of Allergic Airways Inflammation
Lay Description (from application):
Allergic airways inflammation (AAI), which leads to debilitating disease such as allergic asthma, is a condition
medaited by the abnormal activity of the immune system towards essentially harmless inhlaed allergens. Two
special cell types of the immmune system that are important in controlloing the onset and persistence of AAI
are known as dendritic cells (DC) and T helper type 2 cells (Th2 cells). DC are located in all parts of the
respiratory tract and are important in providing control signals to Th2 cells to become switched on and start to
react to an inhaled allergen. Th2 cells then generate a variety of signals that initiate an cascade of immune
responses towards the allergen that ultimately can lead to AAI and asthma if left unchecked, however this
process remians relatively poorly understood. This project aims to examine how DC and Th2 interact, and at
what level DC activity can be regulated so that unchecked Th2 immunity to harmless inhaled allergens can be
controlled. The hope is to be able to identify new cellular and molecular pathways that can eventually become
the target for new generations of preventative and therapeutic drugs.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
Dr Phil Stumbles
Email/Phone no. of contact:
p.stumbles@murdoch.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 290274
Start Year: 2004
CIA Name: Dr David Duffy
End Year: 2006
Admin Inst: Queensland Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Allergy
Total funding: $278,000
Title of research award:
Fine mapping of genes underlying asthma and eosinophiliaFine mapping of genes underlying asthma and
eosinophilia
Lay Description (from application):
Asthma is the fourth most common chronic disease in Australia, and is increasing in incidence. Genetic factors
are known to be important modifiers of disease risk, and several genes have been reported in the literature as
being involved in either causing asthma or altering response to therapy. Immunoglobulin E (IgE) level and
eosinophil count are two factors known to be increased in the blood of asthmatics. In two studies by our group,
one of asthma in families, the other of healthy adolescent twins, we showed these measures to be genetically
linked to two different regions in the genome. Closer examination of these regions found several genes that
might be responsible for the linkage. In the present study, we plan to test which of these candidate genes
actually causes elevated IgE level or eosinophil count. The approach is to compare the frequency of a putative
gene in a child expressing that phenotype to that in their parents. Each child receives one copy of a gene from
the father, and one from the mother, making up a complete genotype (two possibly different versions or alleles
of the gene). Since each parent transmitted only one allele to the child, the remaining allele from each parent
can be used to create a normal control genotype, that is guaranteed to come from the same ethnic background
as the asthmatic child. Therefore, we will collect replacement blood samples in those familes where all the
previously DNA has been used up in our earlier study. We will extract DNA, and measure the genotypes of
parents and children at the 6 genes in our two regions that we think most likely to be involved in eosinophil
count or IgE level. This family based test will allow us to decide which genes are genuinely associated with
asthma in our population. We will also test if these genes interact with other genes thought to be asthma risk
factors. Identification of novel genes involved in asthma will help understand and ultimately treat this
condition.
Research achievements (from final report):
This project involves the fine mapping of chromosomal regions genetically linked to allergy related phenotypes
in two large collections of families, one set of families ascertained through a member reporting asthma, the
other set unselected on any phenotype, but demonstrating linkage of eosinophil count on chromosome 2q.We
carried out genotying at 100 SNPs (single nucleotide repeat polymorphisms) in three regions of interest. One of
the candidate regions has been genotyped in 4 replication datasets, and the results were used to prepare an
Australian provisional patent. A paper describing the results of SNP association fine mapping has been
published, and linkage analysis results for those regions are described in 3 other papers.
Expected future outcomes:
The individuals in the eosinophil study described have subsequently undergone genome-wide SNP genotyping
as part of another study, and we are currently following up on our original findings and any new associations.
Name of contact:
David L Duffy
Email/Phone no. of contact:
david.duffy@qimr.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 339436
Start Year: 2005
CIA Name: Prof Anne Kelso
End Year: 2007
Admin Inst: Queensland Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $481,000
Title of research award:
Generation of multipotential memory CD8+ T cellsGeneration of multipotential memory CD8+ T cells
Lay Description (from application):
Vaccines aim to protect against future infections by inducing memory in the immune system so that the host
can react quickly to the next challenge. Defence against viral infections and some cancers depends in part on
activating CD8+ T cells, a class of white blood cell that can recognise and kill infected or malignant cells. The
ideal vaccines against these challenges would therefore generate high numbers of long-lived CD8+ T cells that
are programmed to make the right response if the infection or tumour re-emerges. Little is known about the
programming of memory CD8+ T cells. We have recently found that some of these cells have the potential to
be reprogrammed to display different functions by exposure to new stimuli. This opens up the possibility that
ineffective responses could be improved by using vaccination to control the production of these flexible or
"multipotential" memory cells or to reprogram them once they are formed. Alternatively, effective responses
might be subverted by pathogens to the detriment of the host. The goal of this project is to learn how the first
exposure to an immune challenge influences the development of these multipotential memory CD8+ cells.
Understanding the signals and processes that generate multipotential memory cells will be the first step towards
developing ways to manipulate them to improve immune defence.
Research achievements (from final report):
Vaccines aim to protect against future infections by inducing immunological memory so that the host can react
quickly to the real challenge. Defence against viral infections and some cancers depends in part on activating
CD8+ T cells which can kill infected or malignant cells. The ideal vaccines against these challenges would
generate high numbers of memory CD8+ T cells that are programmed to make the right response if the
infection or tumour re-emerges., At the start of this project, little was known about programming of memory
CD8+ T cells but it was generally thought that, once activated, their functions were fixed. As we had evidence
that some memory cells could be re-programmed to express new functions, the aim of this project was to
determine how signals received during priming influence the development of "flexible" (multipotential)
memory cells. For this purpose, we established a mouse model in which we could activate development of
memory CD8+ T cells against defined stimuli, track their development, isolate them, then measure their
potential to be re-programmed in vitro using a quantitative assay we had previously developed., Our major
findings were that memory cells were heterogeneous in their ability to be re-programmed, that they were
generally more flexible than effector cells and that certain factors, particularly cytokines and T cell receptor
signal strength, affected their functional flexibility. These findings are a step towards developing ways to
manipulate the development of memory cells. This opens up the possibility that ineffective responses could be
improved by using vaccination to control the production of flexible memory cells or to reprogram them once
they have formed.
Expected future outcomes:
The project has contributed to basic knowledge on memory cell differentiation and function which is being
disseminated through publications and presentations. In the longer term, we hope that it will also stimulate
experimentation to manipulate the programming of memory T cells through the design of prophylactic and
therapeutic vaccines.
Name of contact:
Professor Anne Kelso
Email/Phone no. of contact:
anne.kelso@influenzacentre.org
NHMRC Research Achievements - SUMMARY
Grant ID: 389806
Start Year: 2006
CIA Name: Dr David Duffy
End Year: 2010
Admin Inst: Queensland Institute of Medical Research
Grant Type: NHMRC Research
Fellowships
Main RFCD: Genetics not elsewhere classified
Total funding: $548,878
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
My two main areas of research have been the genetics of asthma, and of malignant melanoma.?My melanoma
work focussed on genes affecting number of moles on the skin (notably the IRF4 and MTAP genes) as well as
skin, hair and eye colour (the OCA2, IRF4, MC1R, ASIP and TYR genes). These all have significant effects on
melanoma risk, and could be used for risk prediction, but our main interest is how these genes function and
whether they might be modified. In the case of asthma, I was involved in characterizing effects of several
genes, including ADAM33 and ELF5. I also contributed to work on other cancers (ovarian, prostate) and
diseases (polycystic kidney, diabetes).
Expected future outcomes:
I am currently analysing data on melanoma risk factors from an international consortium. I am also developing
new statistical software for genetic data?????
Name of contact:
David Duffy
Email/Phone no. of contact:
David.Duffy@qimr.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 389838
Start Year: 2006
CIA Name: Dr Patricia Valery
End Year: 2006
Admin Inst: Queensland Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Respiratory Diseases
Total funding: $97,500
Title of research award:
An education intervention for childhood asthma by local Aboriginal and Torres Strait Islander Health
WorkersAn education intervention for childhood asthma by local Aboriginal and Torres Strait Islander Health
Workers
Lay Description (from application):
There are only a few studies on asthma in Aboriginal and Torres Strait Islander children, and those are
restricted to prevalence and hospitalisation data. We have previously shown that the prevalence of childhood
asthma in the Torres is similar to that of mainstream Australia and that children of this region generally have
more severe asthma than children seen in urban areas. Using a model of care appropriate for Aboriginal and
Torres Strait Islander people, with the involvement of local Indigenous health care workers, we have adapted
an asthma information package. With Study 1, we will examine the effect of local health care workers using
this education package to educate children about their asthma. Our hypotheses is that children who receive
additional asthma education by health worker have better asthma control. So we propose a randomized
controlled trial of a culturally appropriate education intervention with children diagnosed with asthma. Enrolled
children will be allocated by chance to one of the two regimes: (1) additional asthma education intervention:
children will receive a personalised booklet (containing individual data eg. growth, photo of the child, health
worker visits etc) that will be used during the medical consultation. They will also have 3 visits from the health
worker for their asthma. (2) no additional intervention (they will receive usual information about asthma at
the consultation and no health worker visit). With Study 2 we will examine the natural history of children with
asthma and asthma-like symptoms and with symptoms suggestive of sleep breathing problems. Two groups of
children previously seen by this team (5 years ago) will be clinically reassessed. Our hypothesis is that short to
medium term history of asthma in Indigenous children in the Torres Strait is similar to non-Indigenous
Australian children where there is a general improvement with age.
Research achievements (from final report):
Indigenous children in the Torres Strait have more severe asthma than mainland non-Indigenous children and
the parental knowledge of asthma there is poor. As involvement of Indigenous health-care workers in asthma
programs seemed likely to be beneficial, we conducted a randomised controlled trial in this region to examine
the benefits of an education intervention, delivered by local Indigenous health-care workers., Eighty-eight
children diagnosed with asthma were, by chance, allocated to receive either three additional asthma education
sessions with a trained Indigenous health-care worker (35 children) or no additional education (53 children).
We found that this education intervention improved some, but not all, asthma outcomes measured in the study.
Carers in the intervention group were significantly better in the 'knowledge of asthma medication' and the
possession of and ability to interpret their child's 'asthma action plan'. Also, children who received the
education intervention missed fewer school days due to wheezing. However, there was no difference between
groups in the main study measure, namely doctor visits for wheezing ('asthma attacks'). When we compared the
study measures 'before intervention' (one year before the study) with 'after intervention', we found an
improvement in all asthma outcomes that were measured., Delivery of a community-based asthma education
program that includes trained Indigenous health-care workers, improves outcomes for Indigenous children who
have asthma. Our findings provide strong support for the effectiveness of a culturally tailored asthma education
program for Indigenous children with this condition. Interventions such at this could significantly benefit rural
communities at the national level.
Expected future outcomes:
We showed that a community-based education program delivered by trained Indigenous health-care workers
improves asthma outcomes in Indigenous children. Our findings provide empirical support for the effectiveness
NHMRC Research Achievements - SUMMARY
of a culturally-tailored asthma education program for Indigenous children with asthma. A larger RCT to study
the efficacy of a similar program for other chronic illness is advocated.
Name of contact:
Patricia C Valery
Email/Phone no. of contact:
Patricia.Valery@qimr.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 613623
Start Year: 2010
CIA Name: Prof Andreas Suhrbier
End Year: 2012
Admin Inst: Queensland Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Signal Transduction
Total funding: $584,183
Title of research award:
The role of macrophage SerpinB2 in inflammationThe role of macrophage SerpinB2 in inflammation
Lay Description (from application):
After infection with viruses, parasites and bacteria the protein SerpinB2 becomes very abundant in
macrophages, which are white blood cells involved in inflammation. Unfortunately, what this protein is doing
is very unclear. We have found that macrophage SerpinB2 dampens the responses of other immune cells. This
grant aims to determine how this is achieved and thereby help resolve the role of this protein in a number of
diseases such as cancer, lupus, asthma and pre-eclampsia.
Research achievements (from final report):
We have now demonstrated clear immune modulation by SerpinB2 expression in three in vivo systems
(vaccination, schistosome infection and HIV infection) with SerpinB2 expression increasing certain Th2 and
decreasing certain Th1 cytokines. This arguably represents the first physiological function for this "enigmatic"
Serpin and is entirely consistent with clinical observations in a series of different clinical conditions (eg
preeclampsia, lupus, asthma, scleroderma, periodontitis). The mechanism of how SerpinB2 does this has been
remarkably elusive; however, we now have compelling data that SerpinB2 is present on the surface of
microparticles, likely attached to the surface via interactions with phosphatidylserine-bound annexin. This is
arguably a game changer for the field, and argues that the main effect of SerpinB2 expression is not in the cell
making SerpinB2 (the target of most research in the field) but on the cells targeted by the released
microparticles. We have recently been awarded an NHMRC project grant to investigate the potential role of
platelets as a potential target for SerpinB2 expressing microparticles.
Expected future outcomes:
Perhaps the most likely application for these discoveries will be in the diagnosis and/or treatment of
preeclampsia where SerpinB2 levels are lower than they are in normal pregnancy and where both Th1 and
platelet dysfunctions characterise the disease. We have recently been awarded a small clinical grant to analyse
microparticle SerpinB2 in pregnancy sera.
Name of contact:
Andreas Suhrbier
Email/Phone no. of contact:
andreasS@qimr.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 613627
Start Year: 2010
CIA Name: Dr Manuel Ferreira
End Year: 2013
Admin Inst: Queensland Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Quantitative Genetics (incl. Disease and Trait Mapping Genetics)
Total funding: $1,697,640
Title of research award:
Finding the genetic causes of asthma: the Australian Asthma Genetics Consortium (AAGC)Finding the genetic
causes of asthma: the Australian Asthma Genetics Consortium (AAGC)
Lay Description (from application):
Asthma is a major burden on individuals and health systems. Despite many decades of research, no major
effective new treatments for asthma have emerged recently. We will establish a large international consortium
to systematically test nearly all known human genes to identify those that influence asthma susceptibility. We
expect to identify pathways not previously implicated in asthma and so lead to a potential breakthrough in the
development of more effective treatments.
Research achievements (from final report):
In Australia, 2 million people suffer from asthma. Of these, only 13% of patients are classified as having wellcontrolled asthma. Poor control of asthma symptoms arises because patients do not respond or do not comply
with the medication prescribed. There is therefore a clinical unmet need to develop drugs that provide not only
good efficacy but, importantly, improved patient compliance. , The aim of this study was to discover genetic
risk factors for asthma by performing a Genome Wide Association Study (GWAS) in people with and without
asthma. Through the identification of genetic variants associated with disease risk, results from our study were
expected to (1) provide new insights into the molecular pathways involved in asthma pathophysiology; and (2)
lead to the development of new disease treatments., By comparing the genomes of >7,000 individuals, and in
collaboration with both national and international researchers, we identified genetic risk factors for asthma or
related allergic diseases near 9 genes, namely IL6R, LRRC32, OVOL1, ACTL9, IL13, MYC, BCL6, ZBTB10
and CLEC16A. These are now confirmed risk genes for asthma and allergic disease more generally., The
asthma risk variant we identified in the IL6R gene increases the blood levels of IL-6R. As such, we
hypothesised that blocking the IL-6 signalling pathway with tocilizumab - an IL-6R inhibitor currently
approved to treat rheumatoid arthritis - may help prevent asthma symptoms. Based on these observations, we
applied for and were awarded a grant from the Queensland Government (CI Ferreira, 2012-2015) to perform a
proof-of-concept phase I/II clinical trial of tocilizumab in 16 asthma patients.
Expected future outcomes:
The data generated in this project will continue to be analysed to search for additional genetic risk factors for
asthma. Furthermore, we are now attempting to validate ZBTB10 and nearby genes as promising new drug
targets for asthma.
Name of contact:
Manuel Ferreira
Email/Phone no. of contact:
manuel.ferreira@qimrberghofer.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1000513
CIA Name: Prof Leslie Yeo
Admin Inst: RMIT University
Main RFCD: Medical Devices
Total funding: $599,142
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Development Grants
Title of research award:
The Respire™ system: Portable Pulmonary Delivery Platform for Rapid, Flexible and Highly Efficient
Treatment of Elderly, Paediatric and Physically-Compromised Patients with Chronic Respiratory DiseasesThe
Respire™ system: Portable Pulmonary Delivery Platform for Rapid, Flexible and Highly Efficient Treatment
of Elderly, Paediatric and Physically-Compromised Patients with Chronic Respiratory Diseases
Lay Description (from application):
The development of a low-cost miniature drug delivery platform for the treatment of chronic respiratory
diseases is proposed. The portable device has already been shown to be significantly more efficient than
currently available asthma inhalers. In addition, the device offers the possibility of dose adjustment to account
for patient variability, such as age and disease severity, as well as a reduction in patient intervention, thus
making it more appropriate for patients unable to self-medicate.
Research achievements (from final report):
A novel, low cost and portable handheld nebulisation device for delivering therapeutic aerosols for the
treatment of asthma and other diseases has been developed and trialled. The results of the study, both in
laboratory testing as well as testing on sheep, do not only show good therapeutic efficiency for the delivery of
asthmatic steroids. In addition, additional trials remarkably demonstrate the potential of the device for the
delivery of plasmid DNA vaccines. This is extremely novel and promises to revolutionise inhalation therapy
for a wide range of conditions including influenza and malaria, especially since they offer a rapid vaccine
production route without significant side effects or an extensive cold chain. More specifically, the results show
that the therapeutic efficacy of an inhaled influenza vaccine in sheep is comparable to that delivered through
injections, therefore opening up the possibility for deployment of the technology in developing nations that
lack medical infrastructure. The results also comprise the first known successful inhalation vaccine with an
unprotected plasmid DNA in a large animal model. Further, the device offers a glimpse of the exciting
possibilities for personalised drug delivery, where the dose can be tailored to an individual's physiological
profile (age, gender, size, disease severity, etc.). As nebulisers do not require hand-breath coordination and
hence training for effective use, they are also suitable for use by infants, the elderly and those suffering from
severe lung conditions.
Expected future outcomes:
The technology is earmarked for clinical trials and we expect commercial take-up and developent of the
prototype into a commercial-ready product in the next 3 years. The possibilities for expanding the scope of
therapeutics that can be delivered is vast: delivery of monoclonal antibodies, peptides and even microRNA,
offering the possibility for lung cancer and multistrain resistant tuberculosis.
Name of contact:
Professor Leslie Yeo
Email/Phone no. of contact:
leslie.yeo@rmit.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 245502
CIA Name: Dr Sandra Anderson
Admin Inst: Royal Prince Alfred Hospital
Main RFCD: Respiratory Diseases
Total funding: $365,250
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Mannitol in the assessment of bronchial responsiveness in airway diseaseMannitol in the assessment of
bronchial responsiveness in airway disease
Lay Description (from application):
The airways of people with asthma respond by narrowing too easily & too much to a wide range of stimuli.
The tests most commonly used to measure airway responsiveness in asthma are the pharmacological agents
methacholine & histamine. When inhaled, they act directly on bronchial muscle causing it to contract & hence
the airways to narrow. We have developed a non-pharmacological test using a dry powder of a sugar mannitol. When inhaled, mannitol causes narrowing of the airways in asthmatics but little or no effect in
healthy subjects. Many asthmatics respond to mannitol even when they have few symptoms of asthma.
Mannitol causes the airways to narrow 'indirectly' by causing the release of substances from inflammatory cells
in the airways (e.g. histamine, leukotrienes & prostaglandins) that cause the muscle to contract. After the
inflammation has cleared, either by treatment with inhaled steroids or spontaneously, the response to mannitol
is close to healthy subjects. Thus the response to mannitol depends on the presence of inflammation & loss of
responsiveness means resolution of inflammation. The significance of this is that the mannitol test may be used
as an 'inflammometer'. It would be important if airway responsiveness to mannitol could be used to identify
individuals with airway diseases other than asthma, (chronic bronchitis, & chronic obstructive lung disease)
who could benefit from treatment with inhaled steroids. This would be significant as there is currently no test
to identify those individuals & there are unwanted effects from using steroids. Further, it may be possible to
use mannitol to identify individuals with other inflammatory diseases who may be at risk of developing
asthma. Some people with asthma, chronic bronchitis and chronic obstructive lung disease have increased
levels of oxidative stress. We wish to identify those people and to measure change after treatment with
steroids.
Research achievements (from final report):
We report that the attack of asthma provoked by inhaling a dry powder preparation of the osmotic agent
mannitol (AridolTM, Pharmaxis Ltd NSW) is associated with an increase in the urinary excretion of
prostaglandin (metabolite of PGD2) & is blocked by inhaling 40 mg of sodium cromoglycate (SCG). The
increase in leukotriene excretion was not significantly affected by the SCG. Similar results occurred after 12
mcgs of the beta 2 agonist eformoterol. This study provided evidence that the mechanism whereby mannitol
causes bronchoconstriction is via the release of mast cell mediators and the cells are close to the airway
surface. (Brannan JD et al Eur Respir J 2006; 27:944-50) , We report similar finding on mediator excretion
when an attack of asthma is provoked by breathing dry air at high flow rates, as occurs with exercise. The
increase in PGD2 excretion is inhibited following inhalation of 1500 mcgs of beclomethasone diproprionate 5
hrs before challenge. This is the first study reporting an acute effect of corticosteroid on mast cell release of a
mediator. It is not known if the effect is direct or indirect. (Kippelen P et al Med Sci Sports Exerc 2010; 42(2)
:273-80), We made a novel observation on the refractory period that occurs in 50% of asthmatics following
mannitol challenge. We measured the change in urinary excretion following two mannitol challenges approx 1
hour apart. Those subjects who had the levels of urinary mediators on the first challenge were the most
refractory to the second challenge with mannitol. This finding suggests that the smooth muscle becomes
tolerant to the mediators released in response to the initial challenge. This is evidence for an important
'protective' mechanism in asthma. (Larsson et al Abstract Eur Respir J 2009). The long paper has been
submitted for publication August 2010.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Understanding the mechanism of action of these challenge tests is important to developing drugs for prevention
of exercise-induced asthma that is common in people with asthma. Mannitol and hypernea of dry air have the
advantage over pharmacological stimuli in that they simulate the attacks of asthma that occur in daily life.
Name of contact:
Sandra Anderson
Email/Phone no. of contact:
sandra.anderson@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 343000
CIA Name: Dr Evangelia Daviskas
Admin Inst: Royal Prince Alfred Hospital
Main RFCD: Respiratory Diseases
Total funding: $324,100
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Inhaled mannitol for the treatment of mucociliary dysfunction- Its effect and mechanisms on the clearance of
mucusInhaled mannitol for the treatment of mucociliary dysfunction- Its effect and mechanisms on the
clearance of mucus
Lay Description (from application):
Excessive secretion of mucus is a problem in asthma and bronchiectasis. Mucus is secreted from submucosal
glands and goblet cells as a result of inflammation present in the airways. Excessive mucus is not easily
transported by the cilia (hair like structures) in the airways and accumulation leads to productive cough and to
recurrent infections. Cough is a secondary mechanism to clear mucus when the mucociliary system fails.
Cough generates high airflow rates that can move mucus. However, patients with moderately to severely
obstructed airways cannot generate high airflow rates. In addition, cough becomes very inefficient in moving
mucus if it is sticky and viscous. As the cilia cannot transport large quantities of mucus the best approach is to
alter the properties of mucus that would facilitate cough clearance. Increased hydration of mucus could
change its surface and rheological properties. Increased hydration can be achieved by the osmotic movement
of water into the airway lumen in response to inhaling an aerosol of salt or sugar. We have evidence using
radioactive aerosols, that mannitol, a sugar, increases clearance of mucus acutely in patients with excessive
secretions. We also have new evidence that mannitol taken daily over two weeks increases the health status in
patients with bronchiectasis. Further we now have preliminary data demonstrating that mannitol changes the
surface properties of mucus. We aim to study the properties of mucus in relation to its clearance in vivo in
humans. This has not been done before. If we can demonstrate that changes in clearance in response to
mannitol relate to the changes in mucus then we will be able to easily evaluate current treatments and doses for
patients with excessive secretions and to identify new treatments. Mannitol is a potential treatment for
diseases with excessive secretions and understanding of how it works will hopefully lead to better outcomes for
patients.
Research achievements (from final report):
We confirmed that clearance of mucus increases in response to mannitol in patients with bronchiectasis. We
further showed that this beneficial effect of mannitol is increased when the dose of mannitol is increased. Our
findings support doses of mannitol greater than 400 mg for achieving clearance of mucus three-fold from
baseline clearance and for achieving long-term clinical outcomes in patients with bronchiectasis. In addition we
showed that clearance of mucus can be further enhanced if administration of mannitol is followed shortly after
by some cough manoeuvres. Our findings provide guidance concerning the dose of mannitol for treatment in
patients with bronchiectasis and for clinical trials with a large number of subjects to show the long-term
clinical effect. (Daviskas et al Eur Respir J 2008; 31: 765-772)., We further confirmed that inhaled mannitol
and voluntary repetitive coughing improves the sputum physical proprerties (hydration, surface and rheology)
in bronchiectasis patients, however this effect is not dose dependent. The important finding from these studies
was that the changes in the sputum sputum properties cannot predict the efficacy of mucociliary and cough
clearance in response to treatment. (Daviskas et al Respir Med 2010; 104: 371-377). These studies confirmed
the importance of increasing the hydration in the airway lumen in hypersecretory diseases., Our studies in
asthmatics with mucociliary dysfunction showed that inhaled mannitol, when administered after eformoterol,
increases mucociliary and cough clearance even in the small airways. Inhaled mannitol even at a low dose (240
mg) in association with cough improved clearance of mucus and may prove benefial in clearing mucus
effectively long-term in asthmatics with mucociliary dysfunction. (Daviskas et al Respir Med 2010, doi:
10.1016/j.rmed.2010.05.019).
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Inhaled mannitol increases the hydration and reduces the surface and rheological properties of mucus. These
changes in the mucus physical properties are important for an improvement in mucus clearance to be achieved.
As a result, inhaled mannitol is a potential treatment in diseases with mucociliary dysfuncton such as
bronchiectasis and asthma.
Name of contact:
Dr Evangelia Daviskas
Email/Phone no. of contact:
daviskas@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 169901
CIA Name: A/Pr Alan James
Admin Inst: Sir Charles Gairdner Hospital
Main RFCD: Respiratory Diseases
Total funding: $390,509
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Airway inflammation in asthma and chronic obstructive pulmonary diseaseAirway inflammation in asthma and
chronic obstructive pulmonary disease
Lay Description (from application):
In chronic diseases of the airway such as asthma and airway narrowing due to cigarette smoking - chronic
obstructive pulmonary disease (COPD), the airways show inflammation (increased numbers of cells and their
products) and remodelling (increased thickness and scarring) which persist for many years, possibly
indefinitely. The exact mechanisms by which inflammation persists in the airway wall in asthma and COPD
are unknown. We and others have shown that greater numbers of memory T-lymphocytes (T-cells) are present
in the airway wall in asthma and COPD. T-cells orchestrate the processes involved in inflammation. We have
hypothesised that the persistence of airway inflammation in asthma and COPD results from the proliferation of
memory T-cells within the airway wall. Unlike na ve T-cells, memory T-cells have previously been stimulated
and can easily be activated to proliferate and promote inflammation by other cells which are fixed in the
airway. Data from our current work examining this process suggests that, although cells fixed in the airway
such as fibroblasts and macrophages are activated in asthma and COPD and may activate T-cells, they do not
seem to be causing T-cell proliferation. We now wish to extend these studies by determinimg if memory Tlymphocytes are proliferating in the airway wall within aggregations of lymphoid cells which act like lymph
nodes and promote T-cell growth. To do this we will compare the number of these aggregations and the types
of T-cells they contain in mild and severe cases of asthma and COPD with those in normal subjects. This work
will provide new knowledge to help understand the mechanisms for the persistance of airway inflammation in
asthma and COPD and may thereby also provide a focus for effective treatments of these condition.
Research achievements (from final report):
The general aim of this study was to examine mechanisms of persistent inflammation that result in the very
common chronic airways diseases asthma and chronic obstructive pulmonary disease (COPD), which is
overwhelmingly related to smoking. The project found: Firstly, that mast cells were most densely populated on
the airway smooth muscle and mucous glands, and that their degranulation is increased in asthma in relation to
severity and the amount of mucus in the airway lumen. These results have refocussed attention on this
important cell in asthma. Secondly, we found that aggregations of lymphoid cells (mainly T and B lymphocytes
and a small percentage of antigen presenting cells) are common in the outer part of the airway wall and are
increased in size in cases of asthma and in smokers with and without COPD where the seggregation of T and B
cells was reduced. Vascular structures were increased in severe cases of asthma. Airways with aggregations
had increased wall thickness and more smooth muscle. These aggregations may therefore be a local site of
activation of inflammatory cells and require further investigation as targets for treatment. Thirdly, we
demonstrated that in central airways the thickness of the airway reticular basement membrane, which can be
readily biopsied, is related to the thickness of the airway as a whole and of the airway smooth muscle. Thus,
biopsies of central airways may provide information about airway remodeling which will be useful for
monitoring asthma severity and the effects of treatment. Fourthly, we have shown that the increased area of
airway smooth muscle in cases of asthma is not associated with increased markers of proliferation, raising the
possibility that the increased smooth muscle may be present from (or before) the initial onset of asthma. Finally
we have demonstrated that in mild and severe asthma, activated lymphocytes are resistant to cell death, which
will prolong their activity in the airway wall.
Expected future outcomes:
We will report the frequency of inhibitory factors which increase the resistance of activated lymphocytes to cell
death (apoptosis) in asthma. We will examine the degree of activation of antigen presenting cells in
NHMRC Research Achievements - SUMMARY
aggregations of lymphoid cells and we will report differences between cases of asthma and chronic obstructive
pulmonary disease in smokers with regard to lymphoid aggregates.
Name of contact:
Alan James
Email/Phone no. of contact:
ajames@it.net.au
NHMRC Research Achievements - SUMMARY
Grant ID: 343601
CIA Name: A/Pr Alan James
Admin Inst: Sir Charles Gairdner Hospital
Main RFCD: Respiratory Diseases
Total funding: $286,250
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Hyperplasia and hypertrophy of airway smooth muscle in asthmaHyperplasia and hypertrophy of airway
smooth muscle in asthma
Lay Description (from application):
Asthma is common in Australia with significant morbidity and it is the 6th Australian National Health Priority.
Examination of the airways in asthma shows increased thickness of the airway wall (remodeling), and
inflammation. Most long-term asthma treatment is currently focussed on treating inflammation. Since the
contribution of smooth muscle to remodeling and excessive airway narrowing is crucial and may be largely
independent of airway inflammation, new treatments aimed at the smooth muscle are needed. Treatments must
be based on knowledge of the factors which result in more smooth muscle - hypertrophy (enlargement of cells),
hyperplasia (more cells) or deposition of proteins (extracellular matrix) between the muscle cells. Matrix is
produced by airway myofibroblasts which are more numerous in asthma. These various contributing factors
have different signals that can be targeted for treatment, however, information regarding their relative
importance is scant. We propose to examine cases of mild and severe asthma using archived tissue blocks in a
multi-centre collaborative study using stereological techniques not previously applied to the airway in man.
This study is important because it will: 1. Yield new data regarding the degree to which hyperplasia,
hypertrophy and increased extracellular matrix vary in the airways; 2. Provide direction for the development of
treatments of increased smooth muscle in asthma; 3. Provide relevance and direction to animal and tissue
studies of airway smooth muscle; 4. Yield new information on the number of myofibroblasts in mild and severe
asthma; 5. Yield new information on the effects of corticosteroids on smooth muscle, extracellular matrix and
myofibroblasts in severe, fatal asthma, and 6. Relate increased smooth muscle to increased extracellular matrix,
numbers of myofibroblasts and other airway wall dimensions including those close to the airway surface.
These may be used to monitor airway pathology in asthma.
Research achievements (from final report):
Asthmatics have a thicker layer of smooth muscle around their airways, especially if their disease is severe, and
it causes excessive narrowing of the airways. This layer is made up of muscle cells, and tissue in between the
cells, called matrix. No-one knows if more cells, more matrix or larger cells contribute to the thick layer in
most cases asthma and that was the aim of this project. To achieve these aims, we studied postmortem lung
tissue from persons dying of asthma or other causes but who did not have other lung disease. We were able to
bring together a large number of cases that had been studied by colleagues around the world and around
Australia so that we could allow for the effects of different airway size, smoking, age and sex. We found that
increased thickness of the airway smooth muscle layer in asthma is related to the severity of asthma but that
there was only small effects of age or smoking and no effect of how long the asthma had been present or at
what age it began. These findings suggested to us that the increased thickness of the smooth muscle layer
happened early in the history of asthma and could even have preceded the onset of asthma symptoms. This
makes us think about how and when asthma might begin. We have also found that we can apply new
stereology techniques to airway tissues on a large scale using thick and thin sections to count cell numbers, and
assess the amount of matrix and size of cells, respectively. So far, we have found that in the smooth muscle
layer in asthma, the proportions of matrix and muscle are similar in asthma and non-asthma cases. But: a)
because the density (number per volume) of cells is decreased in asthma, it appears that the average cell size is
greater in asthma; and b) because the layer of smooth muscle is increased in asthma, the total number of muscle
cells per length of airway is also increased. These findings will point to new ways of exploring the causes of
and devising treatments for asthma.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Our further analyses will examine the effects of asthma severity, age and smoking on the number and size of
smooth muscle cells and the amount of matrix. This will tell us how asthma may vary between individuals.
Name of contact:
A/Prof Alan James
Email/Phone no. of contact:
alj@westnet.com.au
NHMRC Research Achievements - SUMMARY
Grant ID: 446800
CIA Name: A/Pr Alan James
Admin Inst: Sir Charles Gairdner Hospital
Main RFCD: Respiratory Diseases
Total funding: $298,055
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Assessment of airway smooth muscle hypertrophy in asthma and chronic obstructive pulmonary disease
(COPD)Assessment of airway smooth muscle hypertrophy in asthma and chronic obstructive pulmonary
disease (COPD)
Lay Description (from application):
Asthma and chronic obstructive pulmonary disease (COPD) are common in the Australian community. The
cause of asthma is unknown and although COPD is most often due to smoking cigarettes it remains unknown
why it develops only in some smokers and in some non-smokers. The pathology of asthma and COPD
includes increased thickness of the airway smooth muscle layer. In asthma this is associated with relatively
normal airway lumen size and intermittent, excessive airway narrowing whereas in COPD it is associated with
fixed narrowing of the airway lumens. The increased smooth muscle layer might result from more or bigger
smooth muscle cells or from more connective tissue (matrix) between the muscle cells. This project aims to
determine which of these 3 factors causes the increased thickness of the smooth muscle layer in asthma and
COPD. We hypothesise that in asthma there are more muscle cells and more matrix, and that in COPD there is
only more matrix. These differences would account for the different behaviour of the airways in asthma and
COPD. Currently there is no useful or practical method to measure the amount of matrix in the airway wall,
especially in the smooth muscle. This project will study the amount of matrix and muscle in very thin airway
sections (< 1 m) from a large number of cases of asthma and COPD to allow, for the first time, accurate
assessment of the fractions of matrix and muscle in the smooth muscle layer, since they barely overlap on these
thin sections. The results of this study are important because they will: differentiate between mechanisms of
increased thickness of the airway smooth muscle layer in asthma and COPD and therefore identify different
prevention and treatment strategies; help to develop a method of monitoring airway remodeling in airway
diseases that can be applied to bronchial biopsies.
Research achievements (from final report):
The work supported by this project grant has shown, for the first time, that the amount of smooth muscle in the
airway wall of patients with asthma is increased, not in relation to the duraion of asthma, but in relation to the
severity of asthma. This tells us that, since the severity of asthma remains stable in most patients with asthma
over long periods, that the amount of airway smooth muscle is probably determined very early in the natural
history of asthma and changes very little after. This departs form the current view that airway inflammation
results in progressive remodeling of the airway. It further suggests that intervention to control the amount of
airway smooth muscle early in life (or in the natural history of asthma) may be crucial to the prevention of
moderate or severe asthma. In other work, the project has shown that the tissue between smooth muscle cells,
the extracellular matrix, is different in type but not relative amount, in patients with asthma, whereas in chronic
obstructive pulmonary disease (COPD), as seen in many smokers, the matrix is increased in amount. These
interesting findings suggest that changes inh the matrix may alter the behaviour of airway smooth muscle in
asthma and lead to fixed narrowing of the airways in COPD. This has implications for future strategies of
treatment for these common diseases. For example, manipulation of the type of matrix within the airway might
reduce the ability of the airway smooth muscle to contract in asthma, and alteration of the matrix in COPD may
release the chronic constriction of the airways in this disease, allowing some patients to breathe more freely.
Lastly, in asthma the increase in the layer of airway smooth muscle is due to an increase in the size of
individual muscle cells, an increase in the total number of airway smooth muscle cells and an increase in the
amount of matrix. The abnormalities that drive these changes represent future targets for new therapies.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Studies continue to examine the contribution of these various processes (increased smooth mucle cell number
or size, or increased matrix) to COPD. Differences between asthma and COPD will help understand why
COPD is resistant to therapy.
Name of contact:
Alan James
Email/Phone no. of contact:
Alan.James.SCGH@health.wa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 618700
CIA Name: Prof Alan James
Admin Inst: Sir Charles Gairdner Hospital
Main RFCD: Respiratory Diseases
Total funding: $500,594
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms of airway narrowing in eosinophilic and non-eosinophilic asthmaMechanisms of airway
narrowing in eosinophilic and non-eosinophilic asthma
Lay Description (from application):
Asthma is associated with excessive airway narrowing, increased thickness of the airway wall and
inflammation, most typically with eosinophils. However, 50% of cases have few eosinophils and respond less
well to current treatments. This project will examine differences in airway structure between patients with or
without eosinophils, using post-mortem tissue, as part of an international research collaboration.
Research achievements (from final report):
Variable and excessive airway narrowing results in the variable symptoms diagnosed as asthma. Excessive
airway narrowing results from altered airway structure (remodeling) and inflammation. We hypothesised that
the mechanisms of excessive airway narrowing may differ in cases with different types of inflammation. In 150
subjects, we have compared airway structure, muscle contraction and mucus deposition in cases of asthma with
or without inflammation characterised by eosinophils (white cells related to allergy). Small and large airways
were included in the study. Our results have shown that following: first, the age and sex of the cases with
asthma or the structure of the airways did not distinguish cases with or without eosinophilic airway
inflammation, however eosinophils were associated with more severe asthma. Second, increased thickness of
the layer of airway smooth muscle and of the matrix layer under the epithelium was distributed in distinct
patterns, involving the large airways only in some cases, the large and small airways in some cases but the
small airways in less than 10% of cases. Third, the areas of remodeling were always associated with increased
eosinophil numbers. However increased numbers of neutrophils (white cells related to infection and irritants)
did not match the distribution of remodelling in that they were observed in both the large and small airways but
only in cases where remodeling was confined to the large airways. The type of smooth muscle layer
remodeling (more or larger smooth muscle cells or increased matrix) was not related to the type of
inflammation.
Expected future outcomes:
Our results will be published in peer-reviewed literature and presented at national and international scientific
fora. Follow-up of this work will include the pursuance of possible mechanisms of airway remodeling in
neutrophilic asthma, especially its relationship to obesity and specific symptoms such as cough and phlegm.
Name of contact:
Clinical Professor Alan James
Email/Phone no. of contact:
Alan.James.SCGH@health.wa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 395512
Start Year: 2006
CIA Name: Prof Michael Parker
End Year: 2008
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $509,018
Title of research award:
Determining the structure of a soluble cytokine receptor complexDetermining the structure of a soluble
cytokine receptor complex
Lay Description (from application):
There is a pressing need to develop improved therapeutics to treat many forms of cancer and respiratory
diseases. This proposal concerns the biochemical investigation of a group of protein hormones and their
associated receptors that are implicated in blood cell cancers and for which current treatments are only partly
effective . Our work will focus on determining the 3-dimensional shape and function of this group of proteins
in complex with one another which will provide us with an understanding of how these proteins
"communicate" with one another. This information may provide a basis for the design of new drugs that can
specifically block the activity of these protein hormones, thereby providing new treatment possibilities for
these blood cell cancers.
Research achievements (from final report):
We unravelled the 3D structure of a cell signalling receptor found on the surface of blood cells which, when
damaged, is responsible for diseases such as leukaemia and inflammatory diseases such as asthma and arthritis.
This discovery helps to explain, for the first time, how this receptor is activated and will form the springboard
for the development of new treatments.
Expected future outcomes:
To maximise the drug development opportunities of this discovery both Institutes involved in the discovery
have recently signed an agreement with biopharmaceutical company CSL Limited. Under the agreement the
Institutes will work with CSL to discover and develop new therapeutic antibodies to treat certain types of
leukaemia and inflammatory diseases.
Name of contact:
Professor Michael Parker
Email/Phone no. of contact:
mparker@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299005
CIA Name: A/Pr Peter Zalewski
Admin Inst: University of Adelaide
Main RFCD: Allergy
Total funding: $224,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Role of zinc in the respiratory epithelium and asthmaRole of zinc in the respiratory epithelium and asthma
Lay Description (from application):
This project will use a panel of Zinquin-derived Zn fluorophores developed in our laboratory, as well as probes
for the mammalian family of vesicular ZnT transporters, to carry out a study of the normal physiology of Zn in
the respiratory system and potential abnormalities of this in patients with chronic inflammatory respiratory
disease (asthma, COPD, chronic smoking). Chronic inflammatory diseases of the respiratory tract affect a
significant proportion of the Australian community. For example, asthma affects 12% of adults and amongst
these, 15% waken weekly or more often with their asthma while 6% are hospitalized annually. There is a need
to understand the basic mechanisms underlying these diseases so that new strategies can be developed to
modify bronchocondtriction and inflammation. The project will provide new knowledge concerning the
physiology of Zn in the respiratory epithelium and interactions between Zn deficiency and oxidants on injury in
the respiratory tract. The usefulness of easily accessible nasal epithelial cells as a measure of Zn and Zn
transporter levels deeper in the respiratory tract will be assessed. The project encompasses a number of fields
and utilizes in vitro cellular and animal models, as well as tissues from human subjects.
Research achievements (from final report):
Chronic inflammatory respiratory disease (asthma, COPD, chronic smoking) affects a significant proportion of
the Australian community. For example, asthma affects 12% of adults and, amongst these, 15% waken weekly
or more often with their asthma while 6% are hospitalized annually. The incidence of asthma is even higher in
young Australian children. There is a need to understand the basic mechanisms underlying these diseases so
that new strategies can be developed to modify bronchoconstriction and inflammation and better control the
disease. This project has provided new knowledge concerning the physiology of the essential dietary metal zinc
in the respiratory epithelium and its deficiency in asthmatics. Zinc is particularly important for its protection of
tissues against oxidation. Using specially-engineered chemical probes for zinc (developed by us) we have been
the first to show that there is a rich lining of zinc along the respiratory tract in normal humans and animals and
that this zinc is lost in inflamed airways of asthmatic mice. Next, we showed that depletion of this protective
zinc rendered the lung epithelial cells very susceptible to damage and led to a worsening of the inflammation.
A major unanswered question is how dietary zinc passes from the blood to the respiratory epithelium. Our
studies have now identified a key molecule in this transport of zinc, namely ZnT4. Loss of ZnT4 occurs in the
epithelium of asthmatic mice and this may provide a clue to why some asthmatics become zinc-deficient.
Finally, we showed that supplements of zinc were able to suppress some of the airway inflammation in mice.
Expected future outcomes:
We are now extending these findings to determine: 1) How can we monitor levels of airway zinc in humans by
non-invasive means? 2) How can we best supplement airway zinc levels in humans and 3) How does zinc act
to prevent airway inflammation? The latter is the subject of our NHMRC funded grant for 2008-2010.
Name of contact:
Dr Peter Zalewski
Email/Phone no. of contact:
peter.zalewski@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299024
CIA Name: Prof Justin Beilby
Admin Inst: University of Adelaide
Main RFCD: Primary Health Care
Total funding: $563,625
Start Year: 2004
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Systematic practice-based asthma care in the Australian settingSystematic practice-based asthma care in the
Australian setting
Lay Description (from application):
Asthma is an illness which increasingly is affecting the health and quality of life of millions of Australians.
Much effort has been focused in recent years on ways of improving the management of those people who
suffer from moderate and severe asthma. A recent government initiative has been to promote the use of the 3+
Visit Plan, which encourages a more proactive, systematic approach to assessing and treating asthma in general
practice. There is currently no evidence about exactly how practices can best be organized to provide this
systematic care, in a way which improves the process of care and the health outcomes for patients. This study
aims to evaluate the effectiveness of changing aspects of practice organization and structure, such as setting up
registers of asthma patients, providing recalls or reminders to patients to come in for regular review, having the
GPs provide education and self-management skills to patients, focusing on the contributions which practice
staff can make to the process, and initiating quality assurance measures such as audit and feedback to the GPs
about their quality of care. We anticipate that these changes will provide positive benefits for the patients, but
will also investigate what it costs the practices, patients and government to bring these changes about, within
the perspective of efficiency and cost-effectiveness. The evidence generated by this study will provide an
excellent base for providing advice to policy makers, as well as contributing to the development of bestpractice models of care for asthma patients in general practice.
Research achievements (from final report):
This 12-month trial aimed to discover whether taking a more comprehensive and systematic approach to
management of asthma would lead to improved health outcomes for patients with moderate or severe asthma.
We found that having a register of asthma patients, and sending them a postcard reminder for a specific asthma
review with the GP, led to just under half the patients making such an appointment. , Those who attended
found it useful, as it enabled patients and GPs to focus on asthma management, and led to better understanding
and increased confidence in their ability to control their asthma. The number of patients provided with a written
asthma action plan increased significantly. However, more objective measures of health (such as frequency of
asthma symptoms, lung function measures, days off work, etc) found no statistically significant improvement
in patients who were in the group invited to have the review, compared with those who received their usual
care from their doctors. , Despite this, there were trends towards improvement in many of these areas, as well
as in patients' quality of life. What is not clear is whether these improvements would continue over the longer
term. This research suggests that there may be some patients who would benefit from this type of prompted
appointment, but that more work needs to be done to identify exactly which patients would find it of value, and
what would motivate them to attend for this review when they are well.
Expected future outcomes:
This trial may lead to further valuable research into the patient perspective on management of asthma.
Name of contact:
Prof Justin Beilby
Email/Phone no. of contact:
justin.beilby@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 349573
CIA Name: Prof Justin Beilby
Admin Inst: University of Adelaide
Main RFCD: Respiratory Diseases
Total funding: $500,000
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Strategic Awards
Title of research award:
Spirometry and asthma management in children and adults in general practice.Spirometry and asthma
management in children and adults in general practice.
Lay Description (from application):
Measurement of airflow obstruction, as measured by spirometry, is a vital element in the management of
people with asthma. This study aims to examine the potential benefits to patients of using spirometry in the
management of asthma in children and adults.
Research achievements (from final report):
This study into the benefits of general practices using spirometry testing to help in managing asthma, was
important in providing evidence that clinicians and governments can use in deciding whether to give this a
priority in the future. GPs and nurses in a selection of practices were thoroughly trained in how to perform and
interpret spirometry testing and they felt this training was very useful. However, it do not result in much of an
increase in practices doing spirometry for their patients. We were not able to prove that it made any overall
difference to the quality of care being provided to these patients for their asthma, or to the asthma symptoms
and quality of life of the patients, compared to those attending practices which had not had the training and
encouragement to do spirometry regularly. These findings applied to both adults and children. , However, this
does not mean that GPs should not continue to use spirometry for accurate diagnosis of asthma (especially to
differentiate it from COPD in older patients) nor that some individual patients may not have benefited when
their GP did spirometry and, as a result, changed their medications or provided asthma education. It does,
however, suggest that investing time and money in training for GPs and nurses and promoting regular
performance of spirometry in general practice, is not worthwhile on its own, and may be more effective and
feasible if integrated into a complete chronic respiratory disease management model of care.
Expected future outcomes:
It may be possible to further this work by identifying specific groups of asthma patient who would find this
testing beneficial. It may lead to research into alternative ways of providing spirometry services to the
community, rather than through every general practice, perhaps as part of a complete respiratory care package.
Name of contact:
Prof Justin Beilby
Email/Phone no. of contact:
justin.beilby@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 399123
CIA Name: A/Pr Simon Barry
Admin Inst: University of Adelaide
Main RFCD: Cellular Immunology
Total funding: $483,273
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
The molecular identification of FoxP3 +ve regulatory T cellsThe molecular identification of FoxP3 +ve
regulatory T cells
Lay Description (from application):
The immune system has a series of checks and balances in place to distinguish foreign bodies from normal, or
self-antigens. In healthy individuals this prevents the immune system from attacking the cells and tissues of the
body, food proteins, and the beneficial bacteria of the gut. However in autoimmune disease the system
becomes imbalanced, allowing reactions to benign antigens, causing diseases such as diabetes, asthma and
rheumatoid arthritis. One of the key players in the maintenance of a healthy immune system is a specialized set
of T cells known as T Regulatory cells. These cells are rare, at 1-4% of all T cells, yet are potent modulators of
other T cells, and can prevent the activation of a T cell if it is reacting to a self-antigen. If they can control the
cause of autoimmune disease, and patient Treg cells can be manipulated, it may be possible to use them
therapeutically. Recently the switch that is required to generate regulatory cells was identified from patients
with a rare autoimmune disease called Immunodysregulation, polyendocrynopathy, enteropathy, X-linked
syndrome or IPEX. A mouse disease, Scurfy, with similar symptoms, is caused by the same mutations. The
mutated gene encodes a protein, FoxP3, and this protein is able to bind to other genes in T cells and regulate
their function. Without this protein, there are no T regulatory cells, resulting in autoimmune disorders. At this
time there is very little known about how the FoxP3 gene is able to make a T cell become a regulatory T cell,
and nothing is known about the genes that are turned off and on to facilitate this. If we can understand better
the role of this protein, FoxP3, in the generation and maintenance of T cells with regulatory function, we may
better be able to diagnose and treat autoimmune diseases, and this knowledge will have broad application to
many autoimmune disorders.
Research achievements (from final report):
The major aims of the grant have been achieved as we have now performed 4 chromatin immunoprecipitationarrays (chIP-chip) from biological replicate nTreg cells with our foxp3 immunoprecipitation protocol. We have
performed duplicate promoter arrays and duplicate whole genome arrays, and find over 90% agreement
between the promoter arrays and the whole genome arrays. We are among the first in Australia to perform
human chip-chip for a transcription factor and currently there are no published data for the targets of human
FoxP3, giving us a world first human foxP3 target gene set. The final goal of this grant was confirming by
quantitative-PCR that the ChIP material is enriched for these key target genes, and validation of the regulation
of these genes at the mRNA level. This is now complete, and in preparation for publication. We are now in the
process of testing these genes to define their role in Treg function using lentiviral overexpression or shRNAi.
Expected future outcomes:
We have developed a world first profile of the genes regulated by human foxp3, have discovered a novel Treg
biomarker, and have started to analyse Treg genes in fuctional assays. This may lead to novel therapeutic
targets, and modulation of Treg function will be applicable in autoimmune diseases and transplant tolerisation.
Name of contact:
Dr Simon C Aarry
Email/Phone no. of contact:
simon.barry@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 399124
CIA Name: A/Pr Robert Adams
Admin Inst: University of Adelaide
Main RFCD: Geriatrics and Gerontology
Total funding: $397,155
Start Year: 2007
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Establishing the safety and effectiveness of a diagnostic therapeutic trial for asthma in community
elderlyEstablishing the safety and effectiveness of a diagnostic therapeutic trial for asthma in community
elderly
Lay Description (from application):
Asthma is a major Australian health priority affecting over 2 million people. It is under-diagnosed and a
source of significant morbidity in older people. Previous work by the investigators for the Commonwealth of
Australia has shown that in the over 55-year age group approximately 40% of asthma is undiagnosed. In this
age group severity is comparable with those diagnosed and worse than those diagnosed under the age of 55
years. Most (80%) of asthma deaths occur in the people aged greater than 55 years. There are clear patient and
system factors that contribute to under diagnosis. The patient factors are currently being addressed in a general
practice patient pilot study. System issues make the diagnosis of asthma in general practice a difficult task.
The study is important, as older people are more likely to access the general practitioner than a specialist for
respiratory problems. Spirometry in general practice is not common and is of variable quality. The most
common approach to diagnosis by the general practitioner is a diagnostic trial of medication to provide
evidence of asthma. This can be broken down into four elements of: entry criteria to a therapeutic trial; choice
of drug in a therapeutic trial; length of time for a therapeutic trial, and; assessment criteria in a therapeutic trial.
No evidence-based guidelines are available to assist the general practitioner in each of these stages making the
therapeutic trial a safety and effectiveness issue of major importance, especially in the older person. The
purpose of the study proposed is to conduct a randomised controlled trial in a representative population sample
of older people to determine the evidence-based components of a diagnostic therapeutic trial for the guidance
of general practitioners. The study will also assess which diagnostic questions and medical tests provide
greatest assistance to the general practitioner in diagnosing asthma in the older person.
Research achievements (from final report):
Although there are effective treatments for asthma, in people aged over 50 years asthma has often not been
diagnosed and can cause significant symptoms and reduced quality of life. Participants in this study were over
50 years old who had noticed changes with their breathing but had not been diagnosed with a lung condition.
We compared participants who received asthma preventer inhalers (Seretide) for 6 weeks with those who also
received a 10-day course of oral prednisolone to see if this could improve their breathing and ability to perform
activities. We did not show that oral prednisolone was superior to the inhaler alone in improving quality of life,
lung function or asthma symptoms after 6 weeks of treatment. The prevalence of asthma in this group was
high, suggesting that under-diagnosis of asthma is common among older people. A trial of asthma inhalers may
be a good and safe way of making a diagnosis of asthma among people aged over 50 years who are
experiencing symptoms such as cough or shortness of breath. The results of the study will assist health
professionals in working out the best way to diagnose and manage asthma in older people.
Expected future outcomes:
This work will directly contribute to evidence-based guidelines for the diagnosis of asthma in older adults. We
expect that this will positively impact on the asthma morbidity by allowing earlier diagnosis and treatment of
asthma in the expanding aged population, who are known to be at-risk for asthma mortality and morbidity.
Name of contact:
A/Prof Robert Adams
Email/Phone no. of contact:
robert.adams@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510703
Start Year: 2008
CIA Name: A/Pr Vicki Clifton
End Year: 2012
Admin Inst: University of Adelaide
Grant Type: NHMRC Research Fellowships
Main RFCD: Foetal Development and Medicine
Total funding: $625,093
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a reproductive physiologist examining the sex specific differences in human fetal development in the
presence of maternal asthma.
Research achievements (from final report):
I identified asthma as a common condition in pregnancy that has considerable gaps in clinical management and
associated with a poor outcome for the fetus. A poor outcome for the fetus is likely to have a long term effect
on child health. Our results have been startling, identifying an important sex dependent difference in the fetal
growth response to maternal asthma. This work has lead to many prizes for my students, publications in the
asthma and obstetric literature and reviews in high ranked journals. My work has been the subject of editorial
review. Clinically my work has demonstrated that asthmatic women require extra care during pregnancy and I
plan to examine the cost effectiveness of nurse led care which will translate into improved clinical practice.
Scientifically this work has started to create a picture of what sex specific factors are involved in fetal
development.A/Prof Clifton's asthma and pregnancy research has contributed to the formulation of guidelines
for the treatment of asthma during pregnancy both nationally and internationally. Nationally she was the first
female President of the Endocrine Society of Australia (2010-2012) and she has been fundamental in the
society's development of a PhD and Postdoctoral Fellow funding scheme. Internationally she was an Executive
member of the International Federations of Placental Associations (2001-2006) and she organised an
international conference in Adelaide for this society in 2009. She is currently an executive committee member
of the international Society for the Developmental Origins of Adult Disease. Prof Clifton scientific ability has
been recognised with her appointment as Editor of the Placenta journal (2012-present).
Expected future outcomes:
My vision in the next 5 years is 1) to significantly improve policy and practice in the area of asthma and
pregnancy.; 2) to decipher the mechanisms that contribute to worsening maternal asthma and reduced fetal
growth and 3) to determine the intergenerational impact of maternal asthma so as to develop interventions that
improve health outcomes for the mother and her offspring. I will also develop
Name of contact:
Vicki Clifton
Email/Phone no. of contact:
vicki.clifton@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519206
CIA Name: Dr Peter Zalewski
Admin Inst: University of Adelaide
Main RFCD: Respiratory Diseases
Total funding: $260,780
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Airway epithelial IAPs and their interaction with Zn ionsAirway epithelial IAPs and their interaction with Zn
ions
Lay Description (from application):
The air we breathe contains a variety of harmful substances. Damage to the lining involves death of the
ciliated cells that line the airways. We have shown that zinc protects these cells from premature death. This
application focuses on a family of proteins called IAPs which bind zinc and regulate cell death in other tissues.
This project focusses on how the IAPs and Zn may act together to mainitain healthy airways and how
abnormalities of these may occur in people with asthma.
Research achievements (from final report):
A major goal of this project was to better understand how zinc protects the epithelial cells that line our
breathing tubes (known as airways) and prevents them from undergoing premature death by a process known
as apoptosis. The importance of this is that zinc deficiency appears to be a risk factor for developing asthma
and, in asthmatics, the airway epithelial cells die prematurely. This grant has enabled us to show that zinc
deficiency causes a rapid loss by proteolytic degradation of a zinc-rich protein known as XIAP that acts a
sentinel on the pathway by which cells normally die. We have also shown that vesicles of zinc lie in close
proximity to XIAP in the epithelial cells and that a special protein known as ZnT4 is involved in bringing zinc
to this region of the cell. This has now been published in the journal Nutrients. An exciting preliminary finding
that we subsequently made is that a genetic change in ZnT4 is much more common in human asthmatics who
have severe asthma. This preliminary study suggests that genetic variation in the ZnT4 gene may modulate
asthma severity. We now propose to confirm the link between ZnT4 polymorphism and severity of human
asthma, and to determine if this polymorphism is associated with differences in expression of ZnT4.
Expected future outcomes:
We anticipate at least one more journal manuscript. There may also be further exchange visits between the
laboratories of CIA Zalewski and CIC Murgia as part of the IRSES Scheme (see Section 9).
Name of contact:
Dr Peter Zalewski
Email/Phone no. of contact:
peter.zalewski@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 565347
CIA Name: A/Pr Vicki Clifton
Admin Inst: University of Adelaide
Main RFCD: Respiratory Diseases
Total funding: $224,624
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
The effect of chronic maternal asthma and acute exacerbations on placental function and fetal developmentThe
effect of chronic maternal asthma and acute exacerbations on placental function and fetal development
Lay Description (from application):
Maternal asthma is the most common disease to complicate pregnancies in Australia. The data we have
collected so far suggests that asthma represents a physiological maternal stress during pregnancy that
influences placental function and fetal development. The purpose of this grant is to continue to determine what
changes occur in the presence of maternal asthma that alter fetal growth. The findings of this work will be
applicable to any psycho-social or physiological stressor during pregnancy.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
A/Prof Vicki Clifton
Email/Phone no. of contact:
vicki.clifton@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 545844
CIA Name: Dr Reena Ghildyal
Admin Inst: University of Canberra
Main RFCD: Respiratory Diseases
Total funding: $613,514
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Functional significance of subcellular localisation of viral 3C protease in rhinovirus pathogenesisFunctional
significance of subcellular localisation of viral 3C protease in rhinovirus pathogenesis
Lay Description (from application):
Rhinovirus (RV) infections are the major cause of virus induced asthma attacks and common colds, causing
significant morbidity and mortality. The incidence of asthma is increasing worldwide with new strategies
urgently needed to reduce RV-associated disease. We have observed RV 3C protease in the nuclear
compartment of infected host cells and propose to determine its significance in RV pathogenesis with relevance
to asthma therapies.
Research achievements (from final report):
Rhinovirus infections cause the majority of asthma exacerbations, leading to significant morbidity and
mortality in the world. Data from our research has resulted in improved understanding of the mechanisms that
may underlie the process of asthma exacerbation and thus are important first steps towards new and effective
drugs and/or vaccine strategies to limit the severity of asthma exacerbations. We have shown that a rhinovirus
protease localises to the nucleus of infected cells and can disrupt nuclear trafficking pathways that are essential
for normal cellular processes and host responses to external stimuli. We have elucidated some of the
mechanisms of nuclear localisation of the protease; these motifs may be targeted for drug development or for
attenuation for vaccine strategies.
Expected future outcomes:
This research will lead to future identification of new drug targets to limit disease in RV-induced asthma
exacerbations, and yield new approaches to attenuate RV for vaccines that will be applicable to other
picornaviruses.
Name of contact:
Reena Ghildyal
Email/Phone no. of contact:
Reena.Ghildyal@canberra.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145693
Start Year: 2001
CIA Name: Prof Alastair Stewart
End Year: 2003
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Clinical Pharmacology and Therapeutics
Total funding: $377,037
Title of research award:
Self-limiting anti-inflammatory actions of glucocorticoids in asthmaSelf-limiting anti-inflammatory actions of
glucocorticoids in asthma
Lay Description (from application):
Asthma is a disease characterised by excessive narrowing of the airway tubes resulting in difficulty exhaling air
from the lungs. Symptoms of asthma include coughing, wheezing, shortness of breath and difficulty in
breathing. Asthma affects almost 1 in 5 Australians and is especially prevelant in children. One in every three
Australians will suffer from symptoms of asthma at some time in their life and despite current therapy, asthma
is responsible for the deaths of more than 700 Australians every year. Airway tubes of asthmatics have more
and larger contractile muscle cells lining the tubes. This increase in muscle mass results from chemicals that
are released from white blood cells that migrate into the airway tubes during and after asthma attacks. This
thickening slows airflow through the airway tubes because the muscle mass bulges into the holes of the tubes
and when the muscle shortens the total diameter of the tubes decrease. We have recently shown that steroids
used by asthmatics to treat the white blood cell contribution to the disease can reduce the growth of airway
muscle. However, when the muscle has been pretreated with factors that are present in the inflamed airway, the
anti-growth effects of steroids are prevented. This effect of the steroids is due to reduced production of a
substance called prostaglandin E2 which can also reduce the growth of muscle. Thus, whilst steroids may help
in treating some of the symptoms of asthma, they may be suboptimal in the treatment of muscle thickening and
other aspects of the disease which involve cell division and multiplication. Our specific question in the next
phase of this research is whether steroid inhibition of the release of prostaglandins compromises the useful
actions of steroids on the growth of the airway tubes. The findings of this proposed study will provide new
information on the role of steroids in asthma and may lead to better therapeutic strategies for the treatment of
severe asthma.
Research achievements (from final report):
Asthma is a disease with a complex basis that is being better understood by on-going research examining the
factors that make asthmatic patients much more senistive to the airway narrowing effects of many
inflammatory chemical mediators. Our work has been focussed on the long term changes in the structure of the
airways that make the airway walls thicker. This thickening allows the airways to narrow too easily and too
much, producing the symptoms of asthma such as wheezing and chest tightness. To investigate the mechanisms
underlying these growth responses we have managed to culture structural cells (muscle cells and fibroblasts)
from human airway specimens. The drugs used to treat asthma were investigated for their ability to reduce the
excessive growth of these structural cells. We found that the anti-inflammatory steroids (preventer therapy) and
the long-acting beta agonists (smooth muscle relaxant drugs) do reduce the growth of structural cells, but this
action is incomplete. We sought to better simulate the conditions encoutered in the asthmatic airway and
discovered that the scarring present in chronic asthma can interfere with the protective actions of the steroids.
However, the muscle relaxant drug actions were unaffected by exposing the structural cells to a scar-like
environment. These findings provide a potential explanation for the better therapeutic response to combinations
of the muscle relaxant and preventer drugs compared with the use of the preventer drugs alone.
Expected future outcomes:
Our results have alerted the community of asthma researchers to the need to consider the suitability of their
experimental designs , and we now have to re-evaluate previous work in which the potential impact of the scarlike environment in the asthmatic airway has been ignored. Importantly, we now have a much improved way of
identifying novel agents that reduce growth of structural cells.
Name of contact:
NHMRC Research Achievements - SUMMARY
Alastair Stewart
Email/Phone no. of contact:
astew@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299823
CIA Name: Prof Alastair Stewart
Admin Inst: University of Melbourne
Main RFCD: Basic Pharmacology
Total funding: $432,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Impact of airway wall fibrosis on the efficacy of anti-asthma drugsImpact of airway wall fibrosis on the
efficacy of anti-asthma drugs
Lay Description (from application):
Most episodes of asthma are controlled or prevented by current medications. In a small, but significant
proportion of asthmatics (5-10%) symptoms persist despite the use of the best combinations of anti-asthma
drugs. One of the reasons that acute episodes of asthma occur is that the airway tubes slowly change in
structure. These changes involve an increase in the amount of collagen (part of the "cement" between cells)
making the airway stiffer. In this project, we are exploring the impact of the stiffening of the airway on the
way that different cells within the airway wall respond to drugs used to treat asthma. Our initial findings
suggest that when the airway wall becomes stiffer with more collagen, there is a diminished benefit from the
anti-asthma drugs. This new study is designed to identify the molecular mechanisms for the poor response to
the anti-asthma drugs. With this knowledge it will be easier to design and test new drugs that are more
effective in severe asthma.
Research achievements (from final report):
Several diseases affecting the lungs cause damage to the lining tissue of the airspaces. The repair process of the
lung involves replacing the lining cells with new ones, but if the damage is extensive then instead of normal
cells, fibroblasts (the cells that are involving in scar formation) are used to repair the injury. These fibroblasts
cause significant impairment in the function of the lungs, and in some diseases, this can cause respiratory
failure. We set out in this project to identify how such scar tissue influences the function of muscle cells within
the lungs and especially how the actions of different types of medication can be influenced when there is a
great deal of scar tissue. Our work was carried out on human smooth muscle cells maintained in cell culture.
We showed that the actions of the most important group of anti-inflammatory drugs, the glucocorticiods (antiinflammatory steroids), are greatly reduced in this scar environment, whereas the actions of other agents such
as bronchodilator drugs that act to relax the muscle, are not impaired. The components of the scar tissue
responsible for this effect is the collagen and it is collagen in a particular molecular form that signals to cell
surface receptors on the smooth muscle to make the cells glucocorticoid-resistant. One benefit of this
knowledge is the identification of the importance of developing medications that reduce collagen deposition in
the lung and the airways. We also identified therapeutic approaches to stopping this damaging effect of
collagen, using antibodies against the collagen receptors on smooth muscle cells.
Expected future outcomes:
This work has led us to investigate in greater detail the molecular forms of collagen that signal resistance to
commonly used anti-inflammatory drugs and to better define the smooth muscle receptors. These more detailed
studies may lead to several strategies to reverese the collagen-induced impairment of anti-inflammatory drug
actions improving treatment of chronic severe respiratory disease.
Name of contact:
Prof Alastair Stewart
Email/Phone no. of contact:
astew@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299901
CIA Name: A/Pr Shyamali Dharmage
Admin Inst: University of Melbourne
Main RFCD: Epidemiology
Total funding: $358,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Risk factors for chronic respiratory diseases in middle age: 36-year follow-up of the Tasmanian Asthma
StudyRisk factors for chronic respiratory diseases in middle age: 36-year follow-up of the Tasmanian Asthma
Study
Lay Description (from application):
This project will improve our understanding of the causes of chronic respiratory diseases (CRDs) in adults.
CRDs are clearly a major public health problem, but there are no good data on the natural history and risk
factors for these diseases. Regular follow-up through childhood to adulthood is the best method to examine
these factors, but such data is lacking due to difficulties in conducting long-term studies. The Tasmanian
Asthma Study (TAS), based on 8,585 Tasmanians (i.e. probands) born in 1961, is one of the worlds most
important resources of such information. The probands, their parents (16,267) and siblings (21,044) were first
investigated for respiratory problems in 1968. Subsequently, three follow-up surveys were carried out at ages
13 (1974), 20 (1981) and 31 (1992) on either the total or sub-samples of the probands. In 1992, the children
and spouses of the probands were also surveyed. Information on all respiratory problems was collected in all
the follow-ups, although the main focus of the TAS to date has been asthma. The probands are now reaching
the age at which all CRD as a group are beginning to inflict an increasing disease burden, which will become
greater in the next two decades. Hence, TAS now provides an ideal opportunity to examine the potential risk
factors and natural history of and of CRDs using data collected to date and new data collected at age 43. Also,
it will provide a platform for future studies to investigate the progression of CRDs in this cohort. Hence, we
propose to carry out the 36 year follow-up of this cohort focusing on CRDs. This will provide important
information for preventing chronic respiratory morbidity and disability in the future, which will be original and
significant not only in Australia but also internationally.
Research achievements (from final report):
The Tasmanian Asthma Study (TAS), based on a cohort of 8,583 Tasmanians (referred to as probands) born in
1961, their parents (16,267) and siblings (21,044), was commenced in 1968. We have conducted 36-year
follow-up of the probands in order to achieve the above aims. NHMRC funded us to conduct a postal survey of
all the probands and a clinical (laboratory) study of a sample of participants living in either Tasmania or
Victoria. , , We traced 90% (7,638) of the probands. Of them, 2.5% were deceased. 80% (5,943) of those who
were traced and surviving responded to our postal survey. Five manuscripts arising from analyses of this and
past data were published in 2006. Four further manuscripts are in preparation. , , Three laboratories in
Tasmania (Launceston, Burnie and Royal Hobart Hospital) and one in Victoria (The Alfred Hospital) tested the
participants. Laboratory attendance rate was approximately 65% and ~1100 participants were tested. After we
obtained the NHMRC grant, we were awarded a grant from the Queensland Asthma Foundation to conduct
laboratory studies on TAS participants living in Queensland. With these funds we tested a further 80 probands
in two laboratories (Royal Brisbane Hospital and Gold Coast Hospital).
Expected future outcomes:
We have already analysed postal survey data and published the results. The analysis of laboratory data has
commenced. New hypotheses have been developed through theses analyses and a funding application has
already been submitted to test some of these hypotheses.
Name of contact:
Shyamali Dharmage
Email/Phone no. of contact:
s.dharmage@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300087
CIA Name: A/Pr Shyamali Dharmage
Admin Inst: University of Melbourne
Main RFCD: Epidemiology
Total funding: $262,875
Start Year: 2005
End Year: 2008
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Epidemiology of chronic respiratory diseases: 35 year follow-up of the Tasmanian Asthma studyEpidemiology
of chronic respiratory diseases: 35 year follow-up of the Tasmanian Asthma study
Lay Description (from application):
Not Available
Research achievements (from final report):
During my fellowship I was successful in winning three NHMRC project grants and a strategic program grant
to re-establish and conduct the follow-ups of two major cohort studies. Utilising these cohort studies I have
now built an independent research program in allergy and respiratory epidemiology at the Centre for
Molecular, Environmental, Genetic and Analytic Epidemiology. My research program provides
multidisciplinary doctoral and post doctoral opportunities to work at the forefront of allergy and airway disease
research. Currently there are three postdoctoral fellows and three PhD students conducting their work within
this program. I have also developed exceptionally productive national and international collaborations. As a
result, I am growing a significant international reputation and have already earned a national reputation in my
field. My recent research is helping resolve some controversies by providing strong evidence. For example,
since asthma allergies have started to rise, childhood immunization and long-term allergies has been a
contentious issue. Recent findings from the Tasmanian Asthma Study are now quoted as conclusive evidence
that childhood immunization does not have any long-term effects on allergies as this is the first prospective
study to look at this issue from childhood to adulthood. A recent paper of the Melbourne Atopic Cohort Study
has substantially contributed to resolving a methodological issue in allergy epidemiology by providing
evidence that at least part of the association observed in relation to the duration of breast feeding and childhood
allergies is related to reverse causation. This paper has been acknowledged as a land mark paper in the field.
Expected future outcomes:
The type of research that I am currently doing, combining life course epidemiology of longitudinal studies with
studies of biological markers and of genetics is at the leading edge internationally and promises much in
helping to understand and ultimately control these important diseases.
Name of contact:
Shyamali Dharmage
Email/Phone no. of contact:
s.dharmage@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350333
CIA Name: Dr Stuart Mazzone
Admin Inst: University of Melbourne
Main RFCD: Autonomic Nervous System
Total funding: $438,700
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
ORIGIN AND REGULATION OF VAGAL PREGANGLIONIC NEURON SUBTYPES CONTROLLING
AIRWAY SMOOTH MUSCLE TONEORIGIN AND REGULATION OF VAGAL PREGANGLIONIC
NEURON SUBTYPES CONTROLLING AIRWAY SMOOTH MUSCLE TONE
Lay Description (from application):
The primary role of the airways is to allow the exchange of oxygen and carbon dioxide between the
environment and the lungs. However, the airways are not merely a series of static tubes, but rather their size
(or caliber) is subject to breath-by-breath alterations, thereby regulating gas exchange to match the body's
demands. Regulation of airway caliber is achieved largely by subconscious changes in the tone of the muscle
lining the airway wall. Airway muscle tone is primarily under the control of the parasympathetic division of
the autonomic nervous system. Two distinct types of parasympathetic nerves innervate the airways: One type
employs the neurotransmitter acetylcholine which causes airway muscle to contract and the airways to
constrict, while the other type employs nitric oxide which evokes airway dilatation. The normal regulation of
airway caliber is altered in a variety of inflammatory airways diseases. In asthma and chronic obstructive
pulmonary disease (COPD) there is an increase in airway muscle tone (airway constriction) which
compromises the normal movement of gasses and contributes to the morbidity and mortality of the diseases.
There is a growing body of evidence to suggest that exaggerated airway muscle tone may in part result from
dysfunction of either the contractile or relaxant parasympathetic nerves innervating the airways. However, at
present very little is known about the parasympathetic pathways regulating airway caliber. A complete
understanding of the mechanisms controlling airway smooth muscle tone is therefore essential to fully
understanding possible role of autonomic dysfunction in the pathogenesis of obstructive airways diseases. The
aim of this grant is to better define the physiological and anatomical properties of airway parasympathetic
nerves in the brain stem.
Research achievements (from final report):
We performed extensive mapping and characterization of brainstem neurons projecting to the trachea and
oesophagus in guinea pigs. Our studies have revealed that distinct populations of neurons, differentiated by the
expression of the neuropeptide CGRP, regulate airway and oesophageal function. We also identified a novel
population of oesophageal myenteric plexus neurons that project to the trachea and innervate cholinergic
ganglion cells in the tracheal wall, suggesting a novel of the oesophagus in controlling airway functions. The
studies contribute to our understanding of airway control and highlight the interactions that exist between the
airways and oesophagus (relevant to oesophageal reflux evoked asthma). , We identified a role of the
furosemide sensitive Na+/ K+/ 2Cl-co-transporter (NKCC1) in the regulation of airway nerve excitability.
NKCC1 functions to regulate the ionic balance in airway sensory nerve terminals and inhibitors of this cotransporter greatly reduce airway sensory nerve function. We found that distinct subsets of airway sensory
nerve terminals express the transporter protein (particularly those that are responsible for initiating coughing).
We also described a novel class of anticholinergic agents and a role for hyperpolarization activated ion
channels in regulating airway nerve activity. These data contribute to the search for new classes of drugs for
treating the symptoms of airways diseases., Finally, we contributed to study of sympathetic regulation of
airway tone specifically showing that both spinal and vagal afferent pathways can drive sympathetic outflow to
the airway smooth muscle.
Expected future outcomes:
We will continue to build on the results obtained from the project grant.
Name of contact:
Stuart Mazzone
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
s.mazzone@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 359275
CIA Name: Dr Melanie Matheson
Admin Inst: University of Melbourne
Main RFCD: Epidemiology
Total funding: $309,750
Start Year: 2005
End Year: 2009
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Genetic epidemiology of chronic respiratory diseasesGenetic epidemiology of chronic respiratory diseases
Lay Description (from application):
Not Available
Research achievements (from final report):
, During my post doctoral work I have established a research program in the genetic epidemiology of allergies
and CRDs. I have been instrumental in establishing the genetic component of 3 cohort studies. I have published
20 papers during my post-doc period and have been a chief investigator of 6 NHMRC grants including 1 as
chief investigator A. My post-doctoral work has also contributed to change in clinical management and public
health policy. My work on the relationship between breastfeeding and allergic diseases such as asthma has
contributed to the debate surrounding the benefits of breastfeeding. The publication has been widely cited and
has contributed to a paradigm shift away from the conventional wisdom that breastfeeding is protective against
allergies and asthma. Other projects on which I'm a CI are investigating other important public health issues in
the area of CRDs and allergies. The data from these longitudinal studies are just becoming available and they
will contribute substantially to our understanding of the natural history of CRDs and allergies and their risk
factors over time. The results of these projects will have direct impact on the management of CRDs in
Australia. For example, the study of food allergies will provide the first community-based Australian data on
food allergies in infants, which will further inform about extent of food allergy as public health problem in
Australia. It will also provide data on potentially modifiable risk factors which may be targeted for
interventions at a community level.
Expected future outcomes:
One of the major aims of this project was to establish genetic resources for the study of the genetic
epidemiology of CRDs and allergies. The genetic component of 3 longitudinal studies of CRDs and allergies
have been established and funds obtained to perform genetic analysis. Future work will focus on the analysis of
data from these studies.
Name of contact:
Melanie Matheson
Email/Phone no. of contact:
mcmat@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 359298
CIA Name: Dr Karen Holzer
Admin Inst: University of Melbourne
Main RFCD: Respiratory Diseases
Total funding: $135,675
Start Year: 2005
End Year: 2008
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Role of long acting Beta-2 agonists in the management of exercise-induced asthmaRole of long acting Beta-2
agonists in the management of exercise-induced asthma
Lay Description (from application):
Not Available
Research achievements (from final report):
Our study focussed on the effects, if any, of the regular prolonged use of long acting Beta-2 adrenoceptor
antagonists on: the resting lung function, the hyperreactivity to hyperpnoea , and the tolerance to both short and
long term beta-2 adrenoceptor antagonists in elite athletes with exercise-induced bronchoconstriction (EIB).
The study revealed that although a significant proportion of the study population did have problems with a
deterioration in baseline lung function, tolerance and an increased hyperreactivity to hypernoea, there were a
number of athletes whose baseline asthma/EIB control improved, who had no issues with tolerance to beta-2
adrenoceptor antagonists and there reactivity to hyperpnoea was actually reduced. There was no definite
pattern in regards to the presence of underlying asthma, the severity of the EIB, type of sport, or frequency of
ventolin use
Expected future outcomes:
Further studies need to be taken to identify the athletes that are at risk of the negative effects of regular or
prolonged use of long acting beta-2 adrenoceptor antagonists.
Name of contact:
Karen Holzer
Email/Phone no. of contact:
k_holzer@bigpond.com
NHMRC Research Achievements - SUMMARY
Grant ID: 400145
Start Year: 2006
CIA Name: Prof John Hamilton
End Year: 2010
Admin Inst: University of Melbourne
Grant Type: Established Career Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $826,161
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Several achievements in the areas of macrophage and CSF biology were made. Some of these are as follows: ,
Low dose joint implant particles induce monocyte/macrophage survival. Hypoxia prolongs
monocyte/macrophage survival. Glucose metabolism is required for oxidized LDL-induced macrophage
survival., Detection and properties of the human proliferative monocyte subpopulation. The generation and
properties of human macrophage populations from hemopoietic stem cells. The proliferative human monocyte
subpopulation contains osteoclast precursors., GM-CSF and M-CSF (CSF-1)-dependent macrophage
phenotypes display differences in cytokine profiles and transcription factor activities - implications for CSF
blockade in inflammation. GM-CSF- and M-CSF-dependent macrophage phenotypes display differential
dependence on type I interferon signaling. Macrophage lineage phenotypes and osteoclastogenesis complexity in the control by GM-CSF and TGF-beta., The significance and potential benefits of these
achievements will lie in the development of therapeutics to control macrophage and CSF function particularly
in chronic inflammatory/autoimmune conditions such as rheumatoid arthritis, multiple sclerosis, lung
inflammation, psoriasis, nephritis, atherosclerosis etc.
Expected future outcomes:
Drugs will be developed to control the number and activation state of a white blood cell important for the
inflammation and tissue destruction observed in a disease such as rheumatoid arthritis. Recent evidence also
suggests that progression of certain tumours may also be slowed down in the same way.
Name of contact:
Professor John Hamilton
Email/Phone no. of contact:
jahami@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454425
CIA Name: A/Pr Shyamali Dharmage
Admin Inst: University of Melbourne
Main RFCD: Epidemiology
Total funding: $889,220
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Genetic epidemiology of chronic respiratory diseases from childhood to adulthood: A prospective study of
sibshipsGenetic epidemiology of chronic respiratory diseases from childhood to adulthood: A prospective
study of sibships
Lay Description (from application):
Chronic Respiratory Diseases (CRDs) are a major public health problem. It is known that CRDs change over
time but we have no information on causes of these changes. Some childhood asthmatics continue to have
asthma as adults and/or develop Chronic Obstructive Pulmonary Disease (COPD) while others are free of any
adult CRD. Some of those who do not have childhood asthma develop asthma and/or COPD as adults while the
others remain free of CRDs from childhood to adulthood. To investigate risk factors for these changes,
following up siblings over time is a powerful tool. As siblings share the childhood environment but not the
adult environment, it helps to disentangle childhood environment, adult environment & genetic factors. The
Tasmanian Asthma Study (TAS) is amongst worlds' major longitudinal respiratory studies & it is unique
because it was conceived as a family study, with all the family members and the family environment being
surveyed. TAS commenced in 1968 by investigating 8,585 school children born in 1961 (referred to as
probands), their parents (16,267) and siblings (21,044). By the end of 2006, we will have completed the 37year follow-up of the TAS probands, which focuses on non-genetic risk factors for middle-age CRDs. This
follow-up together with baseline data now provides a unique opportunity for conducting a sibling study, which
can concurrently examine genes, childhood environment & adult environment for change in CRDs. Also, it will
provide a platform for future studies to investigate the progression of CRDs in this family cohort. Therefore,
we now seek funding to extend the current follow-up to include the siblings. This will be the world's only
population-based respiratory sibling study that spans childhood to adulthood. This will provide information for
preventing chronic respiratory morbidity & disability in the future, which will be original and significant not
only in Australia but also internationally.
Research achievements (from final report):
The Tasmanian Longitudinal Health Study (TAHS), based on a cohort of 8,583 Tasmanians (referred to as
probands) born in 1961, their parents (16,267) and siblings (21,044), was commenced in 1968. We have
completed the 36-year follow-up of the probands and commenced the 36-follow-up of the siblings in early
2007. NHMRC project grant 454425 funded us to trace and conduct a postal survey of all the siblings, and a
clinical (laboratory) study of a sample of participants of the postal survey (~2000) living in Tasmania,
Queensland or Victoria. , We have traced 82.1% (17,254) of the siblings through Australian electoral rolls, the
Tasmanian marriage registry, family members, the Health Insurance Commission database and Tasmanian
Transport Department database. This includes 946 (4.5%) deceased, 506 (2.4%) withdrawn and 186 (0.88%)
living overseas. We conducted a postal survey of those traced and have achieved a response rate of 72.9%
(11895 returned surveys sent to 16308 alive traced siblings). We have completed the laboratory study of the
siblings conducted over three laboratories in Tasmania, one in Victoria, one in NSW and one in Queensland.
We have completed testing of 1673 participants. We have just completed genotyping the blood of probands and
siblings and the data analysis is currently underway.
Expected future outcomes:
The family data collected within this study will document the natural history of change of chronic respiratory
diseases from childhood to adulthood and allow clarifying the adult risk fators for CRDs better as the sib pair
analysis will exclude confounding by partial genetics and shared environmental factors.
Name of contact:
A/Prof Shyamali Dharmage
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
s.dharmage@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454437
CIA Name: Dr Kenneth Snibson
Admin Inst: University of Melbourne
Main RFCD: Respiratory Diseases
Total funding: $318,917
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Functional and structural relationships of the peripheral airways in chronic asthmaFunctional and structural
relationships of the peripheral airways in chronic asthma
Lay Description (from application):
It is now considered that airway wall thickening (airway remodeling), a consequence of persistent airway
inflammation in asthmatics, significantly contributes to the symptoms and risk of death from asthma. Despite
recent advances in the field, there are still many clinically relevant questions that have not been addressed.
Some important issues still to be elucidated are: What is the precise sequence of tissue changes in remodeling?
Which components of remodeling are reversible in the absence of allergen provocation? At what point does
airway remodeling become irreversible? Does early intervention with anti-inflammatory medication have long
term benefits in terms of reducing long-term remodeling? As there have been few appropriate models for
addressing these types of remodeling issues, we propose to utilise a large animal model for chronic asthma to
address these questions. One of the main focuses of this proposal is to identify biomarkers or functional indices
of the different stages of remodelling. The sheep model is well placed to achieve these objectives given that the
structure, physiology and asthma pathophysiology of sheep airways is similar to human airways. The novel
experimental design is to expose four spatially separate lung regions (segments) in individual sheep with
different durations of repeated weekly doses of HDM. The strength of the proposal is that lung function and
structure of challenged segments from successive stages of remodeling can be assessed in one sheep. A
separate experiment will examine how lung structure and function return to normal in chronically HDM-treated
lung segments over successive months after exposure to HDM ceases. It is expected that information gained
from this research will lead to a greater fundamental understanding of disease mechanisms in chronic asthma.
This will increase the chances of improving current treatments, and allows for new strategies to be devised for
treating asthma more effectively.
Research achievements (from final report):
Major achievements of project grant 454437:, We have developed an exciting novel large animal model of
asthma which shows all the hallmark structural and functional changes in the airways that occur in asthmatics.
The model helps us understand the underlying disease mechanisms associated with a complex and expensiveto-treat disease such as asthma. In particular, we have developed a method for measuring a lung function
indicator called Bronchial Hyperresponsiveness in lung segments of sheep; this measures the twitchiness of the
airways which is an indicator of asthma. Our experiments show that after repeated exposure to House Dust
Mite (HDM) allergen, resting lung function in the small airways declines with increasing exposure to HDM.
Our research shows that the early-hase-sthmatic response of the small airways, a physiological indicator of
asthma, increases with increasing exposure to HDM. Interestingly, in this disease model, lung function is
protected with more airway mast cells. Mast cells are resident immune cells traditionally thought to trigger
asthma when stimulated with appropriate allergens in the environment. Our data is still consistent with this
notion, but also goes further, in that mast cells also protect against lung function in certain circumstances. This
data is consistent with the human literature, and so the model will be useful for dissecting out the disease
mechanisms associated with mast cell activation in well-controlled experiments. Ultimately, a better
understanding of this area will allow for better treatment strategies to be devised for asthmatics.
Expected future outcomes:
Over the next year, we expect to publish all of the experimental data that were funded by this project grant.
This will allow the disease mechanisms of asthma to be better understood in the wider clinical and scientific
communities and thus make better treatment options possible for this disease.
Name of contact:
NHMRC Research Achievements - SUMMARY
Ken Snibson
Ken Snibson
Email/Phone no. of contact:
ksnibson@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454856
Start Year: 2008
CIA Name: Prof Shyamali Dharmage
End Year: 2012
Admin Inst: University of Melbourne
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $893,559
Title of research award:
Predictors and Consequences of allergies that impact on children getting a healthy start to life:a prospective
studyPredictors and Consequences of allergies that impact on children getting a healthy start to life:a
prospective study
Lay Description (from application):
Allergic diseases prevent Australian children getting a healthy start to life by causing long term illnesses. This
group of diseases includes asthma, hay fever, eczema and food allergies. Half of all Australian children are
born into families with a history of these conditions and these children are at increased risk. Some of these
children develop allergies while the others do not. It is also known that allergic conditions change over time,
but we have no information on causes of these changes. For example some infants with eczema continue to
have eczema or develop hay fever and asthma, while others do not. The aim of this study is to determine what
factors cause allergies and what factors influence these changes. This will provide evidence to guide health
policy and clinical practice. Looking at the different conditions in family members over time is a good way to
answer these types of questions, because parents and siblings share similar exposures, but not all the same
genes. This helps to disentangle the effects of the environment and genes. The Melbourne Atopic Cohort Study
(MACS) is amongst the world’s major studies on the development of allergies. MACS commenced in 1991-94
by recruiting 620 babies prior to birth. Only infants born into families with a history of allergic disease were
included. MACS is unique because all family members and the home environment were assessed at the time of
birth of the child. These children have been followed regularly over the first ten years of their life. The MACS
now provides a unique opportunity to conduct a family study that can examine genes, childhood environment
and individual risk factors for allergies. This will also allow exploration of the impact of allergies on families
and the health care system, and how we can reduce that impact. Such information will provide evidence to
guide health care policy and clinical practice. Also, the current study will provide a platform for future studies
to investigate the progression of allergies in this family cohort. This will be the world's only longitudinal
family follow-up of allergies that spans all of childhood. It will assist in reducing the impact of these common
conditions, and the findings will be original and significant not only in Australia but also internationally.
Research achievements (from final report):
NHMRC project grant 454856 funded us to trace and conduct a questionnaire survey and laboratory study of
all the probands and family members of the Melbourne Atopic Cohort Study (MACS). The MACS is a cohort
of 620 high risk babies (referred to as probands) born between 1990-1994, and their parents and siblings. We
have now completed the 18-year follow-up of 417 probands and a total of 1423 family members. During this
follow-up we have collected clinical data through a range of tests including Skin Prick Tests, Spirometry,
Exhaled Nitric Oxide, Exhaled Breath Condensate and Trans Epidermal Water Loss. Blood (or saliva) was
collected and genotyped for a selected group of candidate genes. Blood samples have also been processed and
stored as serum, plasma, whole blood and gutherie Guthrie cards.This project has generated multiple
publications in high impact journals, and has supported the work of 3 post-doctoral research fellows, and 4
PhD candidates. The results from this reseearch are being developed into future publications, and previously
published results are impacting on evidence base for the prevention of allergic disease and informing current
clinical and public health practice.?????
Expected future outcomes:
The data collected within this study will enable identification of modifiable risk factors in allergic conditions
from early childhood to adolescence and high risk groups for targeted interventions. This will also provide
further opportunities for postdoctoral researchers and PhD students.
Name of contact:
NHMRC Research Achievements - SUMMARY
Prof Shyamali Dharmage
Email/Phone no. of contact:
s.dharmage@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509001
Start Year: 2008
CIA Name: Prof Alastair Stewart
End Year: 2010
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $431,839
Title of research award:
Understanding and controlling remodelling in pulmonary fibrosis and asthmaUnderstanding and controlling
remodelling in pulmonary fibrosis and asthma
Lay Description (from application):
The development of scar tissue is a normal response to tissue injury. When airway and lung tissue is injured
by exposure to irritants, scarring greatly diminishes the function of the lung to allow transfer of oxygen to the
tissue. In severe disease, the scarring may be fatal. We discovered that two factors involved in formation of
scar tissue neutralise each other's effects. We are examining this interaction in human lung to develop new
treatments for scarring-related lung diseases.
Research achievements (from final report):
In chronic inflammatory diseases such as asthma the inflammatory damage to tissue is accompanied by a repair
process. Proteins called growth factors cause scar tissue to form as part of the wound healing response. Our
work investigated the idea that a balance of activity between different growth factors would limit the amount of
scar tissue left after a wound healing response in the airways. Using human smooth muscle cells in culture, we
discovered that a growth factor involved in tissue development and growth, called basic Fibroblast Growth
Factor, was able to inhibit the formation of contractile apparatus (a group of cell proteins that form contractile
filaments which have the ability to shorten). We were able to show that the reduction in contraction prevented
the smooth muscle cells from making hard scar tissue. We interpret these observations to mean that basic
Fibroblast Growth Factor could limit the stiffening of asthmatic airways and allow them to conduct air to the
lungs more easily. These findings open up new pathways for developing novel anti-asthma drugs.
Expected future outcomes:
This work has provoked new ideas about how to limit airway stiffening in asthma. In particular, our current
research is investigating which of the many "signals" that basic fibroblast growth factor delivers to smooth
muscle cells is responsible for inhibiting the development of the contractile apparatus. Once the responsible
signal is identified, it may be possible to mimic the signal with drugs
Name of contact:
Prof Alastair Stewart
Email/Phone no. of contact:
astew@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509199
CIA Name: Prof Francis Carbone
Admin Inst: University of Melbourne
Main RFCD: Cellular Immunology
Total funding: $504,097
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
TSLP and dysregulation of anti-viral immunity in atopic dermatitisTSLP and dysregulation of anti-viral
immunity in atopic dermatitis
Lay Description (from application):
Eczema (atopic dermatitis) is a frequent allergy in Australia. People with eczema can suffer very severe skin
infections with some viruses, including the virus that causes cold sores, but we do not know why this happens.
A newly discovered protein called TSLP is now known to be made by skin affected by eczema and there is
evidence that TSLP may interfere with the way the body fights viruses. We will examine whether TSLP
programs the immune system so that it is less able to fight viruses.
Research achievements (from final report):
Around 30% of patients with atopic dermatitis have bacterial or viral infections of the skin. Suppression of
virus control in atopic dermatitis lesions is particularly problematic during infection with herpes simplex virus
(HSV) and vaccinia virus (VACV). Thymic stromal lymphopoietin (TSLP) is a soluble immune modulator
recently found to be associated with dermatitis. In this grant, we proposed to examine how TSLP affected
disease progression associated with these viruses and altered immune control of skin infection. In our approach
we used two published methods to switch on TSLP production in the skin. Both gave rise to signatures of
dermatitis, such as increased skin infiltration of eosinophils, which are key histamine secreting cells in
dermatitis and directly contribute to this disease. Despite these manifestations, control of infection was not
compromised compared to normal skin. While we are still pursuing the means by which TSLP modulates skin
immunity, it would appear that it does not impact clearance of local virus infection of the skin at least in the
manner that is predicted by the current literature. The reasons for this remains unclear and is the subject of
ongoing investigations.
Expected future outcomes:
Possible future outcomes from this research is the use of blocking agents specific for soluble immune
modulator, thymic stromal lymphopoietin (TSLP), to alleviate dermatitis with the potential that they may have
an indirect impact on the progression of skin infection.
Name of contact:
Professor Francis R. Carbone
Email/Phone no. of contact:
fcarbone@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509239
CIA Name: Dr Jane Ward
Admin Inst: University of Melbourne
Main RFCD: Respiratory Diseases
Total funding: $307,436
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Peroxisome proliferator activated receptor gamma is a novel therapeutic target for inflammation and
remodelling in asthmaPeroxisome proliferator activated receptor gamma is a novel therapeutic target for
inflammation and remodelling in asthma
Lay Description (from application):
Asthma affects over 2 million Australians with 300 deaths each year. Current drugs are not always effective. A
new approach is to reduce the thickening and stiffening of the airway muscle found in asthma. Rosiglitazone,
an antidiabetic drug in current use, inhibits growth of airway muscle in the test tube & chest tightening in a
mouse model of asthma. Cells from asthmatics will be used to confirm these positive findings, and to support
rapid clinical evaluation of this drug to benefit patients.
Research achievements (from final report):
This project has identified a novel use for a drug class of drug called PPARgamma agonists. These drugs are in
current clinical use for the treatment of diabetes, but we have demonstrated that they may also be of benefit in
airway diseases such as asthma. In cell-based studies, we have shown that they inhibit production of proteins
that contribute to inflammation and fibrosis. Of particular significance, they caused rapid relaxation of isolated
airways from mouse and sheep models of asthma. In these settings , the drugs were effective under conditions
where responses to current therapy (beta2-adrenoceptor agonists e.g. Ventolin) is limited, suggesting that they
act via different mechanisms. If these findings can be demonstrated in the whole animal and then translated to
the clinic, they may offer signficant benefit to patients whose symptoms of asthma are not well controlled.
Expected future outcomes:
Confirmation that the improved bronchodilator efficacy of PPARgamma agonists relative to beta2adrenoceptor agonists is maintained in the whole animal and further insights into the mechanisms underlying
how these drugs overcome the limitations of current therapy will support their clinical evaluation in people
with poorly controlled asthma.
Name of contact:
Jane Bourke
Email/Phone no. of contact:
jane.bourke@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509382
CIA Name: Prof Shyamali Dharmage
Admin Inst: University of Melbourne
Main RFCD: Epidemiology
Total funding: $420,872
Start Year: 2008
End Year: 2012
Grant Type: Career Development Fellowships
Title of research award:
Allergies and Chronic Respiratory Diseases: Causes, Biological Pathways and InterventionsAllergies and
Chronic Respiratory Diseases: Causes, Biological Pathways and Interventions
Lay Description (from application):
Allergies and chronic respiratory diseases are major causes of illness and death in Australia. Worryingly there
are still many gaps in knowledge on how best to prevent and manage these diseases. The proposed program
will investigate these questions and provide evidence to guide health policy and clinical management. As this
program is built on state-of the-art methods and technology, these original Australian findings will be of great
importance internationally.
Research achievements (from final report):
, My research has influenced both practice and policy. For example, my work has provided confirmatory
evidence that early eczema leads to asthma. Prior to this work, it was believed that eczema and asthma simply
"co-manifest" and were not sequentially related. This work has shifted this perspective and highlighted the
importance of maintaining skin barrier function and treating childhood eczema and allergic rhinitis rigorously,
as both could help prevent development of childhood asthma or its continuation into adulthood. This shift has
put eczema in the research spotlight and has increased studies into the causes of eczema including genetics.
Another landmark paper of my work demonstrated that feeding children a hydrolysed or hypo-allergenic infant
formula (which is currently advocated for children at high risk of allergy) did not reduce their risk of
developing allergic disease, when compared to feeding regular cow's milk formula. This evidence is currently
being integrated into the existing Cochrane review. Given that this is the second-largest trial of its kind, it is
likely that the revised Cochrane review will result in global changes to various guidelines and how children are
fed in early life. My work has also provided the strongest evidence that the link between childhood paracetamol
use and subsequent asthma is not causal, but actually due to the respiratory infections for which paracetamol
was used. This work has informed clinical guidelines and clinicians, and has helped focus research and clinical
communities on the importance of carefully considering available evidence before instituting widespread
changes in practice.
Expected future outcomes:
My 5-year plan is to build on the momentum of the well established studies . Because some of my projects
have now finished, the next 5 years will be very productive in terms of having an impact on the discipline
through publications in the areas of modifiable risk factors for asthma and allergies. These publicatons are
likely to have a substantial impact on policy and practice.
Name of contact:
Dr Melanie Matheson
Email/Phone no. of contact:
mcmat@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566904
CIA Name: A/Pr Kenneth Snibson
Admin Inst: University of Melbourne
Main RFCD: Respiratory Diseases
Total funding: $353,254
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The relationship between vascular remodelling and mast cells in chronic asthmaThe relationship between
vascular remodelling and mast cells in chronic asthma
Lay Description (from application):
It is known that the airwalls of asthmatics have increased numbers of small blood vessels which can contribute
to poor lung function in asthma. The proposed research uses a novel sheep model for chronic asthma to
investigate the progressive changes to the blood vessels in the airway walls of asthmatic lungs. The information
gained from our sheep model will assist the understanding of blood vessel growth and thus ulitmately help in
devising new strategies to treat the effects of asthma.
Research achievements (from final report):
The NHMRC project grant 566904 has achieved all the aims of the proposal. We show in a relevant large
animal model that new blood vessel growth occurs in small airways exposed to chronic allergen administration.
Increased numbers of airway blood vessels are normally associated with poorer lung function in airway
disease. The chronic exposure to allergen also resulted in poorer lung function this model. We also show that
these new blood vessels persist for months if the allergen is withdrawn from the lungs. In addition, our other
data shows that the administration of a novel anti-asthma drug impedes some aspects of new blood vessel
growth, and also improves lung function. Importantly, our data shows that we can partially reverse the
detrimental new blood vessel growth that is associated with asthma. Six peer-reviewed publication have come
from this NHMRC supported project, these comprise four original research articles based on the data collected
from the project's data, and two reviews of the scientific area.The likely impact of this work centres on the
potential future use of this large animal preclinical model to test novel anti-asthma drugs, which impede
detrimental new blood vessel growth. The testing of these novel anti-angiogenesis drugs would provide a
relevant screen for the suitability of these drugs' entry into clinical trials. Ultimately, successful testing in
clinical trials would contribute to better patient treatment/management options for chronic asthma in particular,
and other chronic respiratory diseases (e.g. COPD) as well.
Expected future outcomes:
We show in a relevant large animal model that detrimental new blood vessel growth occurs with chronic
exposure to allergen, and persists long-term if the allergen is withdrawn. The successful use of a novel antiasthma drug, which impedes aspects of blood vessel growth, supports the use of this large animal model for
testing novel anti-angiogenesis drugs for suitable entry into clinical trials.
Name of contact:
A/Prof Ken Snibson
Email/Phone no. of contact:
ksnibson@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566931
CIA Name: Prof Shyamali Dharmage
Admin Inst: University of Melbourne
Main RFCD: Epidemiology
Total funding: $593,840
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Epidemiology of middle-age BHR: a prospective study from childhood to middle ageEpidemiology of middleage BHR: a prospective study from childhood to middle age
Lay Description (from application):
Increased airway reactivity (BHR) in middle-age increases the risk of chronic respiratory diseases (CRDs) in
old age, which are recognised as a major public health problem. Knowledge on the causes of these conditions is
currently limited. This project will improve our understanding of the childhood and adult causes of increased
reactivity of the airways in middle-age. Such knowledge will help in identifying preventive strategies for
middle age BHR and thereby CRDs in old age.
Research achievements (from final report):
NHMRC project grant 566931 funded us to assess bronchial hyper-reactivity (BHR) among those who were
part of the 5th decade lab study of the Tasmanian Longitudinal Health Study (TAHS) and this sub study is
referred to as the TAHS BHR study. TAHS is the world's largest longest running study of respiratory health.
TAHS began in 1968 by investigating 8,585 school children born in 1961 (referred to as probands) and their
families. Since that time, the probands have been followed up regularly. We completed the 5th decade followup of probands between 2003-2007, which included a survey of all the probands and a laboratory study
including lung function and allergy testing on 1400 probands. The TAHS BHR study ran from 2009 to 2012
and we have now tested 820 participants in Tasmania, NSW, Queensland and Victoria. We have commenced
the analysis and presented the preliminary results of the TAHS BHR study in the 2013 Annual Scientific
meeting of the Thoracic Society of Australia and New Zealand. TAHS project has generated multiple
publications in high impact journals, and has supported the work of 3 post-doctoral research fellows, and 4
PhD candidates since 2003. The results from this reseearch are being developed into future publications, and
previously published results are impacting on evidence base for the prevention of allergic disease and
informing current clinical and public health practice.
Expected future outcomes:
The data collected within this study will enable identification of modifiable risk factors for BHR and high risk
groups for targeted interventions.
Name of contact:
Prof Shyamali Dharmage
Email/Phone no. of contact:
s.dharmage@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628513
CIA Name: Dr Melanie Matheson
Admin Inst: University of Melbourne
Main RFCD: Epidemiology
Total funding: $308,585
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
A population-based family study of filaggrin mutations and allergic disease risk in AustraliaA populationbased family study of filaggrin mutations and allergic disease risk in Australia
Lay Description (from application):
It is biologically plausible that the association of known environmental risk factors for asthma may be different
for genetically susceptible individuals. Few studies have examined the interaction between genetic and
environmental factors. that have not considered genetic susceptibility are estimating an average risk of asthma
across all genotypes in the population which may not be relevant for a particular sub-group.
Research achievements (from final report):
The Tasmanian Longitudinal Health Study (TAHS), based on a cohort of 8,583 Tasmanians (referred to as
probands) born in 1961, their parents (16,267) and siblings (21,044), was commenced in 1968. We have
completed the 36-year follow-up of the probands and siblings in early 2007. NHMRC project grant 628513
funded us to trace and conduct a postal survey of all the alive and traced parents. We traced 79.3% (12,588) of
the parents including the Australian electoral rolls, the Tasmanian marriage registry and family members. This
includes 5321 (32.8%) deceased, 556 (3.4%) withdrawn and 30 (0.18%) living overseas. We conducted a
postal survey of those traced and have achieved a response rate of 70.3% (5111 returned surveys sent to 7267
alive traced parents). We have completed genotyping for 5 common FLG mutations in the siblings and
probands and the data analysis is currently underway.
Expected future outcomes:
The true allele frequencies and penetrance of allergic disease in carriers and non-carriers of the common FLG
null mutations will be identified in an Australian population. This will help characterise disease phenotypes
accurately, which will facilitate accurate diagnosis and more directed therapies and preventive strategies
through identification of environmental modifiers.
Name of contact:
Melanie Matheson
Email/Phone no. of contact:
mcmat@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628691
CIA Name: Prof Alastair Stewart
Admin Inst: University of Melbourne
Main RFCD: Basic Pharmacology
Total funding: $453,288
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Glucocorticoid resistance: identifying new anti-inflammatory drug targetsGlucocorticoid resistance: identifying
new anti-inflammatory drug targets
Lay Description (from application):
The control of chronic inflammatory diseases such as asthma involve use of drugs related to the steroid
hormone cortisol. Up to 40% of patients with more severe disease respond poorly or not at all to these drugs.
The remaining non-steroid treatments are only partially effective. Poor disease control is a great health and
economic burden. We have identified a molecular mechanism for steroid resistance and propose new studies to
identify novel drugs that act to reverse steroid resistance.
Research achievements (from final report):
Treatment of chronic diseases that affect the airways and lungs, like asthma and COPD involves the use of
drugs which widen the airways and descrease the instensity of inflammation. In severe forms of asthma and
COPD the effectiveness of the major class of anti-inflammatory drugs, the glucococortcoids, is very limited.
Our research has identified an important mechanism for the development of this resistance. A protein that
causes scarring, called TGFbeta, dramatically reduces the ability of glucocorticoids to increase the expression
of anti-inflammatory proteins. We are now working on new drugs that can inhibit some aspects of the action of
TGFbeta to see whether they can reverse the limitations in glucocorticoid effectiveness.
Expected future outcomes:
We have commenced studies of tranilast and pirfenidone in human airway cell culture to establish a proof-ofconcept for their use as clinical therapies to reverse steroid resistance. If successful, a rapid translation impact
on chronicairway disease could be expected.
Name of contact:
Prof Alastair Stewart
Email/Phone no. of contact:
astew@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1009374
Start Year: 2011
CIA Name: A/Pr Ivan Bertoncello
End Year: 2013
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Regenerative Medicine (incl. Stem Cells and Tissue Engineering)
Total funding: $586,965
Title of research award:
Lung epithelial stem cells in chronic respiratory diseaseLung epithelial stem cells in chronic respiratory disease
Lay Description (from application):
The World Health Organisation estimates that by 2020, 12 of 68 million deaths worldwide will be attributed to
lung disease with Chronic Obstructive Pulmonary Disease ranked the 3rd leading cause of death. Current
therapies are palliative, providing symptomatic relief but no prospect of cure. In this project, we aim to
determine how the ability of lung stem cells to repair the lung is compromised in disease in order to develop
innovative therapies to arrest or reverse the disease process.
Research achievements (from final report):
The broad aim of this research was to use best-practice animal models to analyse the organisation and
regulation of regenerative cells in the adult lung in order to understand how these cells are compromised in
lung diseases such as asthma and emphysema, and how they can be harnessed to repair the lung., In the course
of this work we have developed and refined methods and assays for the identification, isolation and
characterisation of lung stem cells that provide the field with powerful tools for measuring their ability to
regenerate and repair the lung. We have used these tools to analyse the behaviour of these regenerative cells
following lung inury, and in the diseased lung. We have shown that the interaction of regenerative cells in the
airways with intimately associated stromal cells in their microenvironment is critical in regulating their ability
to repair the lung, and have identified potential regulatory molecules which mediate this effect. This work, in
turn, has provided a "roadmap" for ongoing studies which aim to identify and analyse the behaviour of
comparable regenerative cells in the adult human lung which could be targeted to attenuate disease progression
and improve lung function in chronic lung disease.
Expected future outcomes:
This research provides valuable insights into the nature and properties of regenerative cells in the adult lung,
and the mechanisms that regulate their ability to repair the lung following insult, injury or disease. This
information will inform the development of novel stem cell based therapies in lung regenerative medicine.
Name of contact:
A/Prof Ivan Bertoncello
Email/Phone no. of contact:
Ivanb@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157067
CIA Name: Prof Carolyn Geczy
Admin Inst: University of New South Wales
Main RFCD: Pathology
Total funding: $392,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms of inflammation by S100A12Mechanisms of inflammation by S100A12
Lay Description (from application):
This project will characterise the biological and functional properties of a novel human pro-inflammatory S100
protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators
of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells.
These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location
makes them prime targets to trigger vascular and inflammatory events. They are known to be important in
allergy and infection and have a proposed role in chronic inflammatory processes. Although the mechanisms
of mast cell activation contributing to acute responses in allergic reactions are well accepted, ways in which
they are activated in asthma and other chronic inflammatory disease are virtually unknown. We will use lung
biopsies from patients with asthma to detect patterns of expression of the protein and determine its effects on
lung mast cells. A murine model will be used to define the characteristics of inflammation induced by the S100
protein and the role of mast cells in this process. Structural studies will define the parts of the protein necessary
for mast cell activation. We will attempt to identify its receptor on mast cells to enable future studies to define
how the protein triggers the cells to produce mediators such as histamine and those causing blood vessel
changes. This knowledge could lead to design of novel drugs that could regulate this process. Results from this
project will provide new knowledge of chronic inflammatory processes and could result in designing novel
strategies to regulate these. Studies are relevant to infectious diseases and many other conditions with a chronic
inflammatory basis, including asthma, rheumatoid arthritis, cardiovascular disease, cystic fibrosis and
infection.
Research achievements (from final report):
We discovered a novel activator of mast cells, important cells that, when stimulated, generate mediators that
cause asthma and allergy. This protein is a natural constituent of white blood cells that migrate to sites of
inflammation, paarticularly in response to infection. Upon release from these cells, the novel activator caused
mast cells to release histamine and other molecules that cause inflammation. It also amplified the response to
allergens. We identified a possible receptor on mast cells and were able to partially antagonise responses to the
protein. Administration of the protein caused inflammation and swelling and mice and provoked an
inflammation of the gut. We prepared antibodies against the activator, but these did not neutralise the
response., Mast cells are pivotal to the initiation of hbost responses to infection but the mechanisms whereby
activation occurs in these circumstances are undescribed. The significance of this work is the discovery of a
key mechanism that may regulate mobilisation of white blood cells to sites of infection. However when these
cells migrate to the lung in an episode of actute asthma, the severity of the attack may be exacerbated.
Indetification of a putative receptor for the novel activator may allow the design of new therapies that may
reduce severity. , We also studied the gene regulation of 3 new inflammation-associated proteins and found that
one of these, S100A8, that may be a novel anti-oxidant, is upregulated in the skin by UV light and by oxidants.
In addition, the gene is upregulated selectively in several cell types by corticosteroids, that are normally
immunosuppressive and we postulate that S100A8 plays an important protective role in preventing tissue
damage as a result of inflammation.
Expected future outcomes:
The project recieved continuing funding from the NHMRC aimed at characterising the receptor for the novel
mast cell activator. This will allow us to characterise the responses and may lead to design of new drugs that
would be more effective in treating patients with asthma.
Name of contact:
NHMRC Research Achievements - SUMMARY
Carolyn Geczy
Email/Phone no. of contact:
c.geczy@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300431
CIA Name: Prof Steven Krilis
Admin Inst: University of New South Wales
Main RFCD: Allergy
Total funding: $465,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
IL-16 regulates mast cell chemotaxis and function through the tetraspanin CD9.IL-16 regulates mast cell
chemotaxis and function through the tetraspanin CD9.
Lay Description (from application):
Mast cells are found in humans and other mammals at strategic sites such as skin, lining of the airways and gut
and provide a first line of defence against a variety of infections. These cells use a number of products that
have profound effects in humans. In particular, these products are thought to be involved in defence against
bacteria, viruses and are implicated in allergic conditions such as asthma. In normal circumstances mast cells
are only found in the tissues and not in the peripheral blood. However, we have made the first observation that
mast-like cells occur in the peripheral blood of patients with asthma and allergic conditions but not in normals.
This finding changed the prevailing paradigm for mast cell biology. The products that can influence mast cell
growth and function are vital to the understanding of how mast cells are involved in conditions such as human
asthma. We have demonstrated that a protein (CD9) on mast cells in the tetraspanin family is a receptor for a
product (IL-16) which is thought to be important in asthma and other inflammatory conditions. The
understanding of how mast cells are regulated by IL-16 may lead to potential new therapies in conditions such
as asthma and HIV-1 infection.
Research achievements (from final report):
We have identified a substance in cells that are implicated in asthma and other human conditions. This
substance has been shown by us to control how these cells may exert their effects in patients with asthma.
Understanding more about this substance and how it acts in the human body will lead to new therapies for
conditions such as asthma.
Expected future outcomes:
New therapies in asthma.
Name of contact:
Steven Krilis
Email/Phone no. of contact:
s.krilis@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300433
CIA Name: Prof Carolyn Geczy
Admin Inst: University of New South Wales
Main RFCD: Allergy
Total funding: $481,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
S100 PROTEINS IN ALLERGIC INFLAMMATIONS100 PROTEINS IN ALLERGIC INFLAMMATION
Lay Description (from application):
This project will examine new ways in which the major effector cells of allergy migrate to sites of
inflammation, such as the lung and the skin and are activated locally by a novel S100 protein mediator. We
have found a natural protein of the innate immune system, present in macrophages and neutrophils in the lungs
of patients with acute fatal asthma, which activates mast cells causing release of mediators that trigger asthma
attack. We have identified a potential receptor for this protein on human mast cells grown in culture. We will
characterise the chemical nature of this receptor and verify that it is functionally important in mast cell
activation. Because mast cells reside in almost all body tissues and are also important mediators of host
responses to infection and in chronic inflammation such as rheumatoid arthritis and psoriasis, our studies may
indicate novel and unexpected ways in which they are activated. Another key cell in allergic and parasitic
diseases is the eosinophil. We have found that two other S100 proteins are expressed in eosinophils from the
blood of normal individuals and that the genes that encode these proteins are regulated by mediators that
regulate eosinophil migration and survival at allergic sites. However although the numbers these cells are high
in lung biopsies from patients with asthma, we find that these proteins are generally not expressed. Because
one of the S100 proteins, S100A9, was recently found to be important in the ability of other blood cells to
migrate to signals that recruit them into tissues, we will examine whether this protein regulates the ability of
eosinophils to migrate. Results from this project will provide new knowledge concerning mechanisms of
allergy and may lead to the design of novel strategies to regulate the process. Results may have broader
ramifications applicable to other inflammatory and infectious diseases.
Research achievements (from final report):
We found new ways that cells involved in allergic inflammation, a process that can cause an asthma attack, can
be activated. A protein, called S100A12 present in blood neutrophils that migrate to sites in the body in
response to inflammation, was also expressed in other cells in asthmatic lung. Mast cells, present in high
numbers in lung, release histamine and pro-inflammatory mediators when they bind an allergen to which a
person is sensitised. These mediators contribute to an asthma attack. We showed that S100A12 also activates
mast cells and profoundly amplifies the IgE-allergen-induced response. When injected into mice, S100A12
caused mast cell-dependent inflammation which increased blood vessel permeability to cause swelling, and
recruited white cells from blood. We showed for the first time, that eosinophils in lung, but not in blood,
strongly express S100A12, thus potentially contributing to an acute asthma attack. S100A12 also promoted
mast cell migration and may contribute to sequestration of these cells in inflamed lung. We developed reagents
for an assay to measure S100A12 in body fluids. We found elevated levels in sputum from patients with
eosinophilc asthma, indicating that S100A12 levels may discriminate between different types of asthma.,
Because S100A12 is also present in other types of inflammation, such as rheumatoid arthritis, in which mast
cells are involved, we investigated its expression in arteries from patients with cardiovascular disease and
found high amounts. We found high levels in the blood from these patients compared to normals. This may be
the basis of a diagnostic test currently being developed.
Expected future outcomes:
Uncovering new mechanisms modulating allergic inflammation. Common processes in chronic inflammatory
diseases are also be modulated by S100 proteins; this has opened new research areas. An assay to quantitate
S100 protein levels in may represent a diagnostic tool. S100A12 is a potential therapeutic target; we are
developing models to test this.
Name of contact:
NHMRC Research Achievements - SUMMARY
Carolyn Geczy
Email/Phone no. of contact:
c.geczy@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300445
CIA Name: Prof Rakesh Kumar
Admin Inst: University of New South Wales
Main RFCD: Respiratory Diseases
Total funding: $329,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Cytokines regulating airway inflammation, remodelling and hyper-reactivity in chronic asthmaCytokines
regulating airway inflammation, remodelling and hyper-reactivity in chronic asthma
Lay Description (from application):
This project examines a new approach to treatment of asthma, based on immunisation against the body's own
chemical signals. The investigators will also be continuing studies on how "twitchy airways" develop in
asthma, the mechanisms by which scarring of the airway walls progresses, and the signals that trigger
inflammation of the airways. These studies will use a much-improved mouse model of the disease. In this
experimental model, which was developed by the investigators, sensitised mice are chronically exposed to low
concentrations of aerosolised egg white protein. The proposed studies will involve comparisons with animals
that are immunised against certain inflammation-related molecules, as well as with mice that are genetically
deficient in their ability to produce such molecules. The results of these studies may help in the development of
methods for long-term suppression of the changes that develop in the airways of asthmatics.
Research achievements (from final report):
Using a model of chronic asthma that resembles the human disease more closely than any other experimental
model, we have demonstrated that interactions between different groups of chemical signals contribute to the
development of inflammation and structural changes in the walls of the airways, as well as to the increased
reactivity of asthmatic airways to external stimuli. This result, which contradicts some currently held views
about which mediators are important in asthma, suggests that therapy which combines activity against these
different classes of mediators may be a more effective approach. We have also made some interesting
observations about the roles of various cell types involved in asthmatic inflammation, which may be of value in
defining future targets for therapy. Furthermore, we have for the first time described a valid experimental
model of an acute exacerbation of chronic asthma.
Expected future outcomes:
In the future, our model of an acute exacerbation of chronic asthma will allow us to undertake further
investigation of the mechanisms involved in the development of this complication, as well as the basis of
susceptibility to exacerbations.
Name of contact:
Prof Rakesh K. Kumar
Email/Phone no. of contact:
r.kumar@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300452
Start Year: 2004
CIA Name: Dr Nicodemus Tedla
End Year: 2006
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $254,250
Title of research award:
Leukocyte immunoglobulin-like receptors regulate the function of the major cells involved in allergic
inflammation.Leukocyte immunoglobulin-like receptors regulate the function of the major cells involved in
allergic inflammation.
Lay Description (from application):
An important aspect of the immune system is its ability to maintain a delicate equilibrium between the
extremes of reactivity and quiescence. A break in this equilibrium can lead to unchecked activation of immune
cells or inability of these cells to mount an effective defence. Potential outcomes of the unchecked activation
of cells are autoimmune diseases such as rheumatoid arthritis or allergic diseases such as asthma. A new
family of cell surface proteins termed leukocyte immunoglobulin-like receptors (LIRs) has been shown to
regulate immune cells by either increasing or decreasing their activity. In this project we will study the role of
LIRs in regulating the activity of the major cells involved in allergy and asthma. This study would provide
important insights to mechanism(s) of regulation of immune cell activation during protective immune
responses such as the fight against infections and cancers and during pathological inflammations such as
asthma and rheumatoid arthritis. Understanding the role of the LIRs in the regulation of immune cell activation
might lead to new therapeutic strategies aimed at restoring the balance between the inhibitory and activating
LIRs.
Research achievements (from final report):
The objectives of this project were to understand how activating and inhibitory LIRs regulate the balance
between protective and pathologic inflammation in vivo with special emphasis on allergic inflammation. , We
completed all the intended aims of the project and also extended aspects of our studies beyond the initial aims.
We determined the functions of activating and inhibitory LIRs on basophils was determined and published in
Blood (Blood. 2004: 104:2832-2839). We observed differential expression of LIRs between immature and
mature mast cells indicating developmental regulation of these molecules in mast cells. A manuscript was
published in Journal of leukocyte Biology reporting the above findings. , We recently published in
Rheumatology showing the effects of disease modifying anti-rheumatoid drugs on in vivo expression of LIRs
in rheumatoid synovium and in vitro function of LIR s on macrophages. We have also recruited 10 rheumatoid
patients and 10 age and sex matched controls and investigated the expression of LIRs in their peripheral blood
leukocytes. Our data shows that significantly higher proportions of lymphocytes from patients with rheumatoid
arthritis have an activating molecule LIR-6 as compared to controls suggesting that this molecule might play
important role in the activation of lymphocytes in RA. We obtained a new NHMRC Project grant (2008-2010)
to investigate the functions of LIR-6 and LIR-4 in RA and identify novel LIR ligands. We identified a potential
high affinity ligand for LIR-4 on the surface of monocytes with dissociation constant of 2.4x10-8M and
approximately 5000 ligand molecules per cell.
Expected future outcomes:
Determining the immune regulatory functions of LIRs in the pathogensis of allergic inflammation and
inflammatory arthritis may provide new theraputic approaches.
Name of contact:
Nicodemus Tedla
Email/Phone no. of contact:
N.Tedla@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350853
CIA Name: Dr Jane Butler
Admin Inst: University of New South Wales
Main RFCD: Motor Control
Total funding: $324,500
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Cortical, descending and reflex control of human inspiratory musclesCortical, descending and reflex control of
human inspiratory muscles
Lay Description (from application):
Of all the skeletal muscles, the breathing muscles perform the most crucial action, that is, they maintain
ventilation. The neural control of respiratory muscles must be finely integrated to maintain ventilation while
we are awake, asleep, exercising, eating and talking. The neural circuitry for the respiratory muscles is unique.
Control of respiratory muscles differs from that of limb muscles because the respiratory motoneurones are
activated rhythmically but are controlled via two descending pathways. During automatic breathing,
descending neural drive arises from the central respiratory pattern generator in the brainstem. Through this
system, disturbances are reflexly compensated for without conscious effort. However, in addition, to automatic
control, respiration can also be controlled voluntarily from the motor cortex, for example during speech or a
breath hold. However, in humans the neural connections and interactions between these two centres are poorly
understood. In addition to descending signals, the activity of inspiratory muscles is affected by sensory reflex
inputs. The proposed studies will investigate three aspects of the control of human inspiratory muscles that act
to 'pump' air into the lungs and upper airway 'dilator' muscles that act to keep the airway open. Because
expiration is usually passive during quiet breathing we will focus on the neural control of inspiration. First, we
will investigate some of the reflex connections of human 'pump' and 'dilator' muscles in people with and
without obstructive sleep apnoea. Second, we will study the descending control of inspiratory muscles using
single motor unit recordings. In addition, we will make the first detailed analysis of single motor unit activity
from the tongue. This muscle critically helps preserve breathing when we sleep. Finally, we will examine the
interactions between the motor cortex and medulla in the control of breathing about which relatively little is
known in awake humans.
Research achievements (from final report):
The first recordings of single motor units were made during breathing from the human tongue. This is an
important step in understanding the control of the upper airway during breathing which is comprimised in
diseases such as sleep apnoea. , We showed for the human parasternal intercostal muscles, that there is a
gradient in the distribution of neural drive to the muscles of the different intercostal spaces that is related to the
mechanical advantage of the muscles. The mechanisms for this have been investigated in a second study that is
completed. We examined the distribution of neural drive to various human inspiratory muscles. These studies
have improved our understanding of the neural control of human respiration., We have found that the shortlatency inhibitory reflex to inspiratory muscle loading was prolonged in people with obstructive sleep apnoea.
The duration of the inhibitory response was correlated with the severity of OSA. We demonstrated the
reproducibility of the technique to assess the inhibitory responses to loading in the scalenes muscles. We have
compared the reflex during hypercapnic and matched voluntary breathing and the size of the reflex was not
altered, suggesting that the reflex is not mediated via structures in the medulla.
Expected future outcomes:
I expect to continue to research the control of human respiration and develop new techniques to investigate this
topic as well as continue and develop new national and international collaborations.
Name of contact:
Jane Butler
Email/Phone no. of contact:
j.butler@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455201
Start Year: 2007
CIA Name: Prof Steven Krilis
End Year: 2009
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $580,433
Title of research award:
The role of RasGRP4, a mast cell specific protein in mast cell growth, differentiation and activationThe role of
RasGRP4, a mast cell specific protein in mast cell growth, differentiation and activation
Lay Description (from application):
Mast cells are cells found in the body which are strategically located at mucosal sites and skin where they form
a very important barrier in the immune defence. Mast cells have been implicated in a range of inflammatory
disorders such as asthma and more recently they have been shown to participate in immunity against bacteria,
viruses and fungi. Although a lot of work has been performed to analyze how mast cells respond to different
stimuli and what factors are important in their activation, there is little work available concerning what in the
mast cell controls it's ability to become a mast cell and not any other cell. We have identified a specific protein
that has been designated RasGRP4 which is restricted to mast cells and has, we believe, an important role to
play not only in guiding immature cells to become mast cells but also in controlling some of the important
functions of mast cells. Understanding this molecule more extensively will give us a much better
understanding of diseases that the mast cell is involved in such as asthma and other inflammatory disorders. In
addition it may shed insights into how mast cells are involved in immunity against bacteria and viruses.
Research achievements (from final report):
A substance produced by a cell (mast) has been identified as being critical in the function of these cells in
human conditions such as asthma. The current studies will delineate the role of this substance and results may
be used to produce new treatments for allergic conditions such as asthma.
Expected future outcomes:
The current studies will delineate the role of this substance and results may be used to produce new treatments
for allergic conditions such as asthma.
Name of contact:
Steven Krilis
Email/Phone no. of contact:
s.krilis@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455223
CIA Name: Prof Rakesh Kumar
Admin Inst: University of New South Wales
Main RFCD: Respiratory Diseases
Total funding: $508,528
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Influence of early-life viral infection on severity of murine chronic asthma and acute exacerbationsInfluence of
early-life viral infection on severity of murine chronic asthma and acute exacerbations
Lay Description (from application):
This project examines the relationship between certain childhood infections with respiratory viruses and the
progression of asthma later in life. The experimental work will use mouse models of mild chronic asthma and
of an acute exacerbation of the illness -- these unique models have been developed in the laboratories of the
chief investigators. It will employ the most appropriate mouse models of infection by the relevant group of
viruses. We expect to obtain new information about mechanisms of airway inflammation and airway hyperreactivity, which are characteristic features of chronic asthma and of acute exacerbations. This could help to
identify candidate signalling molecules and pathways that could be targeted by new treatments. The findings
might also provide a basis for development of ways to modify the immune response after respiratory viral
infection in childhood.
Research achievements (from final report):
We continued our studies on the mechanisms of inflammation in our model of an acute exacerbation of chronic
asthma, which yielded new information about the basis of steroid-resistant inflammation in asthma. In parallel,
we developed a new animal model which has allowed us to investigate how viral infection in early life and
subsequent exposure to allergens may interact to increase the risk of developing asthma in childhood. This
model closely simulates the sequence of neonatal infection with respiratory syncytial virus; sensitisation to
allergens via the respiratory tract; followed by low-level ongoing exposure to inhaled allergens. We showed
that in this model, some features of asthma can be elicited by either early-life infection or allergen exposure,
but both are required for development of the typical manifestations of the disease. Just as in children who
develop asthma, a pattern of immune response characterised by production of specific inflammatory signalling
molecules was necessary for progression of asthmatic inflammation. Importantly, we showed that inhibition of
mediators which promote this characteristic pattern of response can prevent the progression of changes of
asthma. These findings raise the possibility that this sort of approach might be relevant to primary prevention
of disease.
Expected future outcomes:
Continuing studies will focus on how the pattern of immune response that leads to production of specific
inflammatory signalling molecules is induced in and retained by responding lymphocytes. Future development
of experimental models such as that of early life viral infection may allow us to investigate the role of other
potential triggers of asthma in childhood.
Name of contact:
Prof Rakesh K. Kumar
Email/Phone no. of contact:
r.kumar@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455307
CIA Name: Prof Carolyn Geczy
Admin Inst: University of New South Wales
Main RFCD: Respiratory Diseases
Total funding: $561,978
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
S100 Proteins in asthmaS100 Proteins in asthma
Lay Description (from application):
This project will examine new ways in which the major effector cells of allergic inflammation and asthma are
regulated by novel S100 protein mediators. We find two natural proteins of the innate immune system, present
in cells in the lungs of patients with acute asthma. These have apparently opposing activates: one, S100A12,
activates mast cells to release mediators that trigger asthma attack. We will characterise how this proteins is
regulated in eosinophils, key cells in asthma. Because mast cells reside in almost all body tissues and are also
important mediators of host responses to allergy, infection and in chronic inflammation such as rheumatoid
arthritis and psoriasis, our studies may indicate novel and unexpected ways in which they are activated. A
second S100 protein (S100A8) is an efficient scavenger of oxidants that can cause damage to the lung. We find
both S100A12 and S100A8 that has been modified by oxidants, in sputum from pateints with asthma. In
addition to its anti-oxidant effects, S100A8 can downregulate production of some of the inflammatory
mediators that promote allergy and asthma. This is an important finding that will help us understand how drugs
used in treatment, such as steroids, are acting. We will generate a mouse expressing this protein in its lungs
and determine how this affects normal lungs and the course of asthma. If, as we expect, asthma is reduced, we
will have found a novel new pathway that is important in the resolution of asthma. Results from this project
will provide new knowledge concerning mechanisms of regulation in allergy and asthma and may lead to the
design of novel strategies to regulate the process. Results will have broader ramifications applicable to other
chronc inflammatory where these proteins are expressed. We have new reagents that could also assist in the
diagnosis of these conditions and may be useful for monitoring treatment.
Research achievements (from final report):
Asthma affects >3million people worldwide and is the most common chronic disease of childhood. We have
discovered a counter-inflammatory suppression of this abnormal airway response to allergens by an S100
protein generated by the inflammatory response, and suggest another mechanism of corticosteroid action. We
defined new oxidant-scavenging properties of S100A8 and S100A9; some of the oxidised proteins may limit
key processes in asthma pathogenesis. Novel adducts, or S100 expression in blood eosinophils may have
diagnostic potential. Understanding how these S100 proteins enhance anti-oxidant defense, and antiinflammatory pathways, may have the potential to broaden the limited therapeutic range of anti-asthma
therapies for eventual use in clinical practice.
Expected future outcomes:
S100A8 may be of therapeutic benefit in asthma. Potential effectiveness is indicated and will be tested more
thoroughly in animal models of asthma. Novel adducts, or S100 expression in blood eosinophils may have
diagnostic potential.
Name of contact:
Carolyn Geczy
Email/Phone no. of contact:
c.geczy@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568616
CIA Name: Prof Rakesh Kumar
Admin Inst: University of New South Wales
Main RFCD: Respiratory Diseases
Total funding: $495,711
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The Role of Pulmonary Macrophages in the Pathogenesis of an Acute Exacerbation of Chronic AsthmaThe
Role of Pulmonary Macrophages in the Pathogenesis of an Acute Exacerbation of Chronic Asthma
Lay Description (from application):
We will examine the role of lung defence cells, known as macrophages, in triggering the inflammation of acute
severe asthma. The experimental work will use unique mouse models of mild chronic asthma and of an acute
exacerbation of the illness, which have been developed in our laboratories. We will study the mechanisms of
activation of the asthmatic response and assess whether treatment with drugs that suppress the function of
macrophages can help to control steroid-resistant exacerbations.
Research achievements (from final report):
We investigated the role of a population of cells that are normally involved in host defence, known as
macrophages, in the development of acute severe episodes of asthma. We used a mouse model of an acute
exacerbation of chronic asthma for these studies. Our experiments demonstrated that macrophages in the lungs
are activated when a an asthmatic person is exposed to a trigger for an acute severe episode. We investigated
particularly how such activation occurs and how the activated macrophages then interact with other cells such
as T lymphocytes, to drive the production of mediators of allergic inflammation. We also commenced studies
to assess whether blocking the mediators involved in the activation of macrophages might be an effective way
of treating an acute severe episode of asthma.
Expected future outcomes:
This work has the potential to lead to development of new treatments for episodes of acute severe asthma,
which are the main reason asthmatics are admitted to the emergency department at a hospital.
Name of contact:
Prof Rakesh K Kumar
Email/Phone no. of contact:
r.kumar@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568812
CIA Name: Dr Cristan Herbert
Admin Inst: University of New South Wales
Main RFCD: Respiratory Diseases
Total funding: $295,984
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Th17 cell Cytokines in Airway Wall Remodelling in Chronic Asthma.Th17 cell Cytokines in Airway Wall
Remodelling in Chronic Asthma.
Lay Description (from application):
In asthma, structural changes in the airway wall occur which thicken the muscle and epithelial layers, stiffen
the airways and increase mucus production. This 'remodelling' makes breathing more difficult and is not
effectively reversed with current treatments. We will study the cells and molecules involved in the
development of these changes. This project will increase our understanding of the processes which drive these
changes and may lead to the development of improved medications.
Research achievements (from final report):
The aims of this project were:1. To demonstrate, using a mouse model of chronic asthma, the presence of a
population of Th17 cells in the airway wall which are able to interact with airway epithelial cells (AEC) and
fibroblasts.We showed that inflammatory cells isolated from the lungs of "asthmatic mice" included a group of
CD4 positive T-cells which were producing characteristic Th17 cell cytokines (IL-17A, IL-17F, IL-21 and
IL22).2. To inhibit Th17 cell signalling and assess the effect this had on the development of inflammation and
remodelling of the airway wall.Using genetically modified (IL-17R deficient) mice with impaired Th17 cell
function, we showed that most of the features of chronic asthma develop as they do in normal (wild type) mice.
Airway inflammation, subepithelial fibrosis and epithelial cell thickening developed in both wild type and IL17R KO mice. In contrast, mucus-producing cells were virtually absent in the airways of IL-17R KO mice
suggesting a critical role for Th17 cells in the development of this feature of asthma.3. To characterise cytokine
and growth factor production by airway epithelial cells and fibroblasts in response to stimulation with Th17
cell cytokines (IL-17A and IL-17F).We demonstrated that cultured airway epithelial cells and fibroblasts,
produced a variety of pro-inflammatory cytokines (CXCL-1, IL-6) and growth factors (FGF-1, FGF-2, VEGF)
following stimulation with Th17 cell cytokines. These cytokines are known to contribute to airway
inflammation and may drive the increase in mucus-producing cells in the airways of patients with asthma.
Expected future outcomes:
This project has identified that Th17 cells contribute to the development of asthmatic airway inflammation and
to the increased number of mucus-producing cells in the airways. A manuscript describing the results of this
project is currently in preparation and this should be ready for submission within 4 weeks.
Name of contact:
Cristan Herbert
Email/Phone no. of contact:
C.Herbert@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 630402
Start Year: 2010
CIA Name: Prof Steven Krilis
End Year: 2012
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $636,199
Title of research award:
Delineation of the role of RasGRP4 in mast cell growth, differentiation and activation, using RasGRP4
deficient miceDelineation of the role of RasGRP4 in mast cell growth, differentiation and activation, using
RasGRP4 deficient mice
Lay Description (from application):
Mast cells are important in immunity. Mast cells have been implicated in asthma and more recently they have
been shown to participate in immunity against bacteria, viruses and fungi. We have identified a specific
protein, RasGRP4, which is restricted to mast cells and plays an important role in their development and
function. Understanding this molecule more extensively will give us a much better understanding of diseases
that the mast cell is involved in such as asthma and other disorders.
Research achievements (from final report):
We are interested in a cell in the body called a mast cell. This cell is situated at the interface between the
external environment and the body, such as skin, airway, gut. These cells are important in the immune system
and can fight infections and also are involved in allergic diseases such as asthma. We have been able to identify
a substance that these mast cells make that plays a more broader role in human disease. This substance known
as RasGRP4 has important functions in immunity and in helping other immune cells in the body do their work.
Using mice that have been genetically modified so they do not produce this RasGRP4 we have made a
significant adance in understanding the role of this protein in arthritis in mice and in inflammation of the bowel
in these mice. The potential benefits to human disease are likely to arise from a further understanding of this
substance and also the ability to make drugs that can block the action of this substance.
Expected future outcomes:
It is likely that small drugs will be able to be identified using a drug screen to block the action of this substance
that is produced by mast cells.
Name of contact:
Steven Krilis
Email/Phone no. of contact:
s.krilis@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 630501
CIA Name: Prof Rakesh Kumar
Admin Inst: University of New South Wales
Main RFCD: Respiratory Diseases
Total funding: $517,587
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms of induction and progression of childhood asthma: investigations in a mouse modelMechanisms
of induction and progression of childhood asthma: investigations in a mouse model
Lay Description (from application):
This project investigates how certain respiratory viral infections in very young children might predispose to
developing asthma, and how inflammation in the airways in asthma might then worsen. The experimental
work, which will use unique mouse models developed in the laboratories of the chief investigators, will focus
on changes in genes that control the pattern of immune response to allergens and that regulate the progression
of inflammation.
Research achievements (from final report):
We undertook studies of the onset of childhood asthma, using a novel animal model developed in our
laboratories. In this model, newborn mice that have recovered from a viral infection resembling respiratory
syncytial virus (RSV) infection in children are sensitised to the model allergen ovalbumin (protein from egg
white) and later challenged with an aerosol of ovalbumin over a period of 4 weeks. We had shown that this
leads to the development of airway inflammation and changes in the airway wall which quite closely resemble
those of human asthma, so we wanted to investigate how the switch to an allergic pattern of inflammation
developed, and why it then progressed. Our studies revealed that these changes were related to the increased
production of specific inflammation-associated signals by the cells lining the major airways (epithelial cells).
Moreover, there was a sequence of changes in the genetic elements that control expression of genes (so-called
epigenetic changes) that correlated with a switch towards allergic inflammation and structural changes in the
airways. Thus our work has identified new mechanisms involved in regulating how asthma develops and
progresses, which may in turn help development of new interventions to prevent this.
Expected future outcomes:
Continuing studies on the pattern of the immune response and its regulation may help to identify additional
therapeutic targets, including in particular cells of the innate host defence response.
Name of contact:
Prof Rakesh K. Kumar
Email/Phone no. of contact:
r.kumar@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 100900
CIA Name: A/Pr Vicki Clifton
Admin Inst: University of Newcastle
Main RFCD: Obstetrics and Gynaecology
Total funding: $209,242
Start Year: 2000
End Year: 2002
Grant Type: NHMRC Project Grants
Title of research award:
The impact of severe asthma during pregnancy on placental function and fetal hypothalamic-pituitary-adrenal
functionThe impact of severe asthma during pregnancy on placental function and fetal hypothalamic-pituitaryadrenal function
Lay Description (from application):
This study will examine whether the glucocorticoids administered for the control of severe asthma during
pregnancy affects placental and fetal function. It is known that severe asthma during pregnancy is associated
with low birth weight babies but the events that cause reduced growth of the baby are unknown. However in
both animal and human pregnancies, increased exposure of the baby to glucocorticoids from the mother causes
growth restriction of the baby. Therefore we propose that the increased intake of glucocorticoids for the
treatment of asthma during pregnancy changes how the placenta functions and allows the fetus to be exposed
to maternal glucocorticoids causing changes in fetal development. We will examine placental blood flow and
measure some placental enzymes that may be involved in the control of blood flow in placentas collected from
women with mild, moderate and severe asthma and compare them to non-asthmatic women. We will look at
placental blood flow in utero using Doppler ultrasound and also in vitro after the placenta is delivered. We
want to see if the fetus is affected by increased intake of glucocorticoids by the mother by measuring a
hormone estriol, which originates from the fetus. We will measure estriol throughout pregnancy as it can easily
be detected in the mothers' urine. These studies will tell us if glucocorticoid intake for the treatment of asthma
can exert effects on the placenta and baby during pregnancy. These studies will make a significant contribution
both scientifically and clinically. At a scientific level we will be able to examine how increased maternal
glucocorticoid intake during pregnancy affects placental mechanisms and whether these changes affect the
fetus and clinically the outcome of this study will allow us to optimize asthma therapy during pregnancy so
that we can improve the outcome for the baby.
Research achievements (from final report):
The results of three years work (2000-2002) on the effect of asthma during pregnancy on fetal development
have now been published. My initial research was to examine the asthmatic mother, placenta and fetus and
determine whether the asthma alone or the inhaled steroids used to treat the asthma alter maternal, placental
and fetal function. What we found was very interesting. Asthmatic women who do not use inhaled steroids
have smaller babies. Furthermore maternal asthma only worsens during pregnancy when inhaled steroids are
no used. My data shows that the reduced growth may be due to decreased placental function in terms of
reduced placental blood flow and reduced placental 11beta hydroxysteroid dehydrogenase activity. The
findings of these studies will make a significant contribution to understanding what regulates fetal growth and
what regulates asthma severity in women during pregnancy. This study also covers two important aspects of
womens' health ie: pregnancy and asthma. These findings will influence health practice by determining how we
treat asthmatic women during pregnancy and promote a healthy start for children of asthmatic mothers.
Expected future outcomes:
My future questions are: what causes the increase in asthma severity and what causes the changes in placental
function? We also want to identify the best ways to treat asthmatic women during pregnancy and identify
inflammatory markers that may assist in designing treatment regimes. These treatments will be linked to the
best possible outcome for the baby
Name of contact:
Dr Vicki Clifton
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
Vicki.Clifton@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 104855
Start Year: 2000
CIA Name: Prof Leonie Ashman
End Year: 2004
Admin Inst: University of Newcastle
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $731,116
Title of research award:
c-Kit signalling and cellular responses in haemopoietic cellsc-Kit signalling and cellular responses in
haemopoietic cells
Lay Description (from application):
Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate
cellular growth and function. Mutations in the genes that code for these receptors or their downstream
signalling pathways contribute to many human cancers. The contributions of different signalling pathways
linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not
understood. In this project we aim to use cell and molecular biology approaches to determine the role of
different signalling pathways in cellular responses mediated by the growth factor receptor c-Kit. The c-Kit
receptor has essential functions in blood cell development, skin and hair pigmentation, gut function and the
reproductive system. It is also essential for the development and function of mast cells which trigger allergic
responses such as asthma and eczema. Mutant forms of the receptor have been identified in certain leukaemias
and colon cancers. Many new drugs that target specific intracellular signalling pathways have recently been
developed and are beginning to be evaluated in clinical trials. Better understanding of how individual
pathways contribute to the function of c-Kit and other receptors is essential for optimal use of these new drugs.
For example, it may enable the choice of drugs to block c-Kit dependent cancer cell growth or allergic
reactions without affecting the growth of normal blood cells.
Research achievements (from final report):
The work carried out in this project has contributed to our understanding of how abnormalities in cell
signalling proteins can cause cancer. Most importantly, it has identified factors that determine whether novel
anti-cancer drugs that target specific signalling proteins will be effective in particular patients. This work has
applications in tailoring cancer treatments to individual patients, and correspondingly ensuring the maximum
benefit from health expenditure.
Expected future outcomes:
N/A
Name of contact:
Ms Jennifer Saunders
Email/Phone no. of contact:
(02) 4921 5305
NHMRC Research Achievements - SUMMARY
Grant ID: 141777
Start Year: 2001
CIA Name: A/Pr Peter Wark
End Year: 2006
Admin Inst: University of Newcastle
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $394,416
Title of research award:
Mechanisms of Bronchial Epithelial cell activation in Rhinovirus infection in Asthma, COPD and normal
airwaysMechanisms of Bronchial Epithelial cell activation in Rhinovirus infection in Asthma, COPD and
normal airways
Lay Description (from application):
Not Available
Research achievements (from final report):
The objective of this project was to assess the response of human bronchial epithelial cells from subjects with
asthma to cells from healthy non-asthmatics following infection with the common cold virus rhinovirus (RV).
Asthmatics are known to be more susceptible to infection with RV, with more severe chest symptoms
compared to non-asthmatics. We obtained epithelial cells from volunteers by bronchoscopy and grew them in
vitro. Cells were then infected with RV. We found that RV replicated more efficiently on asthmatic epithelial
cells. While non-asthmatic cells following infection shut down and underwent programmed cell death
(apopotosis), asthmatic cells did not. In addition this abnormality was linked to reduced release of the anti-viral
factor interferon-beta. When interferon-beta was added to asthmatic cells following infection they underwent
apoptosis and RV replication was reduced. This is the first study to demonstrate that asthmatic epithelial cells
have an impaired innate immune response to RV and may in part account for the susceptibility asthmatics
suffer with RV. This also indicates a potential therapeutic target to minimise the effect of RV infection on
acute asthma.
Expected future outcomes:
Further work is underway to determine the nature of the signalling defect that has led to deficient interferon
release in asthmatic cells. We hope to assess the point in the signalling pathway were this defect occurs.
Furthermore we are planning to determine if a simialer defect is also present in subjects with chronic
obstructive pulmonary disease.
Name of contact:
Dr Peter Wark
Email/Phone no. of contact:
peter.wark@hnehealth.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300737
CIA Name: Prof PETER GIBSON
Admin Inst: University of Newcastle
Main RFCD: Infectious Diseases
Total funding: $407,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Characteristics and mechanisms of persistent asthma after common cold virus infectionCharacteristics and
mechanisms of persistent asthma after common cold virus infection
Lay Description (from application):
Asthma is a major health problem for the Australian community. Recent studies have shown increasing
numbers of people of all ages are developing asthma, and despite a fall in asthma deaths, large number of
people continue to have severe attacks requiring hospitalisation. In most cases the deterioration in asthma
symptoms is related to a cold or flu like illness. Viruses are the leading cause of these infections and are
known to make asthma symptoms worse. We have identified how viruses do this by triggering a type of
inflammation in the airways. We have also found that after a severe attack of asthma some people do not
recover completely. They appear to have persistent problems, and in some cases the virus can still be isolated
from the airways. How and why this occurs is not known. We are seeking to understand this problem and
describe how it affects people with asthma. We plan to investigate what effect certain viruses have on the
lungs of people with asthma by measuring cells and chemicals that are present in sputum. We will use recently
developed technologies to accurately see what viruses are infecting these people, and how the immune system
is working. This study will shed important light on potential causes of unstable asthma and the role that viral
infection plays in this. It may also lead to new opportunities to develop treatments that are more effective in
preventing and controlling asthma.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Deborah Hall
Email/Phone no. of contact:
deborah.hall@hnehealth.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300786
CIA Name: A/Pr Vicki Clifton
Admin Inst: University of Newcastle
Main RFCD: Obstetrics and Gynaecology
Total funding: $421,375
Start Year: 2004
End Year: 2008
Grant Type: Career Development Fellowships
Title of research award:
The effect of asthma during pregnancy on placental function and fetal developmentThe effect of asthma during
pregnancy on placental function and fetal development
Lay Description (from application):
Not Available
Research achievements (from final report):
This project identified that it is important that pregnant women with asthma have combined respiratory and
obstetric care during pregnancy for the best possible outcome for their babies. It also found there are sex
specific differences in how males and females respond to maternal asthma which could have implications for
future obstetric care.
Expected future outcomes:
This work lead to the development of a randomised controlled trial examining better ways to treat pregnant
asthmatic women using non-invasive techniques for assessment of asthma severity.
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 351158
CIA Name: Prof PETER GIBSON
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $332,875
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
The role of lycopene supplementation in the management of asthmaThe role of lycopene supplementation in
the management of asthma
Lay Description (from application):
Asthma is a significant and increasing health problem for Australia and is now listed as a National Health
Priority Area. There is immense community interest in dietary factors affecting asthma. This project examines
the potential for dietary carotenoids to be used to manage asthma. Carotenoids are antioxidants that are found
in orange and red fruits and vegetables, such as tomatoes, carrots and mangoes. Research suggests that dietary
carotenoids may be protective against asthma symptoms and /or onset. It is also likely that increasing intake of
carotenoid-rich foods may be more effective than taking dietary supplements, as the key nutrients or
combination of nutrients may not be known. This project will examine whether carotenoids such as lycopene
can reduce the tendency of asthmatic airways to overreact to common triggers. It also investigates whether
carotenoids can be used to prevent or reduce the severity of asthma attacks. The project will determine whether
tomato juice or lycopene capsules are more effective in this role. This work will provide the necessary
information to develop a large trial testing the ability of carotenoids to improve quality of life for people with
asthma. While there is evidence to suggest that carotenoids may be helpful in asthma, the data to date is
inconclusive. This study provides a scientific approach to evaluating the potential for carotenoids to be used as
a treatment for asthma.
Research achievements (from final report):
This project has examined the role of lycopene supplementation in the management of asthma. It has produced
exciting outcomes, both scientifically and clinically. Clinically this study has demonstrated that short term (10
day) consumption of a low antioxidant diet leads to reduced asthma control and worse lung function.
Scientifically this work has directed further research efforts, as we have demonstrated that these clinical effects
are associated with an increase in airway inflammation. We have also demonstrated that by using lycopene-rich
supplements, either in the form of tomato extract or tomato juice, inflammation in the airways can be reduced.
This mechanism is being further explored in a series of in vitro and animal experiments.
Expected future outcomes:
Having established the importance of lycopene in modifying airway inflammation, we are extending this work
in a larger, longer term clinical trial, to see if clinical improvements can be achieved using lycopene.
Name of contact:
Prof Peter Gibson
Email/Phone no. of contact:
peter.gibson@hnehealth.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401238
CIA Name: A/Pr Philip Hansbro
Admin Inst: University of Newcastle
Main RFCD: Allergy
Total funding: $382,118
Start Year: 2008
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of the association between chlamydial infection and asthma in different age groupsInvestigation
of the association between chlamydial infection and asthma in different age groups
Lay Description (from application):
Asthma is a common and severe lung disease that results from inflammation due to allergy and has symptoms
of breathing difficulties, wheezing, chest tightness, and cough. Asthma is clinically characterised by the
presence of certain types of responses from the immune system. We are looking for ways of preventing and
curing asthma. There is a well known link between certain types of bacteria, called Chlamydia, and asthma but
it is not known whether people develop asthma first and then get chlamydial infection or are infected first and
this leads to asthma. We have shown that if adult mice are exposed to an allergen during chlamydial infection
then the asthma gets worse. However, if newborn mice have a chlamydial infection then asthma is prevented
when they are adults. These are preliminary observations, which we need to expand and understand the
immune mechanisms that result in infection and allergy so that we can target them with antibiotics or vaccines.
We will investigate how the timing of chlamydial infection relative to exposure to allergens (before, during or
after) affects the development of asthma in adult mice. Newborns and young children have different immune
systems to adults, so we will investigate what effects the infection of young mice has on infection and allergy
later in life. We will also test a new vaccine we have developed against chlamydial infection to see if it can
prevent chlamydial infection and infection-induced asthma. We will then examine if there is the same
association between chlamydial infection and asthma in human asthmatics that present to hospital with
exacerbation of their asthma. This work will help us develop new strategies for preventing and curing asthma,
which may vary in different age groups. We will identify whether prevention of chlamydial infection by
vaccination (or antibiotics) can be used to prevent and treat asthma.
Research achievements (from final report):
We have shown for the first time that:, 1. A current, but not resolved chlamydial lung infection in adults may
promote the development of asthma with a predominantly neutrophilic phenotype (ie neutrophilic asthma).
Chlamydial infection induces an increase and decrease in neutrophilic and eosinophilic inflammation,
respectively, in the presence of pre-existing Ova specific (transgenic for the Ova-specific T cell receptor) T cell
responses in adults. This process is driven by the infection-induced influx of neutrophils., 2. Neonatal and
infant, but not adult, chlamydial lung infection induces permanent alterations in immune responses and lung
structure function that enhance allergic airways disease in later life., 3. A novel immunisation strategy that uses
transcutaneous immunisation of mothers, protects against chlamydial infection of neonates., 4. Chlamydia can
infect dendritic cells (DCs), that modulates their phenotype and enhances DC-induced Th2 responses, which
may exacerbate asthmatic responses., 5. We are exploring the translation of this research into human studies. ,
6. These studies have potentially identified novel prevention strategies for asthma i.e. the use of antichlamydial vaccination to prevent asthma.
Expected future outcomes:
Results will be validated in human studies and the mechanisms of how infections in adults or in early life
promote alterations in the phenotype or the development of asthma will be elucidated. Anti-chlamydial
vaccination, as well as other novel treatments to prevent infection-induced asthma will be tested and optimised.
Name of contact:
Phil Hansbro
Email/Phone no. of contact:
Philip.Hansbro@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455508
CIA Name: Dr Jodie Simpson
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $434,083
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Characterisation and Treatment of Innate Immune Dysfunction in Older People with Obstructive Airway
DiseaseCharacterisation and Treatment of Innate Immune Dysfunction in Older People with Obstructive
Airway Disease
Lay Description (from application):
Airway problems in older people are increasing. The two most common airway problems in people over the
age of 60 are asthma and chronic obstructive pulmonary disease or COPD. These diseases have a major impact
of the quality of life of older people. Airway inflammation is an important mediator of symptoms and
exacerbations in younger people with airway disease, however little is understood about airway inflammation
in the elderly. We will study airway inflammation in older people with airway disease and make comparisons
with both younger and older healthy controls. While many changes occur in our bodies with age, we do not
understand how ageing affects airway disease. Some of the changes which occur with ageing include increased
inflammation and an increased susceptibility to infection. We do not understand how these changes affect
people with respiratory disease or how they occur. Respiratory infections in older people with airway disease
often result in hospitalisation, and some bacterial pathogens can survive in the airways for long periods of time
without the typical symptoms of infection. This bacterial persistence can lead to an increased influx of
inflammatory cells and chemicals which can cause destruction of the airways and lead to changes in the airway
structure that are not reversible. We will investigate bacterial infection in older people with and without airway
disease and investigate an important pathway of the immune system called innate immunity. We will assess the
influence of ageing itself on these immune responses, and also the impact of associated airway disease. We
will also trial an anti-inflammatory therapy in older people with airway disease who have persisting bacteria in
their airways to see if this will help reduce inflammation and reduce the bacteria that persist in the airways.
These are new and exciting approaches to a common and increasing problem for older Australians.
Research achievements (from final report):
We have characterised the clinical and inflammatory characterisitcs of older people with obstructive airways
disease and investigated the influence of ageing, smoking and airflow obstruction on airway inflammation and
the innate immune response. Specifically we have identified age and smoking specific alterations in
inflammation and shown these to be most altered in those with chronic obstructive pulonary disease. For the
first time we have also demonstrated that a key receptor for the innate immune response is an independent
predictor of airway neutrophils - a key cell responsible for airway damage. Those participants with obstructive
airways disease also have more mucus secretion problems and reported a higher frequency of chest infections
than the control groups suggesting mutiple exposure to infection and smoking are implicated in the severity of
inflammation and immune dysfunciton in obstructive airways disease. , This research has improved our
understanding of the role of ageing, smoking and development of airflow obstruction in airways disease in
older people. We have also undertaken experiments to determine how specific aspects of the innate immune
system works in older people with airways disease compared to people without airways disease, these findings
will help us determine potential mechanisms for further study in efforts to develop new treatments and
management strategies.
Expected future outcomes:
We expect the results of the trial of antibiotics in older people with neutrophilic obstructive airways disease to
be complete late 2011. This study will help us understand if antibiotics are able to reduce neutrophilic airway
inflammation and bacterial load in the airways of older people with obstructive airways disease.
Name of contact:
Jodie Simpson
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
jodie.simpson@hnehealth.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455567
CIA Name: A/Pr Peter Wark
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $325,967
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Exposure of bronchial epithelial cells to inflammatory stimuli impairs their innate immune response to
rhinovirus.Exposure of bronchial epithelial cells to inflammatory stimuli impairs their innate immune response
to rhinovirus.
Lay Description (from application):
Asthma and chronic obstructive pulmonary disease (COPD) are the most common respiratory conditions in
Australia, both of these conditions are characterised by acute attacks precipitated by respiratory virus
infections. The most common trigger for these acute attacks is the usually innocuous common cold virus,
rhinovirus. The reason for this susceptibility remains poorly understood. We have previously shown that the
cells lining the airways of asthmatics are more susceptible to infection with rhinovirus and fail to react to this
infection effectively. We propose to further elucidate this defect and for the first time determine if it is also
present in subjects with COPD. We will examine the airway cells of subjects with asthma and COPD and look
for evidence of a defective immune response, relating this to the presence of persistent bacterial infection. We
will then grow these and infect them with rhinovirus, carefully examining the mechanisms behind this impaired
response to infection and then see if we can induce such impairment in these cells with chronic exposure to
infection and inflammatory stimuli. Our laboratory is well placed to investigate these problems with an
established track record in investigating patients with inflammatory airways disease and virus infection,
unparalleled access to sufficient well characterised clinical samples and have demonstrated the ability to study
virus epithelial cell interactions. This work will highlight those at risk of developing frequent debilitating
exacerbations along with the reasons for this and identify areas to target novel therapeutic interventions.
Research achievements (from final report):
We have demonstrated that the airway cells from people with asthma and chronic obstructive pulmonary
disease fail to mount an adequate antiviral repsonse to infection with rhinovirus, despite mounting a signifcant
inflammatory response (manuscript in preparation). , In primary bronchial epithelial cells (pBECs) from
subjects with asthma and COPD, this impaired response appears to be highly dependent on early immune
signalling of infection via the molecule MDA-5. We have determined that this early signalling can be inhibited
by exposure of the cells to oxidative stress. Furthermore we have shown that reversing this using naturally
occurring anti-oxidants effectively restores the antiviral response.
Expected future outcomes:
We aim to determine how oxidative stress impairs the responses of these cells, specifically, what factors are
associated and can be found in subjects with asthma and COPD. We plan to then develop strategies to
overcome this effect, specifically targetting the damage that occurs as a result of oxidative stress on cellular
mitochondrial function.
Name of contact:
Peter Wark
Email/Phone no. of contact:
peter.wark@hnehealth.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455592
CIA Name: Prof Peter Gibson
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $842,150
Start Year: 2007
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Managing Asthma in Pregnancy: the MAP studyManaging Asthma in Pregnancy: the MAP study
Lay Description (from application):
Asthma is a common problem for women during pregnancy. There is concern about how asthma and its
treatment may effect the baby, and also concern that asthma may deteriorate during pregnancy. Variable
adherence to treatment compounds this situation. Current clinical measures are not very accurate in
determining the correct dose of inhaled therapy to be used for asthma. However, there is now good evidence
from clinical trials in nonpregnant adults and children that this situation can be improved by using markers of
inflammation to guide therapy. One of the promising tests of inflammation is exhaled nitric oxide. We wish to
determine whether asthma can be better managed during pregnancy by using nitric oxide to guide therapy. We
will examine whether this approach leads to fewer asthma exacerbations, lower doses of corticosteroid, better
asthma control, and better outcomes for the baby. To do this we have put together a team with expertise across
each of the important areas of asthma, pregnancy, and research methods. This will enable the study to provide a
clear indication of which treatment approach is better, and this can then be offered to pregnant women and their
health care team.
Research achievements (from final report):
The MAP study is the first randomised study of its type in pregnancy, and the second largest trial of FENO
guided asthma management in general. We used an improved algorithm that incorporated FENO to adjust
inhaled corticosteroid dose and asthma symptoms to adjust beta2-agonist dose. Findings from the study showed
that our algorithm based on FENO and symptoms led to significant reductions in asthma exacerbations during
pregnancy, with a 50% reduction in incidence. This reduction was accompanied by important changes in
maintenance asthma pharmacotherapy, including more frerquent use of inhaled corticosteroid, but at a lower
daily dose, and earlier introduction of longacting beta2-agonist. Asthma management during pregnancy can be
improved by the use of measuring FENO concentration, and symptoms to adjust treatment. This algorithmic
approach might also be beneficial for non-pregnant women with asthma.
Expected future outcomes:
Further sub analyses will assess psychosocial outcomes and the effects of rhintis and pregnancy
Name of contact:
Peter Gibson
Email/Phone no. of contact:
peter.gibson@hnehealth.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455593
CIA Name: Dr Vanessa Murphy
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $465,210
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Viral infection and exacerbations of asthma during pregnancy: characteristics, mechanisms and
consequencesViral infection and exacerbations of asthma during pregnancy: characteristics, mechanisms and
consequences
Lay Description (from application):
At least 12% of pregnant women in Australia have asthma and more than half of these women will experience
an acute attack during pregnancy. This puts the fetus at risk of poor outcomes such as low birth weight or
premature birth, which has a significant impact on their health in both the short term and long term. The
mechanisms which lead to exacerbations of asthma during pregnancy are unknown, but have implications for
the treatment of pregnant women with asthma. In non-pregnant adults, the majority of asthma exacerbations are
caused by viral infection and it is likely that a similar mechanism operates in pregnant women with asthma. No
previous studies have identified the viruses responsible for exacerbations of asthma during pregnancy. We
currently have a promising lead in this area, with data showing that one third of pregnant women with asthma
have a severe exacerbation of their asthma requiring medical intervention during pregnancy, and a large
proportion of these are likely to be due to viral infection. We propose that during pregnancy, pregnant women
with asthma are more susceptible to viral infection than pregnant women without asthma. We also suggest that
women with asthma will have more severe viral infections during pregnancy, and that these will contribute to
the majority of acute asthma attacks during pregnancy. This project will determine the rate of infection among
pregnant women with and without asthma and determine the viruses responsible for acute attacks of asthma
during pregnancy. The study will also explore the inflammatory mechanisms which predispose women to viral
infection. These results will contribute to a greater understanding of the mechanisms leading to exacerbations
of asthma during pregnancy and will be used to develop more appropriate asthma monitoring and treatment
strategies for pregnant women, which will have health benefits for both mother and baby.
Research achievements (from final report):
Asthma is the most common medical illness to complicate pregnancy. The findings of this grant have indicated
that pregnant women with asthma are 56% more likely to have "common colds" during pregnancy, and this
may impact negatively by contributing to risk of severe asthma attacks during pregnancy. Pregnant women are
more likely to be adversely affected by severe respiratory illnesses such as influenza during pregnancy and our
work has shown that pregnant women have deficiences in key anti-viral proteins, which may contribute to this
problem. When blood samples collected from pregnant and non-pregnant women were exposed in the
laboratory to viruses inlcuding the common cold virus rhinovirus, seasonal influenza and swine flu, samples
from pregnant women produced less of the anti-viral proteins interferon alpha and lambda. This is an exciting
finding which may explain the increased morbidity and mortality from influenza infection among pregnant
women.
Expected future outcomes:
The severity and identification of viruses reponsible for common colds will be determined in both asthmatic
women and women without asthma. The relationship between eosinophilic lung inflammation and future risk
of exacerbations will be examined and further mechanisms for susceptibility to viral infection in pregnancy
explored.
Name of contact:
Vanessa Murphy
Email/Phone no. of contact:
vanessa.murphy@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455623
CIA Name: Prof Joerg Mattes
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $144,280
Start Year: 2008
End Year: 2011
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Molecular mechanisms of persistent allergic responses.Molecular mechanisms of persistent allergic responses.
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Asthma is the most common chronic disease in childhood and actue asthma attacks cause are a significant
contributor to overall morbidity and mortality. The projects undertaking have led to a better understanding of
the molecules and cells involved in the development and exacerbation of asthma employing experimental
disease models. These experimental discoveries have been translated into clinically significant observations to
develop an innovative foundation for better prevention and treatment strategies. Drug targets for diseaserelevant molecules are currently developed and further proof-of-principal and preclinical studies are performed.
The projects undertaken have also led to the establishment of an infant cohort studies where the preventative
effect of better asthma control during pregancy on the infants' respiratory health is currently under
investigation.
Expected future outcomes:
N/A
Name of contact:
Prof Joerg Mattes
Email/Phone no. of contact:
joerg.mattes@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455626
CIA Name: Dr Vanessa Murphy
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $162,748
Start Year: 2007
End Year: 2013
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Viral infection and exacerbations of asthma during pregnancy: characteristics, mechanisms and
consequencesViral infection and exacerbations of asthma during pregnancy: characteristics, mechanisms and
consequences
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
There have been several significant breakthroughs reported as part of this research award. In particular, the
results of the Managing Asthma in Pregnancy (MAP) study were very exicting. In this randomised controlled
trial, asthma was managed using a novel algorithm where treatment was adjusted based on a marker of
eosinophilic airway inflammation (fractional exhaled nitric oxide or FENO), and this approach was compared
to a group managed according to clinical guidelines, where treatment was adjusted based on symptoms and
lung function. The novel approach resulted in a 50% reduction in exacerbations of asthma during pregnancy, a
significantly longer exacerbation free interval, and a reduction in both oral corticosteroid use and reliever
medication use. In addition, using the FENO based algortihm resulted in more women being treated with
inhaled steroids, but at significantly lower doses. Reducing the corticosteroid burden is a significant benefit
among this cohort of pregnant women, who assign risk to the use of asthma medications in pregnancy. As well
as the positive impacts of this management approach on pregnant mothers, there was evidence of
improvements for neonates (reduced hospitalisations) and infants (reduced episodes of bronchiolitis and croup
at 12 months of age). This research programme has also made a significant contribution by completing a
systematic review of the literature to determine the risks of maternal asthma on adverse perinatal outcomes.
This work found that pregnant women with asthma have increased risks of low birth weight, preterm delivery,
pre-eclampsia, neonatal death and hospitalisation, as well as a small but significantly increased risk of
congenital abnormalities, in particular cleft lip with or without cleft palate. As part of this work, we
demonstrated that active management of asthma in pregnancy reduces the risk of some outcomes, including
preterm labour and delivery.
Expected future outcomes:
The Breathing for Life Trial (a multi-centre RCT of FENO based management vs usual care) has commenced
in a pilot phase at John Hunter Hospital. The aim of this trial is to demonstrate that FENO guided management
of asthma in pregnancy can improve perinatal outcomes, and reduce asthma in the offspring. This trial has the
potential to change clinical practice and improve health in childhood.
Name of contact:
Vanessa Murphy
Email/Phone no. of contact:
vanessa.murphy@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510714
CIA Name: Prof Paul Foster
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $625,655
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The role of microRNAs as new anti-inflammatory targets for the treatment of asthmaThe role of microRNAs as
new anti-inflammatory targets for the treatment of asthma
Lay Description (from application):
Asthma is a significant health and economic burden to our society and its prevalence has increased over the last
25 years. New ways of treating asthma are urgently required as current therapeutics treat the symptoms and not
the cause of the disease. Asthma is widely thought to be due to the abnormal accumulation of white blood cells
(inflammation) in the lungs of diseased individuals. In this project we are exploring new advanced ways to
inhibit inflammation and the development of disease.
Research achievements (from final report):
We have characterised the role of miRNA (molecules that control gene expression) in the regulation of allergic
airways inflammation with particular attention to the role of specific miRNA in response to house dust mite
(HDM) sensitisation and aeroallergen challenge (house dust mite model of allergic asthma). We have
completely characterised miRNA expression profiles in the airway wall following exposure. Unlike messenger
RNA, a discrete set of miRNA were up-regulated during primary sensitisation, and then again on re-exposure
to allergen (7 miRNA of which miR -let7, -21 and -126 and -145 were highly expressed). Increased expression
occurred early after allergen exposure (24hrs) and preceded the induction inflammation, tissue lesions and
airways hyperreactivity (AHR). Our initial focus has been on understanding the role of miR-126 in the
development of hallmark features of allergic asthma. To do this we a have pioneered the development (design,
mode of delivery, effective concentrations, dose response effects and duration of knock down) of novel
inhibitors of miRNA function, antagomirs (cholesterol based anti-sense oligonucleotides), to target specific
miRNA expression in the lung. We can now reproducibly inhibit the function of specific miR in the airways
after intranasal delivery of antagomirs. We have been able to demonstrate, for the first, that miR-126 is a
critical regulator of the allergic inflammatory response and the induction of airways hyperreactivity. Exposure
of mice to antagomir-126 inhibited decreased levels of inflammation, mucus and contrtriction of the lung. The
expression of HDM induced miRNA and inflammation was dependent on TLR4/MyD88 signalling. This work
(Mattes et al., PNAS below) is the first description of the potential of miRNA to control inflammatory
responses.???
Expected future outcomes:
We will continue to develop techniques that will enable us to determine the role of miRNA in asthma
inflammation in humans. The long term goal is to develop more specific ways to treat disease.
Name of contact:
Paul Foster
Email/Phone no. of contact:
Paul.Foster@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510715
CIA Name: Prof Paul Foster
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $564,625
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The mechanisms underlying pneumoviral-induced angiogenesis of the lung and its impact on the asthmatic
response.The mechanisms underlying pneumoviral-induced angiogenesis of the lung and its impact on the
asthmatic response.
Lay Description (from application):
Asthma, is a serious respiratory disease resulting in structural changes to the lung and breathing difficulties,
and is often compounded by respiratory viruses. We have shown that viral infection of newborn mice causes
the growth of new blood vessels in the lungs (a feature seen in human asthmatics). This project will investigate
the mechanisms involved and determine the potential of this feature as a therapeutic target.
Research achievements (from final report):
We have characterised viral clearance and the nature of the inflammatory response following early life
pneumoviral infection. This was correlated with the development of angiogenesis (increased numbers of blood
vessels), which was shown to be PVM specific (infection with influenza did not induce vascular remodelling).
These studies have been complimented with detailed qPCR profiling of angiogenic factors using a mouse
specific PCR array system, which has become recently available. The time course following PVM infection has
been mapped in terms of collagen deposition and fibrosis of the lung by immunohistohemistry (IHC). With AI1 we have described a model of childhood infection which demonstrates that administration of allergen at the
time of viral exposure (first 24hrs of life), primes the immune system for Th2 cell (asthma) responses. We
demonstrated for the first time that this occurs via a novel IL-25 regulated mechanism. We have mapped the
development of pulmonary angiogenesis using IHC to quantitate CD31 (Pecam-1) and CD105 (Endoglin)
immunoreactive cells in the airways and have shown that the number of small blood vessels (<500µm)
significantly increases 28 days following infection. Following a re-infection in adulthood this same increase in
small blood vessels is observed with the majority of the change being associated with blood vessels directly
localized to the airways. We have also shown an important role for IL-3 in the development of PVM induced
angiogenesis as mice deficient in IL-3 do not develop any changes in pulmonary vasculature following
infection and have extended this study with blockers of angiogenesis. Treatment with the endogenous
angiogenic inhibitor tumstatin during infection can prevent the development of pulmonary angiogenesis. We
have also demonstrated for the first time that PVM infection early in life predisposes to Th2 driven allergic
inflammation via a novel IL-25 regulated mechanism.
Expected future outcomes:
We hope in the future to determine new ways to treat the downstream effects of viral infection by modulating
the host immune response to stop new blood vessel growth. We will be exploring the role of miRNA in this
process.
Name of contact:
Paul Foster
Email/Phone no. of contact:
Paul.Foster@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510716
CIA Name: Prof Paul Foster
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $610,037
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Targeting the shared beta-chain of the IL-3, IL-5 and GM-CSF receptors as therapy for allergic
inflammationTargeting the shared beta-chain of the IL-3, IL-5 and GM-CSF receptors as therapy for allergic
inflammation
Lay Description (from application):
This research aims to develop new treatments for allergic diseases such as asthma and allergic rhinitis, which
remain significant public health problems in Australia. We will develop therapies targeting a common receptor
pathway with the potential to completely suppress acute and chronic disease whilst maintaining a single
molecular target. We will perform preclinical testing of antibodies for treatment of allergic disorders using a
novel mouse strain expressing the human form of this receptor
Research achievements (from final report):
Our proposed experiments sought to test the specific hypothesis that inhibition of IL-3/IL-5/GM-CSF
signalling through the common beta receptor subunit (?c) will block eosinophil expansion and tissue infiltration
and attenuate acute and chronic phases of asthma and allergic rhinitis. Using validated models that are well
established in our laboratory in concert with ?c/?IL-3 double knockout mice, we have shown for the first time
that the absence of IL-3/IL-5/GM-CSF signalling through the ?c receptor inhibits the expansion and tissue
infiltration of eosinophils during acute allergic inflammation and attenuates the development of pathological
features of asthma including airways hyperresponsiveness (AHR), mucus hypersecretion, and Th2 cytokine
production. Further, we have elucidated several key immunological mechanisms by which ?c regulates allergic
disease, including the control of Th2 lymphocyte-driven inflammation in the lung compartment, and the
regulation of myeloid dendritic cells in the lung in response to antigen provocation. In the last phase we have
characterised the role of the ?c in our model of allergic rhinitis. We can now report that this receptor subunit
also plays a critical role in regulating eosinophilia and Th2 responses in the upper respiratory tract. Thus,
targeting the ?c may provide a uniform approach to treating allergic inflammation of the upper and lower
respiratory tracts and is now under clinical trial investigations.
Expected future outcomes:
Following proof-of-concept studies showing that absence of ?c affects asthma outcomes in gene deleted mice,
we will employ a clinically relevant approach to block receptor function using mAb as tools for targeting ?c
Name of contact:
Paul Foster
Email/Phone no. of contact:
Paul.Foster@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510717
CIA Name: Dr Ming Yang
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $524,457
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Innate immune factors regulate steroid-resistant airways hyperreactivity and asthmaInnate immune factors
regulate steroid-resistant airways hyperreactivity and asthma
Lay Description (from application):
Infection induced asthma is often difficult to manage because of lack of efficacy of steroid treatment. The
innate immune system plays an important role in inflammation associated with infection. I have shown that two
innate immune factors, IFN-gamma and lipopolysaccharide (LPS), induce airways hyperreactivity that is
resistant to steroid therapy in a mouse model. Identification of how this pathway works may help in the
treatment of infection induced steroid-resistant difficult to manage asthma.
Research achievements (from final report):
, Infection induced asthma is often difficult to manage because of lack of efficacy of steroid treatment. The
innate immune system plays an important role in inflammation associated with infection. We have determined
the roles of neutrophils, macrophages and the TLR4/MyD88 pathway in mouse models of steroid resistant
asthma. Glucocorticoids have been used widely to treat many inflammatory diseases, especially those of the
airways, skin and joints. However, under some conditions inflammation is poorly controlled by
glucocorticoids, and the mechanisms leading to the induction of steroid insensitive components of
inflammation are largely unknown. An excellent example is severe asthma where steroids fail to suppress
inflammation that drives bronchial constriction (airway hyperresponsiveness (AHR)). We have described, for
the first time, how the innate immune system suppresses glucocorticoid signalling in the lung, which results in
steroid-resistant macrophage activation and AHR. We further demonstrated that IL-27/IFNgamma/MyD88
pathways are integrated (previously unknown) to inhibit GR signalling and that this pathway is
proinflammatory. Furthermore, identification of this pathway has significant implications for how
inflammation is regulated by macrophages, and potentially how steroid resistance develops in asthma and other
chronic inflammatory diseases. ,
Expected future outcomes:
We have identify the molecular mechanisms underpinning the LPS/ IFN-gamma regulated AHR. We have
determined the roles of these mechanisms in the development of steroid resistant asthma providing important
directions for future studies into the molecular pathogenesis and treatment of AHR in human asthma.
Name of contact:
Ming Yang
Email/Phone no. of contact:
ming.yang@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510727
CIA Name: Dr Lisa Wood
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $510,798
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
High fat diets and airway inflammation in asthmaHigh fat diets and airway inflammation in asthma
Lay Description (from application):
This project examines how high fat diets affect inflammation and asthma outcomes. Research regarding the
relationship between asthma and obesity is inconclusive. This project examines high fat intake as an initiator of
both these conditions. We explore statins as a treatment for diet-induced inflammation. By increasing our
understanding of how fat affects inflammation, we will be able to plan a dietary approach to improve asthma
outcomes.
Research achievements (from final report):
This New Investigator grant has enabled Dr Wood to confirm the key hypothesis underpinning the grant, that
high fat diets augment airway inflammation in asthma. We have demonstrated that in asthmatics, a high
fat/high energy challenge leads to an increase in airway neutrophilia, which is associated with an increase in
the gene expression of TLR4, which is a cell surface receptor found on sputum cells. This confirms our
hypothesis that dietary fat activates innate immune mechanisms in the airways. We also demonstrated that the
airway inflammatory response to fatty acids depends on the quality of the fat consumed, with trans fatty acids
leading to a significantly greater increase in airway neutrophilia than non-trans polyunsaturated fatty acids. In
addition, we have demonstrated that an inflammatory response occurs both in asthmatics that are of healthy
weight, as well as those who are obese. A key clinical finding is that a high fat/ high energy meal suppresses
postbronchodilator lung function recovery. This is highly significant, as it suggests that the type of diet often
consumed by obese individuals, may reduce the response to asthma medications, thereby interfering with
pharmacological asthma management.
Expected future outcomes:
The finding that a high fat/ high energy meal suppresses postbronchodilator lung function recovery was
unexpected, yet has highly significant clinical implications. Investigation of the mechanisms behind this effect
is the subject of a current NHMRC project grant application.
Name of contact:
Dr Lisa Wood
Email/Phone no. of contact:
Lisa.wood@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510762
CIA Name: A/Pr Peter Wark
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $395,560
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
The mechanisms of infection of bronchial epithelial cells by human and avian influenza viruses in chronic
airways diseaseThe mechanisms of infection of bronchial epithelial cells by human and avian influenza viruses
in chronic airways disease
Lay Description (from application):
Influenza is an important infection that causes disease every year in the Australian population. People with
lung disease are at particular risk to its effects. The ability of the virus to grow in birds and change its
appearance to our immune system allows this virus to cause severe disease every year. We will examine the
immune response to this virus in human cells, comparing this response to human and bird strains of the virus
and see why subjects with lung disease are more susceptible.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
Peter Wark
Email/Phone no. of contact:
peter.wark@hnehealth.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510803
CIA Name: Dr Kelly Asquith
Admin Inst: University of Newcastle
Main RFCD: Allergy
Total funding: $150,442
Start Year: 2008
End Year: 2012
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Therapeutic potential of the IL-3-IL-5-GM-CSF common beta receptor to treat upper and lower allergic
airwayTherapeutic potential of the IL-3-IL-5-GM-CSF common beta receptor to treat upper and lower allergic
airway
Lay Description (from application):
This research aims to develop new treatments for allergic diseases such as asthma and allergic rhinitis, which
remain significant public health problems in Australia. We will develop new therapies with the potential to
completely suppress acute and chronic allergic disease targeting a common receptor protein that controls
multiple facets of allergic inflammation. We will test antibodies intended to treat human asthma using a novel
mouse strain expressing the human form of this receptor.
Research achievements (from final report):
Allergic asthma has increased in incidence in Western countries in the last 30 years. Despite this, therapeutic
options are limited and no effective strategies exist to prevent life-threatening 'asthma attacks'. This project has
provided 'proof of concept' evidence (using animal models) for the design of novel therapeutics targeting the
Bc receptor subunit which addresses many of the weaknesses of other asthma therapies. Further, we have also
shown that this therapy may also be effective to treat other allergic disorders such as rhinitis. These findings
are highly novel and facilitate movement of this investigation from animal models into the next phase where
mechanisms of targeting the Bc receptor subunit in humans can be explored. If successful this could represent
one of the most targeted, effective treatments for highly prevalent diseases such as asthma and allergic rhinitis.
Expected future outcomes:
Our findings support the development of human therapeutics targeting the Bc receptor subunit, which have the
potential to greatly reduce the health burden produced by patients suffering from asthma and other allergic
diseases. This includes reducing the number and severity of exacerbations, improving productivity and quality
of life.
Name of contact:
Kelly Asquith
Email/Phone no. of contact:
kelly.asquith@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569219
CIA Name: Prof Philip Hansbro
Admin Inst: University of Newcastle
Main RFCD: Allergy
Total funding: $616,196
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms and treatment of early life chlamydial infection and associated asthmaMechanisms and treatment
of early life chlamydial infection and associated asthma
Lay Description (from application):
Asthma is a serious respiratory disease that results from certain immune responses to allergens and there are no
cures. Immune responses and lung structure may be permanently altered by respiratory chlamydial infection
early in life that leads to reduced lung function and asthma but how this occurs is unknown. In this project we
will determine how early life infections affect immune responses, lung function and asthma and test novel
treatments and preventions for infection-associated asthma.
Research achievements (from final report):
Asthma is an important respiratory disease and current treatments only treat the symptoms. There are no cures
and treatments do not work in some people. The role of bacterial infections in the induction of asthma and
increasing asthma severity is not understood and enhancing our understanding may identify new therapeutic
opportunities. In this project we have identified important roles for infection of the respiratory with Chlamydia
in both inducing and increasing the severity of asthma in early life and in adulthood im mouse models of
asthma. In early life infection increased mucus prduction and reduced lung function this occurred through the
induction of previously unknown immune responses (TLR2, IL-13 and TRAIL). In adults infection increased
asthma severity and induced resistance to steroid therapy through other immune responses (IL-17 and IFNgamma). We also showed similar effects with other bacteria that are associated with asthma (Haemophilus)
whereas other bacteria (Streptococcus penumoniae) are protective. This shows that we may be able to develop
new preventions and treatments for asthma based on targeting pathogenic infections or by utilising protective
ones. We may be able to use vaccination or antibiotics or target the new immune factors we have identfied in
new preventions and treatments for asthma.
Expected future outcomes:
We will determine the best preventions and treatments for infection-associated asthma by testing different
combinations of vaccination, antibiotics and steroid treatments as well as targeting the novel immune factors
involved in immune responses to infection that we have identified.
Name of contact:
Prof Phil Hansbro
Email/Phone no. of contact:
Philip.Hansbro@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631075
CIA Name: Prof Joerg Mattes
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $605,096
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The role of microRNAs in the regulation of antiviral and inflammatory responses during experimental
rhinovirus infectionThe role of microRNAs in the regulation of antiviral and inflammatory responses during
experimental rhinovirus infection
Lay Description (from application):
Asthma exacerbations due to viral infections are a major health and economic burden to our society. Treatment
of asthma exacerbations focuses on reducing the symptoms rather than the cause of the disease. Virus-induced
asthma exacerbation are widely thought to be due to an abnormal influx of white blood cells into the lungs
(inflammation) and an altered anti-viral responses. In this project we will explore novel strategies to inhibit
inflammation and to promote the anti-viral response.
Research achievements (from final report):
Virus-induced lung infections and asthma attacks are very common but current treatments are supportive rather
than deal with the cause of disease. We determined the role of small molecules called micro(mi)RNAs during
virus infections of the lung and found that different viruses (e.g. rhinovirus versus respiratory syncycial virus)
activate very specific miRNAs. We characterised the temporal and spatial distribution of these miRNAs in the
lung and investigated the interaction of these miRNA with cellular immune receptors (e.g. TLRs). We
demonstrated an important role of a TLR in the antiviral response. We designed and validated drugs that
specifically block specific miRNAs and investigated their therapeutic potential in preclinical disease models.
We found that inhibition of specific miRNAs impaired inflammatory responses in the lung and modulated
interferon release induced by viruses. This was associated with changes in levels of suppressors of cytokine
signalling (SOCS) 1 which is targeted by a specific miRNA. Our studies also identified RV-induced
upregulation of a novel E3 ubiquitin ligase called Midline-1 and we found that targeting this molecule also
resulted in amelioration of inflammatory responses in rhinovirus infection. Together we identified novel
signalling pathways modulated by or interfering with miRNAs which regulate virus-induced lung inflammation
and that may be exploited for the development of novel therapeutic strategies.
Expected future outcomes:
We will continue to characterise the identified novel signalling pathways modulated by or interfering with
miRNAs in disease models, human cells and clinical studies to translate these discoveries into new treatments
and clinically significant findings.
Name of contact:
Prof Joerg Mattes
Email/Phone no. of contact:
joerg.mattes@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1004185
CIA Name: Prof Paul Foster
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $665,532
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Mast cell proteases suppress respiratory viral infections and alleric inflammation of the airwaysMast cell
proteases suppress respiratory viral infections and alleric inflammation of the airways
Lay Description (from application):
Severe RSV infection and asthma accounts for poor quality of life in our community and current treatments
have limited effects. Although the factors regulating these disorders are poorly understood, mast cells (MCs)
may play important roles. We have shown MC protease-6 protects against viral infection. Here we will identify
how MC and their factors are involved in the control of severe respiratory infections and allergic disease of the
lung, and identify potential new ways to treat these conditions.
Research achievements (from final report):
We investigated of the role of mast cells a type of white blood cell in the innate immune response to respiratory
viral infection. The granular component of the mast cell called mMCP-6 is important in host defence against
bacterial and helminth infections however its function in viral infections is unknown. Through our studies we
demonstrated that once mMCP-6 is released from mast cells it has a prominent immunoprotective role in the
early stages following a respiratory viral infection. The presence of mMCP-6 was associated with increased
lung inflammation and histopathology whereas the absence of mMCP-6 was associated with an increased viral
load at early time points during infection as well as decreased release of key factors important in the host antiviral response. This is the first demonstration of a beneficial role for mast cells in host defence against an acute
viral infection.
Expected future outcomes:
We have initiated detailed miRNA profiling of mast cells as they differentiate to identify their role in mMCP6
biosynthesis.
Name of contact:
Paul Foster
Email/Phone no. of contact:
Paul.Foster@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1004267
CIA Name: Prof Paul Foster
Admin Inst: University of Newcastle
Main RFCD: Respiratory Diseases
Total funding: $675,031
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Targeting microRNA (miRNA) as a unified therapeutic approach to the treatment of asthma and allergic
inflammationTargeting microRNA (miRNA) as a unified therapeutic approach to the treatment of asthma and
allergic inflammation
Lay Description (from application):
Approximately 30% of our community suffers from allergic inflammation (asthma/rhinitis/dermatitis) that
results in poor quality of life. The factors regulating these disorders are poorly understood and current
treatments only target the symptoms and not the cause of disease. MicroRNA control gene expression and are
emerging as potential regulators of inflammation. This project will identify the role of microRNA in the
regulation of allergic diseases and their potential as new therapeutic targets.
Research achievements (from final report):
We have characterised the allergic inflammatory response in our models of asthma, allergic rhinitis (AR) and
allergic dermatitis (AD). These models are characterised by an allergic (Type 2) immune response. We
observed changes in the tissue structure in our model of AD and chronic asthma and this was associated with
increased levels of IL-22, a chemical messenger thought to be involved in tissue repair mechanisms. This is a
novel observation and supports emerging clinical data for this factor in disease. We have also shown a new role
for small molecules called microRNA in the regulation of allergic inflammation. Blocking the function of these
miRNA (mR-145) significantly attenuated inflammation and the development of hallmark features of allergic
airways disease. Further, inhibiting the function of miR-145 was as effective as the delivery of systemic
steroids. We have previously shown that miR-126 is important for the development of acute allergic
inflammation of the lung and have now investigated the effect of blocking this miR in a model of chronic
asthma. Inhibition of the function of miR-126 attenuated the recruitment of eosinophils into the airway wall but
did not significantly inhibit remodelling of the airway wall. Cooperative analysis of miRNA arrays has
demonstrated that one miRNA is unique to all three allergic inflammatory conditions and we are currently
designing experiments to inhibit the function of this miR in each model.
Expected future outcomes:
Cooperative analysis of miRNA arrays has demonstrated that one miRNA is unique to all three allergic
inflammatory conditions and we are currently designing experiments to inhibit the function of this miR in each
model.
Name of contact:
Professor Paul Foster
Email/Phone no. of contact:
Paul.Foster@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157085
CIA Name: Prof Paul Hodges
Admin Inst: University of Queensland
Main RFCD: Motor Control
Total funding: $168,958
Start Year: 2001
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Physiology and pathophysiology of trunk control mechanismsPhysiology 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 intra-abdominal 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.
NHMRC Research Achievements - SUMMARY
Name of contact:
Paul Hodges
Email/Phone no. of contact:
p.hodges@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219193
CIA Name: A/Pr William Young
Admin Inst: University of Queensland
Main RFCD: Not Allocated
Total funding: $112,500
Start Year: 2003
End Year: 2007
Grant Type: SRDC - Research
Title of research award:
Case-control study to promote oral health in asthmatic children:Natural dietary strategies to conserve teeth
erosionCase-control study to promote oral health in asthmatic children:Natural dietary strategies to conserve
teeth erosion
Lay Description (from application):
Asthmatic children are at risk of dental corrosion, from medications that shut off saliva. Saliva protects teeth
from acids in soft drinks and stomach-acid reflux. Dentist, William George Young and Nutritionist, Peter
Davies, at the University of Queensland study children’s teeth, diet and lifestyles for the best natural methods
to promote oral health. They will counsel parents and children on diets that conserve the teeth from dental
erosion and decay by salivary stimulation. Patients need to self-manage their asthma and diets to avoid
negative outcomes and costs in acute medical and dental therapy for these two chronic conditions.
Research achievements (from final report):
This original study of Australian school children by a dental specialist and a nutrition expert documented their
lifestyles, diets, heights, weights, general and oral health. The impact of sports dehydration and asthma
medications on their teeth were specifically investigated. The severity of the common, chronic condition,
dental corrosion, was assessed from wear on their deciduous and permanent dentitions. Reexamination of their
teeth, one year later, evaluated the success of a natural strategy promoted to prevent continuance of pain,
excessive tooth wear, and need for dental treatment. This natural strategy emerged from the lifestyle interviews
and diet diaries of the children. Parents and children needed to know that: , *Sports dehydration puts children's
teeth at risk of dental corrosion because it shuts of salivary protection of the teeth against acids in soft drinks.
Asthma medications similarly, shut off saliva protection., *Diets high in soft drinks are nutritionally inadequate
and contribute to overweight and obesity in childhood. Their acidity causes dental corrosion. Their sugar
(sucrose) content promotes dental decay (caries)., *Diets high in fresh fruit and vegetables promote oral health.
Their natural acid, sugar, mineral, vitamin and water content aid saliva protection and cause neither dental
corrosion nor decay., *Dairy foods are essential for healthy bones and teeth. Milk, cheese and yoghurt protect
teeth from acids in the diet and from decay-causing bacteria., Pain, excessive tooth wear and the need for
dental treatment were reduced when children and parents adopted these natural strategies.
Expected future outcomes:
Collaborations between parents and health professionals will promote scientifically-based natural strategies to
maintain children's oral health. Dental professionals identify tooth wear in the deciduous dentition, implement
these strategies to maintain the health of the permanent dentition in children at risk from sports dehydration,
from acid drinks or from asthma medication.
Name of contact:
William George Young
Email/Phone no. of contact:
w.young@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 252811
CIA Name: Prof David Fairlie
Admin Inst: University of Queensland
Main RFCD: Enzymes
Total funding: $439,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Design and Development Of Small Molecules To Regulate Protease Activated Receptor Type 2Design and
Development Of Small Molecules To Regulate Protease Activated Receptor Type 2
Lay Description (from application):
A new class of proteins have been discovered on the surface of cells. These are activated by enzymes known as
proteases and are therefore called Protease Activated Receptors (PARs). PARs appear to be very important
'sensors' of proteases outside cells, becoming activated in response to very low concentrations of proteases.
This suggest that proteases may exert some of their biological effects through these receptors, which are now
implicated in a growing number of diseases (e.g. thrombosis, cardiovascular disorders, asthma, inflammatory
bowel disease, Crohn's disease, pancreatitis, stomach and colon cancer, arthritis, and there may also be a role in
wound healing). We are working towards dissecting the roles for one of these receptors (PAR2) in disease by
developing small molecules for selective binding to this receptor. We will particularly distinguish between
compounds that can activate (agonists) or deactivate (antagonists) the receptor. These experiments will involve
computer-assisted compound design, structural comparisons between small molecules with activity and those
without, and cellular studies designed to measure affinity, activation and deactivation of PAR2. The outcome
will be a series of small molecules that bind tightly to the PAR2 receptor and have a well defined function
(antagonist, agonist, partial agonist). While the above studies are in progress some peptides that are known to
activate this receptor will be examined in rodent models of human disease (airways inflammation, pancreatitis,
stomach and colon cancer, arthritis). Studies like this have been very revealing for us in the past (Nature 1999,
398, 156-160 "A protective role for protease-activated receptors in the airways"). Then the designed and
developed compounds will also be examined for signs of therapeutic potential. The work will provide a better
understanding of how this receptor works and a clearer picture of the role of this receptor in human disease.
Research achievements (from final report):
PAR2 has been idntified and investigated on 30 epithelial and endothelial cell types, and a potent agonist has
been examined for effects on gene expression in two cell types. Structure-activity relationships for several
hundred peptidic agonists provided information used to create the first PAR2 antagonists as well as the first
nonpeptidic agonists. The structures of these compounds were determined, a model was created for their
interaction with the transmembrane region of PAR2, and mechanisms of agonismwere investigated.
Preliminary in vivo studies were also conducted to begin documenting the role of PAR2 in inflammatory
diseases.
Expected future outcomes:
The research results pave the way for a new class of antiinflammatory and antiproliferative drugs to be
developed. The information gathered in this project provides new insights to the role of PAR2 in proliferative
and inflammatory processes and disorders and new probes for analysing this novel type of GPCR.
Name of contact:
David Fairlie
Email/Phone no. of contact:
d.fairlie@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 252812
Start Year: 2003
CIA Name: Prof David Fairlie
End Year: 2005
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $473,250
Title of research award:
Agonists and Antagonists Of The Human Complement C3a ReceptorAgonists and Antagonists Of The Human
Complement C3a Receptor
Lay Description (from application):
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis,
multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that
naturally occuring "Complement" proteins in human blood are involved in exacerbating these and many other
human diseases, yet there are no good drugs available to counteract their effects. One of the most important
complement proteins is known as C3a. It is called an anaphylatoxin and is thought to be a pivotal component of
the complement system synthesized by the human body early on in the development of inflammatory and
immune diseases. New compounds that could stimulate or block the activity of C3a are expected : (a) To
lead us to a better understanding of how C3a binds to its receptors on immune cells and its role in the immune
response to infection and injury, and (b) To enable the rapid development of an entirely new class of drugs for
treating autoimmune and inflammatory diseases. No Complement-based drugs are yet available. It is not yet
possible to examine detailed structures of the receptors on cells that interact with complement proteins.
However it is possible to determine and analyse three dimensional structures of small molecules that can bind
to human immune cells, and mimic or block effects of human C3a on cells, rat tissues, and in whole rats. We
will identify and improve such small molecules by optimising their binding to immune cells, by tailoring them
to selectively block or mimic just the effects of C3a, and by making them pharmacologically stable for
administration (preferably by mouth) to rats (and humans). We will then test them in rats for potential future
development into a completely new type of anti-inflammatory drug, one that treats inflammatory disease
processes rather than just the symptoms like most current antiinflammatory drugs.
Research achievements (from final report):
Potent and selective new regulators of the human complement receptor known as C3aR have been created,
their structures determined, and their mechanisms of action investigated on human immune cells. This research
should enable the development of new drugs for the treatment of inflammatory diseases and immune disorders
and provides new insights to natural immune defence mechanisms in human blood.
Expected future outcomes:
We expect that a new class of orally bioavailable antiinflammatory drugs can be developed from the
information and lead compounds generated in this research project. The results will also contribute to piecing
the jigsaw puzzle together on how the surfaces of immune cells trigger physiological responses that protect
humans from infection.
Name of contact:
David Fairlie
Email/Phone no. of contact:
d.fairlie@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 252823
CIA Name: Prof Karl Kunzelmann
Admin Inst: University of Queensland
Main RFCD: Cell Physiology
Total funding: $235,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Role of protease activated receptors type 2 (PAR2) during inflammation of airways and intestineRole of
protease activated receptors type 2 (PAR2) during inflammation of airways and intestine
Lay Description (from application):
Epithelial cells lining the airways and the intestine contain receptors that are activated by proteases, which are
protein cleaving enzymes. Activation of the subtype 2 of these receptors (PAR2) has been shown to cause salt
and water transport in intestinal cells in culture. Little is known about the effects of PAR2-activation in the
native airways and intestinal tissues. These tissues will be studied in the present project. A large increase in
PAR2 is found in various diseases which are paralleled by a strong inflammation. Thus, PAR2 is likely to play
a central role in intestinal diseases such as acute infectious diarrhea and chronic inflammatory bowel disease.
PAR2 may also participate in the severe diarrhea frequently observed in patients with intestinal tumors.
Similarly, inflammatory mediators released during airway infections are likely to act on PAR2, causing
inappropriate secretion and a running nose. Most importantly, PAR2 are found in large excess in the airways of
asthma patients. Since nothing is known about the impact of these receptors on fluid and electrolyte transport in
the airways it appears timely and highly relevant to study the function of PAR2 in the airway epithelium. We
will assess PAR2 mediated responses in human nasal biopsies. A more detailed analysis of the intracellular
processes will be done in mouse trachea. We will further study the function of PAR2 in the intestinal
epithelium. Activation of the ion transport via PAR2 will be examined in the mouse distal colon and in human
rectal biopsies. We will utilize techniques such as Ussing chamber and patch clamp recordings to analyze the
transport processes. The results should gain new inside into the role of PAR2 during inflammatory diseases of
the airways and the intestine such as asthma and chronic inflammatory bowel diseases.
Research achievements (from final report):
Epithelial cells lining the airways and the intestine contain receptors that are activated by proteases, which are
protein cleaving enzymes. Activation of the subtype 2 of these receptors (PAR2) has been shown to cause salt
and water transport in intestinal cells in culture. Little is known about the effects of PAR2-activation in the
native airways and intestinal tissues. These tissues will be studied in the present project. A large increase in
PAR2 is found in various diseases which are paralleled by a strong inflammation. Thus, PAR2 is likely to play
a central role in intestinal diseases such as acute infectious diarrhea and chronic inflammatory bowel disease.
PAR2 may also participate in the severe diarrhea frequently observed in patients with intestinal tumors.
Similarly, inflammatory mediators released during airway infections are likely to act on PAR2, causing
inappropriate secretion and a running nose. Most importantly, PAR2 are found in large excess in the airways of
asthma patients. Since nothing is known about the impact of these receptors on fluid and electrolyte transport in
the airways it appears timely and highly relevant to study the function of PAR2 in the airway epithelium. This
project has provided more detailed analysis of the intracellular processes will be done in mouse trachea, as well
as how PAR2 activates ion transport in the mouse distal colon and in human rectal biopsies. Our results
provide new inside into the role of PAR2 during inflammatory diseases of the airways and the intestine such as
asthma and chronic inflammatory bowel disease This study has provided further evidence for a role of PAR-2
in inflammatory airway disease: stimulation of these receptors may cause accumulation of airway surface
liquid, which, however, may help to flush noxious stimuli away from the affected airways.
Expected future outcomes:
We will assess PAR2 mediated responses in human nasal biopsies. We will further study the function of PAR2
in the intestinal epithelium.
Name of contact:
Daniel Markovich
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
d.markovich@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 254524
CIA Name: Prof John Upham
Admin Inst: University of Queensland
Main RFCD: Respiratory Diseases
Total funding: $408,713
Start Year: 2003
End Year: 2007
Grant Type: Established Career Fellowships
Title of research award:
enhance understanding of the immunological mechanisms involved in asthma and will examine new
approaches to preventingenhance understanding of the immunological mechanisms involved in asthma and will
examine new approaches to preventing
Lay Description (from application):
Not Available
Research achievements (from final report):
During the term of the Fellowship I have completed a number of significant research studies that have led to
significant and novel outcomes, including:, (1) Understanding how changes in the immune system of babies
can predispose to asthma developing in later childhood. This involves using flow cytometry to measure the
number of dendritic cells in the blood. Babies with lower numbers of a type of dendritic cell are at greater risk
of asthma and serious lung infections. , (2) Better understanding of how allergens can change the function of
cells of dendritic cells. I have identifed a novel, unexpected protein that is expressed by dendritic cells from
allergic individuals, but not by dendritic cells from healthy people. This protein is associated with changes in
T-cell function, and may partly explain why some people develop allergies, while others do some do not.
Dendritic cells and the proteins they express may be important therapeutic targets. , (3) Discovery that
lipoproteins from the cell walls of certain common bacteria can inhibit allergic inflammation in vitro.
Expected future outcomes:
These outcomes have shed important light on how asthma develops. More studies will be undertaken to
determine whether measuring dendritic cells in the blood at birth, or within the first 12 months, is an accurate
way to predict future asthma. Ongoing studies will also examine targeting dendritic cells to prevent or treat
asthma and viral lung infections.
Name of contact:
Professor John Upham
Email/Phone no. of contact:
j.upham@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301178
Start Year: 2004
CIA Name: Prof David Fairlie
End Year: 2006
Admin Inst: University of Queensland
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $465,750
Title of research award:
C3/C5 Convertase Inhibitors As A New Class Of Anti-Inflammatory DrugsC3/C5 Convertase Inhibitors As A
New Class Of Anti-Inflammatory Drugs
Lay Description (from application):
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis,
multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that
naturally occuring "Complement" proteins in human blood are involved in exacerbating these and many other
human diseases, yet there are no good drugs available to counteract their effects. Three complement proteins
known as C3a, C5a and MAC (membrane attack complex) are thought to be particularly pivotal components of
the complement system synthesized by the human body early in the development of inflammatory and immune
diseases. New compounds that could block the formation of human C3a, C5a and MAC are expected : (a) To
lead us to a better understanding of how these proteins act on immune cells and of their respective roles in the
immune response to infection and injury, and (b) To enable the rapid development of an entirely new class of
drugs for treating autoimmune and inflammatory diseases. No Complement-based drugs are yet available in
man. In other NHMRC funded work we have developed compounds ("antagonists") that selectively block the
actions of human C3a or C5a, and shown that they are effective antiinflammatory agents in rat models of a
number of inflammatory diseases. In this project we will design and develop small molecules that block the
enzymes ("C3/C5 convertases") that make C3a, C5a and other complement proteins including MAC. We
expect that such inhibitors will be even more effective antinflammatory drugs because they will block
formation of multiple complement proteins that each have proinflammatory activity. We will demonstrate
selective effects of the new compounds on components of complement, and test them in rat models of
inflammatory diseases. We expect C3/C5 convertase inhibitors to be a completely new type of antiinflammatory drug, treating disease processes rather than symptoms like current drugs.
Research achievements (from final report):
In this project we have studied some very important enzymes from human blood (the serine proteases known as
Complement factor B, C2, and C3 convertase) that are known to contribute to both immune defence and
inflammatory diseases. We have : (a) profiled their biochemical functions, (b) identified conditions that
allowed the first observation of catalytically active factor B and C2, (c) successfully created the first assay
protocols for efficient screening of inhibitors, (d) designed and developed the first potent small molecules to
block the functions of these enzymes, and (e) shown blockade of the formation of downstream products of
complement activation (namely C3a, C5a and membrane attack complex). These enzymes are not affected by
other serine protease inhibitors that we have tested. These studies are facilitating the development in our
laboratories of an entirely new class of antiinflammatory drug that intervenes directly in disease development
rather than targetting symptoms of inflammatory disease.
Expected future outcomes:
Our discovery of potent inhibitors of human complement enzymes has potential to be developed into human
pharmaceuticals with antiinflammatory properties and to be used to gain further insights to different paths of
complement activation in humans. Our focus on human enzymes, cells and inflammation in rodents is expected
to extend to more animal studies and ultimately a clinical trial.
Name of contact:
Professor David Fairlie
Email/Phone no. of contact:
d.fairlie@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301210
CIA Name: Dr Matthew Sweet
Admin Inst: University of Queensland
Main RFCD: Cellular Immunology
Total funding: $465,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Regulation Of Macrophage Function And Gene Expression By The Th2-Promoting Stimulus, ES-62Regulation
Of Macrophage Function And Gene Expression By The Th2-Promoting Stimulus, ES-62
Lay Description (from application):
White blood cells are responsible for co-ordinating the immune response against foreign micro-organisms.
Macrophages are a particular type of white blood cell that attempt to destroy microbes during the initial stages
of an infection, but also release toxic substances that are responsible for pathology and side effects during
many immune responses. This project aims to address how macrophages are involved in a particular type of
immune response that develops when individuals are susceptible to certain diseases including asthma and
diseases associated with intracellular infections. We are identifying genes expressed in macrophages during
these immune responses that are likely to be involved in susceptibility to such diseases.
Research achievements (from final report):
Many parasitic worm infections result in a particular type of immune response called a "Th2 response". Th2
responses can enable our bodies to effectively combat some parasitic worm infections, but these responses are
also responsible for the symptoms of allergy and asthma. Th2 responses are also important because they can
reduce the symptoms of some chronic inflammatory diseases, for example Rheumatoid Arthritis. Despite the
importance of Th2 responses, how these responses develop are not clearly understood. This project set out to
identify the genes that are responsible for the development of a Th2 response. In this project, we identified how
one important parasite (Schistosoma mansoni), which is of major significance to human health, causes a Th2
response. It does so by turning on a particular gene in cells called macrophages. This finding will enable us to
understand how this parasite causes disease and will enable the future design of therapeutic strategies that can
regulate Th2 responses.
Expected future outcomes:
Our findings will enable us to further characterize the specific pathways by which parasites cause a Th2
response. Ultimately, we may be able to manipulate Th2 responses for therapeutic applications - this would
have implicatons for a range of different diseases including parasitic worm infections, allergy, asthma and
Rheumatoid Arthritis.
Name of contact:
Matthew Sweet
Email/Phone no. of contact:
m.sweet@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 403911
Start Year: 2006
CIA Name: Prof Peter Sly
End Year: 2010
Admin Inst: University of Queensland
Grant Type: Established Career Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $751,161
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
This fellowship allowed me to continue and expand my work into the mechanisms underlying inflammatory
airway diseases, especially asthma and cystic fibrosis, in children. In addition, it allowed me to develop a
research capacity in Children's Environmental Health and to establish the World Health Organization
Colloaborating Centre for Research on Children's Environmental Health. In 2010, the final year of this
fellowship I moved from UWA to UQ and expanded my collaborations, especially in the viral contributions to
inflammaotry airway diseases and in environmental toxicology.
Expected future outcomes:
Randomized controlled trials of primary prevention strategies in astham and cystic fibrosis.
Name of contact:
Peter Sly
Email/Phone no. of contact:
p.sly@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454776
Start Year: 2007
CIA Name: Dr Stuart Mazzone
End Year: 2011
Admin Inst: University of Queensland
Grant Type: Career Development Fellowships
Main RFCD: Neurosciences not elsewhere classified
Total funding: $490,129
Title of research award:
Regulation of Airway Defensive ReflexesRegulation of Airway Defensive Reflexes
Lay Description (from application):
Not Available
Research achievements (from final report):
This award was a Career Development Fellowship with the aim of providing training and mentoring to an
emerging research scientist in the field of biomedicine. During the tenure of this fellowship I published 15
original manuscripts in international scientific journals or books, all describing novel findings in the field of
neural control of airway function. This work has provided new insights into clinical symptoms of airways
disease, including mechanisms of chronic cough and excessive airway obstruction. I presented this work at
over 20 national and international forums. I used the fellowship to build an independent research team and an
international reputation within the field. The following summarises this: I serve on 4 international journal
editorial boards, I have provided expert review over 50 manuscripts and grants and over 100 NHMRC
fellowship applications, I sit on 2 national expert committees, I have train (or I am training) over 15 hons and
PhD students and I have secured (to date) in excess of $3M in competetive grant funding.
Expected future outcomes:
I now hold an NHMRC CDF level 2 (2012-2015) award and will contiue to build an internationally
competetive research program in the field or airway neurobiology.
Name of contact:
Stuart Mazzone
Email/Phone no. of contact:
s.mazzone@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455949
CIA Name: Dr Jack Flanagan
Admin Inst: University of Queensland
Main RFCD: Basic Pharmacology
Total funding: $517,960
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Design and use of human hematopoietic prostaglandin D2 synthase inhibitors in allergic asthma and bone
diseasesDesign and use of human hematopoietic prostaglandin D2 synthase inhibitors in allergic asthma and
bone diseases
Lay Description (from application):
Many currently used non-steroidal anti-inflammatory drugs are burdened by side effects such as
gastrointestinal bleeding or increased risk of heart attack. This is because they ablate the production of a class
of molecules called prostaglandins. We believe it is possible to fine tune the action of these drugs and reduce
the side effect risk. There is evidence to suggest that only some prostaglandins are involved in inflammation, so
the risk of side effect can be reduced by blocking the production of only a small set. One prostaglandin,
prostaglandin D2, is known to cause many characteristics of allergic asthma and may also contribute to
osteoarthritis, although the evidence for this is contradictory. We will determine any therapeutic benefit to
blocking the production of prostaglandin D2 in these diseases by developing compounds that only inhibit the
enzyme responsible for its production.
Research achievements (from final report):
This was a very succesful project. We developed a drug design method that capitalises on the availability of
millions of commercially available compounds and applied this method to the development of the most potent
and selective inhibtors of prostaglandin D2 synthase (HPGDS) that are known. HPGDS is a well validated
target for treatment of allergic disease and outcomes of this resarch have the potential of providing new
therapies for treatment of asthma.
Expected future outcomes:
The objective of this research program were met. Future objectives include analysising the drug developability
of key compounds discovered.
Name of contact:
Mark Smythe
Email/Phone no. of contact:
m.smythe@imb.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 456187
CIA Name: Dr Shayna Street
Admin Inst: University of Queensland
Main RFCD: Allergy
Total funding: $309,133
Start Year: 2007
End Year: 2011
Grant Type: Early Career Fellowships (Australia)
Title of research award:
The role of RelB in Atopic AsthmaThe role of RelB in Atopic Asthma
Lay Description (from application):
Not Available
Research achievements (from final report):
For the clinical development of strategies for the induction of antigen-specific immune suppression of
inflammatory diseases, including asthma and autoimmune diseases, it is essential to understand 1. the
mechanisms underlying antigen-specific immune suppression and 2. the inflammatory antigen-specific T cell
responses underlying the disease to be treated. The first part of my work carried out during the fellowship
advanced understanding of the mechanisms by which the transcription factor RelB influences dendritic cell
suppression of inflammatory diseases, including allergic airways and autoimmune diseases. Dendritic cells are
a natural component of the immune system which educate T lymphocytes towards antigen in the lymph glands.
RelB is a key switch in dendritic cells for activation of immune responses. During this fellowship I found that
when RelB is activated in dendritic cells, they promote the production of interferon-gamma by T cells, which
helps to regulate inflammatory diseases such as asthma through specialised cells known as regulatory T cells.
When dendritic cells deficient in RelB are introduced into healthy mice, they interact with a population of B
lymphocytes which regulate immune responses though the production of an anti-inflammatory cytokine,
interleukin-10. The second part of my work advanced understanding of the inflammatory T cell responses in
rheumatoid artrhitis patients. I found that T cells from patients produced inflammatory cytokines, especially
interleudin-6, in response to a range of modified proteins derived from self-tissues. I developed an assay for
measurement of these responses in patients, to monitor disease progress and assess response to immune
therapies including antigen-sepcific suppression by dendritic cells.
Expected future outcomes:
My work will allow the analysis of immune outcomes in clinical trials of antigen-specific suppression using
RelB deficient dendritic cells.
Name of contact:
Ranjeny Thomas
Email/Phone no. of contact:
ranjeny.thomas@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510718
CIA Name: Dr Simon Phipps
Admin Inst: University of Queensland
Main RFCD: Respiratory Diseases
Total funding: $408,469
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Pneumovirus infection in infancy affects the development of life-long adaptive immunity.Pneumovirus
infection in infancy affects the development of life-long adaptive immunity.
Lay Description (from application):
Respiratory syncytial virus is the most important cause of acute lower respiratory tract infection (RTI) in young
children worldwide. Hospital admission rates in Western societies for RTIs are around 3% for children younger
than 1 year. A vaccine to RSV is not yet available and repeat infections occur thoughout life, suggesting that
the immune response does not develop correctly. In this project we are exploring the mechanisms that underpin
disease development and promote incomplete immunity.
Research achievements (from final report):
Lower respiratory tract infections can lead to severe bronchiolitis in infancy and are a major risk factor for
asthma. It is not known whether bronchiolitis is causal or whethet a common defect results in the development
of both diseases. Using a mouse model of virus-associated bronchiolitis we demonstrated that the absence of an
innate immune receptor led to severe bronchiolitis, and following a secondary infection, the development of
asthma. Thus, both diseases were caused by a defect in one gene. Therefore it is likely that severe bronchiolitis
in early life unmasks those individuals who are at risk of developing asthma in childhood and later life.
Expected future outcomes:
we have identified novel pathways that contribute to host defense and protection from the development of
severe bronchiolitis. Our unique model of asthma will be used to identify novel pathways involved in the
development of aberrant immune responses that underpin asthma pathogenesis.
Name of contact:
Dr. Simon Phipps
Email/Phone no. of contact:
s.phipps@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519768
CIA Name: A/Pr Raymond Steptoe
Admin Inst: University of Queensland
Main RFCD: Cellular Immunology
Total funding: $420,872
Start Year: 2008
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Tolerance induction by antigen-presenting cell-targeted antigenTolerance induction by antigen-presenting celltargeted antigen
Lay Description (from application):
We have found that by ‘targeting’ antigen to the cells that ‘train’ the immune system we have been able to
prevent the development of autoimmune disease. In the research proposed here we aim to develop new ways
in which antigens can be targeted to these cells so that this approach can be applied clinically. The proposed
studies will also determine how antigens targeted in this way restore self-tolerance and prevent autoimmune
disease.
Research achievements (from final report):
This funding was used to show that memory CD4+ and memory CD8+ T cell responses could be 'turned off'.
These findings formed the basis of a possible therapeutic approach to treatment of autoimmune diseases and
inflammatory diseases such as asthma. This is a significant discovery as it had previously been thought that
memory T cells were resistant to such efforts and had always been considered a substantial barrier to treatment
of in flammatory diseases. During this award I also defined a role for regulatory T cells in modulation of CD8+
T cell responses and that this uncovered a key mechanism of how these cells work to do this. The work has
uncovered important basic information that promotes understanding of how immunotherapies ccould be
applied.
Expected future outcomes:
The outcomes of the funding will form the basis for future studies that explore the possible use of these
findings as a 'therapeutic'.
Name of contact:
Ray Steptoe
Email/Phone no. of contact:
r.steptoe@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566734
CIA Name: Dr Stuart Mazzone
Admin Inst: University of Queensland
Main RFCD: Respiratory Diseases
Total funding: $431,146
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Identification of brain regions involved in the regulation of coughingIdentification of brain regions involved in
the regulation of coughing
Lay Description (from application):
Cough is a symptom of more than 100 clinical conditions of the respiratory system, and is the most common
reason that people seek medical advice. However, currently available cough suppresant drugs are at best only
modestly effective at treating cough disorders. In this study we aim to better understand how the brain regulates
coughing in the hope to identify new therapeutic targets for relieving cough.
Research achievements (from final report):
, , This project has provided unprecendented insights into the brain networks that sense airways irritation and
control coughing. We identified networks that control the intensity of an individual's perception of airway
irritation, their ability to voluntarily control coughing and their emotional behaviours. The outcomes add
significantly to our understanding of cough and have generated predictions about how cough becomes
dysfunctional in disease.
Expected future outcomes:
We are now assessing how these brain networks behave in patients with chronic cough.
Name of contact:
Stuart Mazzone
Email/Phone no. of contact:
s.mazzone@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631020
CIA Name: Dr Simon Phipps
Admin Inst: University of Queensland
Main RFCD: Respiratory Diseases
Total funding: $678,755
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The pathogenesis of distinct endophenotypes of asthma is underpinned by the collaborative activation of
specific PRRs.The pathogenesis of distinct endophenotypes of asthma is underpinned by the collaborative
activation of specific PRRs.
Lay Description (from application):
Asthma is a chronic airway disease caused by inflammation. Although asthmatics can be sub-typed based on
the type of inflammatory cells present in the lungs, medication specific for the treatment of these sub-types is
not yet available. In this grant we will investigate the immune processes that orchestrate the development of the
distinct inflammatory sub-types of asthma. This information will help us develop new therapies that will be
tailored to target the appropriate type of inflammation.
Research achievements (from final report):
The project sought to understand the endotypes (mechanistic processes) that underlie different phenotypes of
asthma such as eosinophilic asthma and neutrophilic asthma. We successfully identified a new pathogenic
mechanism that underlies neutrophilic asthma, implicating a role for inflammasomes and associated caspases in
inducing IL-1b, a potent neutrophilic chemoattractant via IL-8. These clinical studies were complemented by
mouse models of experimental asthma which for the first time identified an important new role for the tissue
alarmin high mobility group box 1 (HMGB1) in allergic sensitisation. Our findings suggest that different
subtypes of the asthma syndrome need to be treated differently to improve outcomes, rather than employing
generic anti-inflammatories as is presently the case with conventional therapies (eg steroids).
Expected future outcomes:
New treatments aimed at neutralising HMGB1 or its receptor will hold promise for the treatment of
eosinophilic asthma. Targeting the IL-1b pathway will offer treatment for neutrophilic asthma.
Name of contact:
Dr. Simon Phipps
Email/Phone no. of contact:
s.phipps@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511345
CIA Name: Dr Matthew Haren
Admin Inst: University of South Australia
Main RFCD: Epidemiology
Total funding: $287,321
Start Year: 2008
End Year: 2011
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Familial, behavioural and environmental determinants of respiratory and metabolic fitness in regional South
Australia.Familial, behavioural and environmental determinants of respiratory and metabolic fitness in regional
South Australia.
Lay Description (from application):
South Australia is the fattest state in Australia. Limited health surveillance data suggests that Whyalla is fatter,
less active, consumes more alcohol and has worse respiratory health than Adelaide. Obesity is linked to poorer
respiratory health. Public concern over the effects of air pollution on the health of Whyalla families has
prompted us to examine respiratory and metabolic health in Whyalla families in comparison to those in the
north-west suburbs of Adelaide.
Research achievements (from final report):
This research has helped identify the major chronic disease related public health priorities for the regional
community in which this research was conducted. Importantly, we identified a significant prevalence of
abdominal obesity and a window of opportunity for the prevention of type 2 diabetes, one of the most
expensive chronic conditions in Australia costing $18B annually. In addition we were able to quantify the
excess diagnosis of asthma in this community, which has been a tangible yet unmeasured problem in this
community for some time.The research included the establishment of strong links within the community to
form coalitions to promote healthy lifestyles, obesity and diabetes prevention in the community. Significantly,
findings from this research formed the evidentiary basis for a $0.5M grant awarded to the community for
healthy community initiatives.
Expected future outcomes:
In addition to the community-led grant, we are enagaged with local industry stakeholders in a workplace health
promotion program for the prevention of abdominal obesity and type 2 diabetes through financial contributions
from industry and university sectors and the Federal Government .
Name of contact:
Matt Haren
Email/Phone no. of contact:
Matt.Haren@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 137860
Start Year: 2001
CIA Name: Dr Christopher Jolly
End Year: 2003
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Main RFCD: Humoral Immunology and Immunochemistry
Total funding: $392,546
Title of research award:
Cell division and the regulation of immunoglobulin switch recombination at the molecular levelCell division
and the regulation of immunoglobulin switch recombination at the molecular level
Lay Description (from application):
The B lymphocyte is an important cell in the immune response as it generates protective antibody against
invading pathogens. The effectiveness of an antibody response partly depends on the type of antibody made
(there are eight different types). This attribute alters as the immune response progresses in a poorly
understood and highly complex way. However, our recent studies have revealed a simple underlying order that
can be dissected using new methods. The key to the underlying simplicity is a cell division clock used to relate
and promote cell changes. Here we intend to apply this new concept and the new methods to dissecting the
molecular events associated with linking division to the changing properties of antibody selection. Our aim is
to accurately model the process of changing antibody types at both the molecular and whole tissue levels.
These studies will give us new insights into how the immune response may be directed to make the most
appropriate (effective) response during infection and vaccination.
Research achievements (from final report):
N/A
Expected future outcomes:
My research is investigates the accelerated mutation of antibody genes that is a normal part of the immune
response that we mount against infections. I aim to understand how the immune system takes specialised DNA
repair enzymes that evolved to combat mutation of the genome and uses them to instead introduce (admittedly
useful) mutations into antibody genes. I want to establish whether occasional errors in the antibody mutation
process lead to cancer, and if so how these errors can be prevented. In the future I will test whether the
introduction of the specific inability to mutate antibody genes in mice can lead to an inability to combat some
infections. If I find this is the case, I will go on to test whether human disease is sometimes caused by the same
defect.
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 153778
CIA Name: Dr J. Margaret Hughes
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $437,546
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Cell interactions in asthmatic inflammationCell interactions in asthmatic inflammation
Lay Description (from application):
Asthma is a significant burden to the health care system and to individual sufferers. Currently we can treat
asthma with corticosteroids to reduce inflammation in the lung but the side effects of these medications,
particularly in children, make them less than ideal treatments. In order to design a more specific treatment for
asthma, which would only target the inflammatory cells which are involved in the lung, we need to understand
how these cells behave and what initiates the cascade of events in the lung. This project is designed to
investigate how chemical mediators, cytokines, are produced by various cells in the lung and how they induce
lung cells to make structural changes to the lung tissue and increase the inflammation. The source and specific
types of cytokines released are being investigated to provide important information regarding the disease
process of asthma. From this new knowledge, design of specific new treatments, with fewer unwanted sideeffects, should be possible.
Research achievements (from final report):
N/A
Expected future outcomes:
It is now clear from our findings that intrinsic alterations in airway smooth muscle behaviour contribute to the
changes to the airway wall and inflammation that underpin the increased sensitivity and contractility of the
airways of asthmatics. We have provided new information about the various functions of airway smooth
muscle in an inflammatory environment driven by lymphocytes and so revealed new aspects of the biology of
both types of cells. We will now investigate the mechanisms underlying the differences in asthmatic airway
smooth muscle behaviour and the pattern of asthmatic airway inflammation.This new information will help us
focus our interventions for asthma in the future.
Name of contact:
Ed Micallef
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 153809
CIA Name: A/Pr Gregory King
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $196,528
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Abnormal smooth muscle behaviour in asthma: toward an in vivo testAbnormal smooth muscle behaviour in
asthma: toward an in vivo test
Lay Description (from application):
In order to understand asthma better, and to improve our ability both to prevent and to treat the disease, we
need to understand why the airways of people with asthma narrow too easily and too much. Airway
hyperresponsiveness is almost certainly a downstream consequence of several different abnormalities. Airway
inflammation, resulting from an allergic reaction in the airways, probably plays a major role. It is also likely
that the smooth muscle in the airways contributes to airway narrowing, but at present we have no way to
measure airway behaviour in the living human. In this project we will examine the response of the airways to
a deep breath, to determine if this is an indicator of smooth muscle behaviour. When the airways are narrowed,
taking a deep breath stretches them and helps to overcome the narrowing. It is well known that this stretching
mechanism is impaired in asthma, probably as a result of inflammatory changes to the airway wall. What is
less well known is that after the airway has been stretched by a deep breath, it re-narrows, and there is new
evidence that the rate of re-narrowing is increased in asthma. Based on our knowledge of how the smooth
muscle behaves in the organ bath, and of the types of abnormal behaviour found in muscle from allergic and
some asthmatic people, it seems likely that the rate of airway re-narrowing following a deep breath is an
indicator of smooth muscle behaviour. This hypothesis has not been tested before. If we can establish that the
rate of re-narrowing is an indicator of smooth muscle behaviour, we can then determine if abnormal muscle
behaviour occurs in asthma, and examine the factors associated with abnormal muscle behaviour. This will
improve our understanding of the basic abnormalities in asthma, and facilitate studies to see if this test can
predict who is at risk from developing asthma. Evidence that smooth muscle behaviour is abnormal in asthma
may suggest new directions for drug therapy.
Research achievements (from final report):
N/A
Expected future outcomes:
The funding of this study significantly contributed to the establishment of the forced oscillation technique in
our Lab for studying the way airways behave during normal breathing in asthmatic patients. These studies were
a departure from previous ways of looking at airways in that the existing tools that are currently used to look at
how airways and lungs function are give just an ‘overview’ of what’s going on. The forced oscillation
technique contrasts to this by giving ‘high definition’ information as patients breathe. We have demonstrated
clear differences in the way airways respond to breathing and deep breaths and have thereby gained a better
understanding of the important factors that could be deranged in asthma and which therefore could be
responsible for the asthmatic condition. , , The forced oscillation technique has the potential to be used
routinely and widely in routine clinical practice to aid diagnosis of airway diseases because it is potentially
easier for patients and doctors to conduct. However, before this comes about, there needs to be many more
studies using this technique in patients to gather the data that are necessary to properly interpret the results
from a diagnostic and prognostic point of view. Another potential application will be in measuring the scarring
in airways that occurs in asthma and other airway diseases and this could be important and useful for drug
studies as well as monitoring treatment in general practice. We would like to pursue these directions based on
the results of our current study.
Name of contact:
Ed Micallef
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 165722
Start Year: 2003
CIA Name: Dr Janette Burgess
End Year: 2006
Admin Inst: University of Sydney
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $306,273
Title of research award:
Mechanisms of airway remodelling in asthmaMechanisms of airway remodelling in asthma
Lay Description (from application):
Not Available
Research achievements (from final report):
Asthma affects 2 million Australians. We have found that airway smooth muscle cells are abnormal in asthma
in that they contract more and grow more rapidly. This award allowed me to study the contribution of the
extracellular matrix - the scaffolding surrounding the muscle - to these abnormalities. I have found that: cells
from asthmatic individuals release more of a factor that promotes the accumulation of matrix proteins in the
lungs, release less of a factor that inhibits their growth and express more cell surface receptors that allow them
to interact with inflammatory cells. I also found that the matrix proteins released from the asthmatic cells are
different to those released from the nonasthmatic cells and that the matrix proteins laid down by the asthmatic
cells promote greater growth than those from the nonasthmatic cells. When I studied the influence of the
current asthma therapies on these processes I found that they are not effective at inhibiting the deposition of
some of the matrix proteins and, in fact, some of the drugs can increase the deposition of these proteins. I also
looked at the potential of a new drug class, that is currently being trialled as an asthma therapeutic, and found
that it was able to inhibit the deposition of the matrix proteins. It is important to understand the processes that
underlie the differences in the asthmatic airways to enable new therapies, directed at the features of asthma that
are not addressed by the current therapuetic regimen, to be developed.
Expected future outcomes:
Repeated attacks of asthma result in structural changes in asthmatic airways which contribute to the worsening
of lung function in these patients. Our work will enable the development of new drugs to reverse or prevent
these changes.
Name of contact:
Janette Burgess
Email/Phone no. of contact:
janette@pharmacol.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211081
CIA Name: A/Pr Jennifer Peat
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $453,300
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
The Childhood Asthma Prevention Study (CAPS)The Childhood Asthma Prevention Study (CAPS)
Lay Description (from application):
The prevalence of asthma in Australia is amongst the highest in the world yet no trials of primary prevention
have been conducted which address the most common known causative agent (housedust mite allergens) and
the most common known protective factor (dietary omega-3 fatty acids). Until the effectiveness of
interventions which address these factors is certain, the value of the wide array of advice given to asthmatics
by various health institutions will not be known. We are applying to continue the Childhood Asthma
Prevention Study (CAPS) which has been underway since mid-1997. CAPS is a randomised controlled trial in
which 616 infants at high risk of developing asthma because of a family history have been enrolled. The
interventions include allergen reduction and dietary supplementation with omega-3 fatty acids. The
interventions are designed to have maximum effect but be simple to implement by parents. Several measures of
compliance are being collected and regular contact is maintained though telephone calls and frequent home
visits. Objective and subjective measurements of exposures, atopy, diet and asthmatic symptoms are being
collected at 3 month intervals and at medical assessments when the children are 18 months, 3 and 5 years old.
It is essential that we continue the study until all children are aged 5 and we will be able to test conclusively
whether the interventions have had a positive effect. If so, CAPS will form the basis for a nationwide public
health campaign which will have the potential to reduce the incidence of childhood asthma in Australia.
Research achievements (from final report):
The study was designed specifically to test house dust mite (HDM) avoidance and dietary fatty acid
modification as interventions to prevent asthma and allergic disease in children with a family history of asthma
and wheezing. We found that neither house dust mite avoidance nor omega-3 fatty acid supplementation had a
beneficial effect in reducing the risk that children will develop asthma or allergy in the first five years. , Parents
testing house dust mite avoidance were instructed to use both physical and chemical methods to reduce their
child's exposure to HDM allergens, including changes to bedding materials and the addition of a benzyl
benzoate-containing solution to the wash at regular intervals. The HDM avoidance strategy resulted in
reduction in HDM allergen concentrations in the child's bed but did not reduce the rate of asthma, wheeze or
atopy. , The dietary intervention was intended to increase the proportion of omega-3 fatty acids consumed in a
diet and reduce the content of omega-6 fatty acids. Parents were provided with cooking oils and margarine high
in omega-3 fatty acids to use in food preparation and food oil capsules were added to the child's formula or to
solid foods from the age of 6 months. , While this dietary intervention did alter blood levels of fatty acids, the
rate of asthma, wheezing, eczema or atopy did not differ between the groups who did and did not receive this
intervention. , The research was undertaken by researchers from the Woolcock Institute of Medical Research,
the CRC for Asthma, the Children's Hospital at Westmead and the School of Public Health, University of
Sydney.
Expected future outcomes:
We are currently undertaking a fourth medical assessment on the cohort at age 8 years because it is possible
that the benefits of the measures taken in early life may not, become apparent until this time. We are also
collaborating with other research teams, including those interested in nutrition and heart health.
Name of contact:
Associate Professor Guy Marks
Email/Phone no. of contact:
Guy Marks [G.Marks@unsw.edu.au]
NHMRC Research Achievements - SUMMARY
Grant ID: 253818
CIA Name: Dr Euan Tovey
Admin Inst: University of Sydney
Main RFCD: Allergy
Total funding: $200,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Personal exposure to fungal allergens in asthmaPersonal exposure to fungal allergens in asthma
Lay Description (from application):
The main purpose of this study is to understand how airborne fungi affect asthmatics who are allergic to them.
Fungi or moulds release large numbers of spores into the air that are inhaled. In many cases fungal spores
outnumber other particles that carry allergen, such as pollens or cat dander, by 100 to 1. This makes fungi the
most common potential allergen in the environment. Fungi have been associated with respiratory diseases
including fungal sinusitis, asthma, rhinitis, allergic alveolitis and sick building syndrome. Largely due to their
diversity and complexity, allergenic fungi have not been well studied and the ways in which individuals vary
when inhaling spores is not known. Unlike other allergenic particles, it is unlikely that fungal spores release
their allergen as soon as they are inhaled because we have shown in earlier in vitro studies that fungi continue
to release allergen over time and this is likely to be the case when they are inhaled. Our laboratory has
developed two new techniques that allow us to measure how many spores people inhale and whether they are
allergic to them. This study will use these tools to detect and identify the important allergenic fungi involved in
domestic and outdoor exposure of asthmatics, the degree of contribution to the total allergen load to which
subjects are exposed and identify in what conditions fungi are the causal agents in location-specific symptoms.
This study will also investigate allergen production of fungi in situ in the human nose, which will have
application in allergic sinusitis and asthma amongst other respiratory diseases. We will investigate how readily
allergenic spores germinate in the nose and under what conditions they release allergen.
Research achievements (from final report):
We have gained important information on several aspects of people's exposure to fungal allergens. We have
found that people's exposure to allergens (allergy causing compounds) from fungi is much more extensive than
previously thought, and is more complex than exposure to other allergens. We have demonstrated that fungal
fragments can be found in the air in peoples' everyday environments, and that many species of fungi are
capable of acting as allergens. This is significant since although it is known that fungal allergens are important
triggers of clinical symptoms, little is known about exposure. Our finding that airborne fungal fragments
represent a significant source of allergens is important since many previous studies only counted intact fungal
spores when measuring airborne fungal allergens. Not only was this source of allergen once neglected, but it
may prove to be most relevant to symptoms, since small particles are more likely to be inhaled deep into the
lungs. We have also developed and published new techniques for the identification of allergenic fungi in
environmental samples, providing valuable tools for future research in this area of growing interest for the
global scientific community. Our experiments investigating the germination of fungal spores in the laboratory
and within the nasal cavities of volunteers have demonstrated that the germination of fungal spores, following
their inhalation, leads to an increased release of allergenic material. This result allows us to better understand
exposure to fungal allergens in comparison to non-living allergens such as house dust mite feacal particles.
Expected future outcomes:
This project has provided valuable information on how people's exposure to allergy-causing fungi can
influence the occurrence of symptoms of asthma and other allergic diseases. Further experiments, based on our
findings, could lead to preventative strategies to reduce the impact of fungal allergies.
Name of contact:
Jason Sercombe
Email/Phone no. of contact:
jasons@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 264598
CIA Name: Prof Ronald Grunstein
Admin Inst: University of Sydney
Excellence
Main RFCD: Respiratory Diseases
Total funding: $2,200,000
Start Year: 2005
End Year: 2009
Grant Type: Centre of Clinical Research
Title of research award:
Centre for Clinical Research Excellence in Respiratory and Sleep MedicineCentre for Clinical Research
Excellence in Respiratory and Sleep Medicine
Lay Description (from application):
The CCRE will enhance Australia's international research reputation in clinical respiratory and sleep medicine
by enhancing links between hospital-based investigators. This will foster development of new clinical
researchers in these fields. Major research projects will include reducing side effects of asthma therapy in the
elderly, better and cheaper ways of diagnosing disorders such as sleep apnoea and blood clots in the lung,
keeping patients with chronic lung diseases out of hospital and avoiding accidents due to lack of sleep.
Research achievements (from final report):
Our research achievements will have an important impact on the respiratory and sleep health of Australians.
Translation of our work has contributed to improved diagnostics, development of novel treatment strategies, a
clearer understanding of disease pathways, and advanced recommendations for ongoing management of
disease. As a result of our research, CCRE investigators have particpated and contributed to the development of
health policy directives and consensus recommendations, and evidence-based guidelines for the treatment and
management of respiratory and sleep disorders. Further, our commitment to training and mentorship of clinical
researchers has established a new generation of skilled respiratory and sleep researchers for the field.
Expected future outcomes:
We will continue our important work in clinical research and care, and translate our research to improve the
diagnosis, treatment and management of respiratory disease and sleep disorders.
Name of contact:
Professor Ron Grunstein
Email/Phone no. of contact:
ron.grunstein@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302073
CIA Name: Dr J. Margaret Hughes
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $527,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Airway smooth muscle - mast cell cross talk in asthmaAirway smooth muscle - mast cell cross talk in asthma
Lay Description (from application):
In Australia 1 in 4 children and 1 in 10 adults are asthmatic and so asthma is a significant burden to our
community and our healthcare system. Currently we treat asthma with corticosteroids to reduce airway
inflammation because, without them, chronic inflammation leads to thickened airways with increased amounts
of smooth muscle that contracts too much and too easily. However, corticosteroids may have side effects ,
particularly in children. In order to design safer more specific treatments for asthma, we need to know more
about the pattern of inflammation that is specific for asthma and what chemical signals cause it. Then we will
be able to target it more specifically. Recent research has demonstrated that in asthma, but not in bronchitis or
in healthy people, inflammatory cells called mast cells are found in increased numbers down in the smooth
muscle layer of the airways. Mast cells are key cells in all allergic reactions. In the airways they release
mediators that contract the airways, induce mucous secretion and promote further inflammation. We think the
effects airway smooth muscle cells and mast cells have on each other are central factors in causing the physical
changes to the airways of asthmatics. We will identify what chemical messages released by the smooth muscle
attract mast cells to it and once they are there, what the mast cells stick to on the smooth muscle. Then we will
investigate how the two cell types interact with each other and affect each other. We will focus on how the
functions of the smooth muscle cells are affected, especially those that would promote further inflammation
and lead to increased amounts of more sensitive, more contractile smooth muscle. We will try to prevent each
of the steps we identify with drugs that have very specific actions. This additional information may lead to the
design of novel treatments for asthma that have fewer side effects.
Research achievements (from final report):
In Australia, up to 1 in 4 children and 1 in 10 adults are asthmatic and so asthma is a significant burden to our
community and healthcare system. Currently we need safer more specific treatments for asthma. In order to
design safer treatments for asthma, or to prevent it, we need to know more about the pattern of inflammation
that is specific for asthma and which chemical signals cause it. From important recent research it has been
established that increased numbers of inflammatory cells called mast cells are present in the airway smooth
muscle in asthma, but not in bronchitis or in healthy lungs. Mast cell numbers increase as lung function
declines and asthma severity increases. Mast cells are key cells in all allergic reactions and release factors that
contract the airways, induce mucous secretion and promote further inflammation. , In this project we have
identified which chemical messages released by the smooth muscle attract mast cells to it. Most importantly we
have established airway smooth muscle cells obtained from people without asthma release inhibitory factors
that prevent mast cell migration toards the smooth muscle layer. Thus this project has increased our
understanding of the cellular and molecular mechanisms underlying asthma and the role of the airway smooth
muscle in its pathogenesis.
Expected future outcomes:
This research has identified a key target for the development of drugs that inhibit the specific chemical
message released by asthmatic airway smooth muscle that attracts mast cells to it. It has also established that
non-asthmatic airway smooth muscle inhibits mast cell migration. These inhibitory factors, once identified,
may delineate ways to prevent asthma developing.
Name of contact:
J Margaret Hughes
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
margh@pharm.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302099
CIA Name: Dr Euan Tovey
Admin Inst: University of Sydney
Main RFCD: Allergy
Total funding: $658,750
Start Year: 2004
End Year: 2008
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
I have continued to provide and facilitate pivotal studies on allergens and allergen exposure. These studies have
involved the use of our nasal filter technology to measure personal exposure to airborne allergens (showing
exposure is continuous and more difficult to avoid than current paradigms suggest); the use of our Halogen
assay to identify fungal allergens (many new species and fungal fragments identified as sources, plus
demonstration of the role of germination in fungal allergen production) and my involvement and analysis of
data from Childhood Asthma Prevention study (showing bell-shaped dose response curve between exposure
and both atopy and asthma. , Application of my understanding of filter technology and analytical methods
within my NHMRC Influenza Project led to our publication this year of the first direct detection of exhaled
rhinovirus and influenza virus from infected subjects. These studies have been extended to show that
exhalation of such viruses is common in children with asthma and on medications even when they do not have
symptoms of a cold. This has provided a new method to measure viral infections and has major implications
for our understanding of the role of viruses and asthma.
Expected future outcomes:
We will explore environmental exposures in allergic diseases to understand their clinical role and to achieve
clinically effective interventions. Additionally we will explore exhaled viruses in the transmission of influenza,
and viral and bacterial bioaerosols in the pathology and exacerbations of asthma, COPD and cystic fibrosis.
Name of contact:
Euan Tovey
Email/Phone no. of contact:
ert@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 352409
CIA Name: Prof Guy Marks
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $530,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Environmental influences on allergic airways disease from birth to 8yrs: long-term outcomes of a randomised
trial (CAPS)Environmental influences on allergic airways disease from birth to 8yrs: long-term outcomes of a
randomised trial (CAPS)
Lay Description (from application):
The prevalence of asthma in Australia is among the highest in the world yet no trials of primary prevention
have been conducted which address the most common known causative agent (housedust mite allergens) and
the most common known protective factor (dietary omega-3 fatty acids). Until the effectiveness of
interventions which address these factors is certain, it will not be possible to give confident advice about how
to prevent asthma. We are applying to continue follow up of the cohort of the Childhood Asthma Prevention
Study (CAPS) which has been underway since mid-1997. CAPS is a randomised controlled trial in which 616
infants at high risk of developing asthma because of a family history have been enrolled. The interventions
include allergen reduction and dietary supplementation with omega-3 fatty acids. The interventions are
designed to have maximum effect but be simple to implement by parents. Objective and subjective
measurements of exposures, atopy, diet and asthmatic symptoms are being collected at 3 month intervals and at
medical assessments when the children are 18 months, 3 and 5 years old. The interventions are stopped at age 5
years. The continued follow up of the cohort to age 8 will enable us to test conclusively if the interventions
have had a positive effect. If so, CAPS will form the basis for a nationwide public health campaign which will
have the potential to reduce the incidence of childhood asthma in Australia.
Research achievements (from final report):
This is an internationally unique project investigating the long-term effects of two interventions, house dust
mite avoidance and dietary modification, both implemented during the first five years of life, for the prevention
of asthma in children at risk for this disease. The project has already yielded important insights into the natural
history of asthma and allergic disease. For example, we have shown that, at least in some children the presence
of eczema in early life may precede the onset of allergy, which is itself an important risk factor for subsequent
asthma and rhinitis. This may open up new approaches to preventing asthma in the future. We have also
confirmed that the presence of pets in households tends protect against the occurrence of allergy. In this cohort,
who all have a family history of asthma, early cessation of breastfeeding did not increase the risk of subsequent
asthma. This is a reassuring finding for women who are unable to continue breastfeeding for one reason or
another. The interventions we tested did not have any beneficial effect on outcomes at age five years and we
are in the process of analysing the outcomes at age eight years. However, we have shown that children who
were exposed to the highest levels of HDM throughout the first five years of life tended to have a reduced risk
of asthma compared with those exposed to intermediate levels. This is a surprising finding, which we are in the
process of investigating further.
Expected future outcomes:
We are in the process of analysing the outcomes of the interventions at age eight years. We anticipate this
cohort will be followed up through adolescence and we will gain further insights into the natural history of
asthma and allergic disease and the long-term effects of early life interventions.
Name of contact:
Prof Guy Marks
Email/Phone no. of contact:
g.marks@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 352427
CIA Name: Dr Euan Tovey
Admin Inst: University of Sydney
Main RFCD: Allergy
Total funding: $263,500
Start Year: 2005
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Exploration of exposures associated with bedding that are risks for childhood allergy and asthma
symptomsExploration of exposures associated with bedding that are risks for childhood allergy and asthma
symptoms
Lay Description (from application):
Asthma prevalence in Australia has doubled in the last 20 years, with 1 in 4 children now affected. House dust
mites are probably the single most important allergen associated with asthma. The prevalence of mite allergy is
linked to exposure, and such allergy when combined with high exposure, is a potent risk factor for asthma
exacerbations. The current international advice for managing mite-allergic asthma, strongly advocates the use
of bedding encasings as the best way to reduce exposure. However, three recent major trials using encasings
and a meta-analysis of earlier trials all fail to show a clinical benefit. One of the applicants (ET) recently
showed, using expertise in measuring personal exposure, that these encasings, as used, fail to significantly
reduce aeroallergen exposure. By contrast, 3 recent Australian studies, involving the applicants, AK, ALP &
NG showed that feather bedding compared to synthetic bedding, was strongly protective for asthma - the
opposite of public advice. The suggested mechanisms involve reduced exposure to mite allergens, or altered
exposure to bacterial endotoxin, but persuasive experimental support is lacking. We also propose a novel
hypothesis that feather exposure may induce allergic 'tolerance'.Currently there is a lack of certainty about
valid approaches to prevent asthma, and the Global Initiative for Asthma has described the need to understand
mechanisms and improve interventions as urgent. This project is an ideal opportunity to combine the expertise
of the CIA (ET) in measuring airborne exposures (mite, endotoxin, proteins) with that of the others who have
expertise in children's asthma, and who are already involved in two large clinical trails involving different
bedding and allergen avoidance. Our measurements of these bedding exposures and their clinical outcomes will
provide, for the first time, a quantitative basis to refine public health allergen-based interventions to prevent
and manage asthma.
Research achievements (from final report):
We measured the airborne exposure of children to endotoxin and mite allergen within another NHMRC funded
study (248802 ) of the effectiveness of the introduction of feather bedding in reducing symptoms of asthma in
children. Such bedding has previously been shown to be associated with less asthma and it has been
hypothesised that this may be the result of it providing lower exposure to mite allergens or differences in
exposure to bacterial endotoxin. However, we were unable to show any significant differences in exposure
between the intervention and control groups to either agent. As it transpired the intervention study did not show
any significant clinical effect of feather bedding so this is consistent with our measurements of no differences
in exposures. The reasons why past observational studies have shown associations of less asthma among
children and the use of feather bedding remain unclear, and it is disappointing that this intervention failed to
have a clinical effect as it would have provided a cost-effective tool to reduce symptom prevalence. Our study
showed it is feasible although technically difficult to evaluate the mechanisms of interventions in terms of
changes to personal exposure to the agents thought to drive disease symptoms. It also suggests that if mite
allergen exposure is to be reduced, then additonal measures other than supplying a type of bedding will be
required. This is consistent with a move to multi-facteted interventions.
Expected future outcomes:
Studies of allergen exposure, ways to modify and the clinical implications remain of on-going importance in
the management of asthma
Name of contact:
Euan Tovey
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
ert@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 358461
CIA Name: Prof Hak Chan
Admin Inst: University of Sydney
Main RFCD: Paediatrics
Total funding: $153,005
Start Year: 2005
End Year: 2005
Grant Type: NHMRC Development Grants
Title of research award:
Bronchoprovocation testing in children using mannitol powder aerosols.Bronchoprovocation testing in children
using mannitol powder aerosols.
Lay Description (from application):
Asthma imposes a substantial burden on the Australian health care system, costing the country $585 to $720
million per year. Asthma is the major cause of childhood hospitalisation and long-term morbidity. Current
diagnosis of asthma in children is unreliable because it relies largely on subjective clinical signs. Over the last
decade a new diagnostic test that involves inhaling a dry powder of mannitol has been developed here in
Australia. While the test has been successfully used in adults, it is not available for young children due to a lack
of a suitable aerosol delivery system for the mannitol powder. Hence, there is a need to design a delivery
system for the mannitol powder so that these children can benefit from early diagnosis and treatment of asthma.
This project aims to develop the delivery system so that a reliable objective assessment technique of
bronchoprovocation testing using inhaled mannitol powders will become available. This will be achieved by a
novel device suitable for use in children using their normal tidal breathing. The concept has been validated in
vitro and a prototype device is available in Sydney University with a provisional patent being filed. The
research has progressed beyond the basic research stage and is progressing into the development phase for the
proof-of-concept testing in children. The results produced in this project will be used to optimise the design and
refine the further development of the delivery system so that it can become commercially available.
Research achievements (from final report):
A prototype of a delivery device to administer mannitol powder by tidal breathing for diagnostic of asthma has
been developed and in-vitro testing has showed comparable dose delivery from this device and adult
commercial dry powder mannitol system (AridolTM; Pharmaxis). This delivery device consists of a source of
compressed air, a solenoid valve, a powder disperser, and a holding chamber. Optimum conditions that
produced fine particle dose in increasing amount have been found. These conditions, which include amount of
powder loaded (varies from 50 to 200 mg), pressure of compressed air (5 or 7 atm), and cross sectional area of
solenoid valve that controls the impaction loss in the holding chamber, can be varied depending on the need.
The fine particle dose increased from 3.6(0.4) mg to 16.8(1.7) mg. An electronic one-way valve to be used in
conjunction with the diagnostic device has also been developed. This valve was invented because the
commercial rubber one way-valve significantly reduced the fine particle dose up to 50%. The electronic oneway valve consists of a pressure sensor that opens and closes a ball valve completely as soon as a patient
inhales and exhales. Because the ball valve is able to open and close completely, it did not reduce the fine
particle dose and consequently the amount of powder loaded did not need to increase to achieve the same fine
particle dose. In fact, the electronic one-way valve can be attached to any delivery system that critically needs
to maintain the amount of fine particle dose.
Expected future outcomes:
At the moment, the delivery device is bulky involving six large items connecting to each other. A small,
portable, commercial diagnostic device with streamlined designs suitable to deliver powder aerosols to children
will be manufactured once in-vivo testing in patients is completed with the desired results produced.
Name of contact:
Professor Hak-Kim Chan
Email/Phone no. of contact:
kimc@pharm.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402423
CIA Name: A/Pr Alaina Ammit
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $299,271
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Understanding corticosteroid-sensitive and -insensitive pathways in airway remodellingUnderstanding
corticosteroid-sensitive and -insensitive pathways in airway remodelling
Lay Description (from application):
Asthma and chronic obstructive pulmonary disease (COPD) are chronic disorders of the airways affecting
millions of people worldwide. Airways become remodelled, or thickened, resulting in airway obstruction and
decline in lung function. Approximately 400 asthmatics and 6000 COPD sufferers die in Australia each year.
Worryingly, COPD is currently the fourth highest cause of death in Australia and this number is predicted to
increase in the future. Unfortunately, the drugs currently available for combating these diseases have limited
success. We need to understand how to control airway remodelling to be able to improve treatments for asthma
and COPD. But first we require a greater understanding of the molecular mechanism/s underlying the
development of airway remodelling. With this proposal we will increase our knowledge of the mechanistic
basis of asthma and COPD and may elucidate novel therapeutic targets for future pharmacological intervention.
Research achievements (from final report):
Asthma is a chronic disorder of the airways affecting millions of people worldwide. Airways become
remodelled, or thickened, resulting in airway obstruction and decline in lung function. Approximately 400
asthmatics die in Australia each year. Unfortunately, the drugs currently available for combating these diseases
have limited success. We need to understand how to control airway remodelling to be able to improve
treatments for asthma. Our study allowed us to achieve a greater understanding of the molecular mechanisms
underlying the development of airway remodelling.
Expected future outcomes:
With this proposal we will increase our knowledge of the mechanistic basis of airway remodelling and may
elucidate novel therapeutic targets for future pharmacological intervention.
Name of contact:
Alaina Ammit
Email/Phone no. of contact:
ajammit@pharm.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402462
CIA Name: Prof Markus Seibel
Admin Inst: University of Sydney
Main RFCD: Endocrinology
Total funding: $464,521
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
GLUCOCORTICOID EFFECTS ON BONE: THE ROLE OF THE OSTEOBLASTGLUCOCORTICOID
EFFECTS ON BONE: THE ROLE OF THE OSTEOBLAST
Lay Description (from application):
Glucocorticoids (usually referred to as "cortisone") are used as therapeutic agents in almost all fields of
medicine, where they have been proven to be of great benefit to countless patients suffering from diseases such
as rheumatoid arthritis, asthma, inflammatory bowel disease and malignancies. Glucocorticoids are also of live
saving benefit to patients who have undergone organ transplantation. It is, however, well known that
glucocorticoids may also exert deleterious effects on bone, muscle, cartilage and skin, causing osteoporosis,
muscle wasting and skin damage. As a matter of fact, cortisone-induced muscle and bone disease is one of the
most frequent and serious side effects associated with glucocorticoid treatment, and substantially affects quality
of life and co-morbidity in many patients. In the present project, we aim to develop new strategies for the
understanding and prevention of costisone-induced bone disease. The first step is to investigate the
mechanisms of actions of glucocorticoids in bone. To this aim, we have generated a model in which a
cortisone- inactivating enzyme is produced in excess in the bone forming cells ("osteoblasts"). Previous studies
have shown that these cells are protected against the effects on cortisone, while other cells not producing this
enzyme remained vulnerable. We now intend to use this model to study the mechanisms of glucocorticoid
action on bone and muscle under normal and diseased conditions (e.g. in a model of glucocorticoid excess and
in a model of rheumatoid arthritis). We also intend to study how internal glucocorticoids affect the
development of bone forming cells. Our long-term aim is to uncover new ways to target drug action to the
desired tissues and cells, while protecting other tissues and cells from deleterious side effects.
Research achievements (from final report):
Our research has resulted in a novel paradigm about the role of glucocorticoids (GC; commonly referred to as
"cortisone") in the skeleton. , We discovered that endogenous (i.e. internal, low level) GC control, the fate of
immature precursor cells and the development of the cranial skeleton in mice. These effects are mediated
through specific signalling molecules secreted by the cells that form bone (the osteoblasts)., We further
discovered that the interaction between endogenous GC and osteoblasts plays an important role in autoimmune
arthritis. Using a well established mouse model of arthritis (K/BxN serum-induced arthritis) we found the
inflammatory response was significantly blunted in animals in which GC action on and in the osteoblast was
blocked. As a result, the bones of these latter mice were protected, while animals with intact osteoblastic GC
signalling showed sever arthritis and bone loss. These exciting and unexpected findings suggest that osteoblasts
are able to modulate the immune-mediated inflammatory response of the joint via a GC-dependent pathway. ,
Finally, we discovered that the effects of exogenous (i.e. external, high level) GC on energy metabolism are
mediated, at leats in part, through the skeleton and here again, the osteoblast. Using a genetically modified
mouse model, in which GC are inactivated in osteoblasts only, we demonstrated that animals with intact GC
signalling gained significantly in total and site specific fat mass, whereas mice with osteoblast-targeted
disruption of GC-signalling did not. These results show that the osteoblast plays a role in the regulation of
energy metabolism. , In summary, our research has revealed hitherto unknown and exciting functions of GC,
bone and its cells that affect not only bone health and development, but also point to a central role of the
osteoblast in mediating auto-immune inflammation and GC-induced effects on bone energy metabolism.
Expected future outcomes:
Our future research will establish the mechanisms that govern GC action in osteoblasts, and how this
interaction determines how osteoblasts comntrol mesenchymal progenitor lineage commitment, immunemediated inflammatory responses, and effects of GC on bone, fat and energy metabolism.
NHMRC Research Achievements - SUMMARY
Name of contact:
Markus Seibel
Email/Phone no. of contact:
mjs@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402659
CIA Name: Dr Graham Jones
Admin Inst: University of Sydney
Main RFCD: Genetic Immunology
Total funding: $483,262
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Functional and genetic analysis of PHF11, a new gene associated with atopic dermatitis and asthmaFunctional
and genetic analysis of PHF11, a new gene associated with atopic dermatitis and asthma
Lay Description (from application):
Atopic dermatitis, or eczema, is an increasingly common severe allergic condition affecting the skin that
afflicts up to 30% of all Australian children. Eczema has significant financial impact on families as well on the
health and well being of the affected child. The majority of asthmatics are also allergic, explaining why many
children who suffer from eczema often go on to develop asthma as well. A familial history of asthma or
eczema is an important risk factors for a child developing the disorder, meaning that allergy is to a large extent
determined by the genes we inherit from our parents. Our genes consist of four different building blocks,
called nucleotides, which are identified by four letters: A, G, C and T. Each gene has a specific "spelling" of
these four letters, although between any two people there will invariably be small single letter differences in the
way a gene is spelt. Normally, these differences have no effect. In an allergic individual, however, these
differences do have an effect. Identifying differences in the way a gene is "spelt" and why this should lead to
eczema or asthma is a major research goal. In the past several years a number of genes have been identified
that play an important role in allergy and we have recently identified a "spelling" difference in a new gene that
we believe is important in the allergic response of eczema and asthma. At the moment, we can only guess how
this gene might work. We know it is expressed in cells of our immune system that are important in allergy. We
also suspect it might be an "on" or "off" switch for other genes important for allergy. This project will test these
ideas and show how differences in the way this gene is "spelt" lead to differences in how this gene works. This
will be important in adding another piece to the puzzle of how genes control allergy and could lead to better
and earlier treatment of these disorders with improved health for affected children as well as adults.
Research achievements (from final report):
Allergic disorders such as asthma, eczema and hayfever affect many Australians. It is now well accepted that
allergy arises through a complex interaction between our genes and the environment. We have shown for the
first time how a newly identified gene, called PHF11, contributes to allergy by turning on genes in our immune
system. In addition, we also found that small differences between individuals in the DNA sequence of the
PHF11 gene, called polymorphisms, can change the amount of PHF11 present in our immune cells. This could
be important in the way the immune system functions in very young children and how this contributes to their
risk of developing allergy. In adults with established disease we believe that PHF11 is also an important
contributor to allergic inflammation. We are continuing our investigation into the role of PHF11 in the immune
system to further clarify the role of this gene in childhood and adult allergy, as well as pursuing ideas to target
PHF11 as a novel therapy in allergic disease.
Expected future outcomes:
The role of PHF11 in turning on genes in our immune system makes it an interesting target in the development
of novel therapeutics to target immune cell activation. In addition to allergy, this could also be of relevance to
other immune diseases such as arthritis.
Name of contact:
Graham Jones
Email/Phone no. of contact:
graham_jones@wmi.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402827
CIA Name: Prof Guy Marks
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $353,495
Start Year: 2006
End Year: 2010
Grant Type: Established Career Fellowships
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
During the course of this Fellowship I undertook research describing the burden of asthma and COPD in
Australia and internationally. My research also described the limitations of current treatment of these diseases
in Australia. I have commenced a number of major studies on air pollution and its health effects in Australian
cities. Finally, my research has examined aspects of the public health response to tuberculosis, both in
Australia and internationally.
Expected future outcomes:
Improved understanding of the role of air pollution in health. Improved approaches to TB control in high and
low burden settings. Better approaches to the management of asthma and COPD.
Name of contact:
Guy B. Marks
Email/Phone no. of contact:
guy.marks@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402835
CIA Name: A/Pr Janette Burgess
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $444,871
Start Year: 2006
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Mechanisms of airway remodelling in asthmaMechanisms of airway remodelling in asthma
Lay Description (from application):
Not Available
Research achievements (from final report):
Asthma, constitutes a huge socioeconomic burden to the Australian community. This research has been
examining the contribution of the extracellular matrix - the structural framework which supports the cells
within the lungs - to disease. We have identified abnormalities in the proteins which constitute the extracellular
matrix in the airways of people with asthma and have characterised the role that these changes play in the
development of disease. We have found that the changes seen in the lungs of people with asthma are not
responsive to current therapies and have been testing the effectiveness of new therapeutic approaches in
reversing these changes. Our work is helping us understand how these differences in the structural proteins of
the lungs leads to the development or worsening of asthma.
Expected future outcomes:
Repeated attacks of asthma result in structural changes in the lungs of people with asthma which contribute to
the worsening of lung function in these patients. Our work will enable the development of new drugs to reverse
or prevent these changes, which are resistant to current therapies.
Name of contact:
Janette Burgess
Email/Phone no. of contact:
janette.burgess@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457346
CIA Name: A/Pr Gregory King
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $256,973
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Does the pattern of ventilation distribution predict airway hyperresponsiveness?Does the pattern of ventilation
distribution predict airway hyperresponsiveness?
Lay Description (from application):
The tendency for airways to narrow too easily when stimulated is called airway hyperresponsiveness (AHR).
AHR is an important feature of asthma, but it also occurs in other diseases, such as chronic obstructive
pulmonary disease (COPD) - an airway disease caused by smoking, and cystic fibrosis. People who have AHR
have more severe respiratory disease, regardless of which disease they have, and are more likely to develop
poor lung function in old age and to be hospitalised or die from their disease. If we can understand the causes
of AHR we will have a better understanding of why some people with respiratory disease have poor outcomes.
We have recently discovered that, in asthma, there is a very close relationship between AHR and the uneven
distribution of air within the lungs. We believe that structural changes in the airways that cause this uneven
distribution make the airways prone to AHR. This raises the possibility that factors that cause uneven
ventilation in other respiratory diseases might also predispose the airways to AHR. If this is true, it suggests
that there is a single physiological basis for AHR in a range of different diseases, and would allow us to focus
research more closely on the causes of uneven ventilation. In this project we will measure the relationship
between AHR and uneven ventilation in people with asthma, COPD or cystic fibrosis. The study is important
because older people with asthma, particularly those with permanently narrowed airways, are likely to have
more structural changes in their airways than young asthmatics, whereas people with COPD and cystic fibrosis
have a different pattern of both structural changes and airway inflammation from that in asthma. The study will
tell us whether there is a consistent relationship between AHR and uneven ventilation. If so, this would be
extremely strong evidence that the factors that cause uneven ventilation contribute to AHR, and will point the
way to studies of new treatments.
Research achievements (from final report):
In this study, we examined whether abnormal ventilation patterns in small airways, called ventilation
heterogeneity, was an underlying mechanism of airway hyperresponsiveness in COPD as well as asthma. We
also examined physiological factors that related to ventilation heterogeneity; namely aging, breathing at low
lung volumes and airway closure. We found that heterogeneity related to airway hyperresponsiveness only in
asthma but not COPD. This indicates that the different pathologies of the two diseases translates to different
functional consequences, which are measured by lung function. We also found that there is a significant effect
of aging where the important abnormality in function moves to the smaller, peripheral airways. Finally,
heterogeneity measured by lung function, does not relate to that seen on a 3-dimensional ventilation scan. This
is because it occurrs in airways too small to be visualised by the imaging method. However, heterogeneity does
predict the amount of lung that closes down during airway constriction that mimics asthma attacks. This
finding is important because the closure of airways has signficant implications for disease mechanisms,
symptomatology and treatment
Expected future outcomes:
Our findings are in the process of submission for publication and will lead on to future studies in obesity and in
elderly asthmatics.
Name of contact:
Gregory King
Email/Phone no. of contact:
ggk@woolcock.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457385
CIA Name: Prof Guy Marks
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $761,553
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Burden of obstructive lung disease in AustraliaBurden of obstructive lung disease in Australia
Lay Description (from application):
We will conduct a survey of respiratory symptoms, lung function, smoking status, occupational exposures, and
other risk factors among 3200 people aged 40 years and over living in five Australian communities:
Melbourne, Sydney, Tasmania, Busselton (WA), and the Kimberley region (WA). In the Kimberley we will
survey 400 Aboriginal people and 400 non-Aboriginal people. We will use a survey methodology that has
been developed by an international expert panel and has been implemented in many other countries (in North
and South America, Asia, and Europe). This study will provide the first nationally-representative information
on the burden of chronic obstructive pulmonary disease (COPD) and the opportunities for health gain by
improving the management of this illness. In Australia, COPD is a relatively silent and under-recognised
disease but nevertheless is the third most important contributor to the burden of disease and the third leading
cause of hospital admission as well as being the underlying cause of 4.2% of all deaths. The information we
will collect is needed to form a basis for prevention and disease management interventions to reduce the burden
of COPD, particularly among population sub-groups who are disproportionately affected, either due to greater
exposure to risk factors (mainly tobacco smoking and occupation), greater susceptibility, under-recognition and
under-diagnosis, or inadequate disease management. Importantly, the study will serve to raise awareness about
the hazards of smoking for all Australians. By identifying target groups, prevalent exposures and management
deficiencies, it will lead the way towards policy-relevant randomised controlled trials testing community-based
interventions to prevent COPD and/or manage it more effectively. The information collected will help advance
knowledge of the prevalence, burden and treatment of COPD that will be relevant to communities throughout
the world.
Research achievements (from final report):
Through funding made available by this project grant we have recruited and tested more than 3,500 adults aged
40 years and over. These sites include coastal Busselton in Western Australia, remote communities of Broome
and Fitzroy Crossing in Western Australia, suburban Melbourne, regional centres of Hobart and Launceston in
Tasminia and Orange and Wagga Wagga in rural New South Wales. We have collected detailed questionnaire
information about respiratory health, risk factors, management practices and will relate this information to post
bronchodilator spirometry which is used to classify participants as having or not having chronic obstructive
pulmonary disease (COPD). Data collection methods have been standardised across sites and rigorous quality
control measures implemented so that any differences in the amount of COPD or risk factors identified will be
due to real differences that exist between the populations.
Expected future outcomes:
We are commencing analysis of these data as soon as the final indigenous participants are recruited and tested.
We hope that this target will be achieved by the end of 2010. At that point we will ensure that the results of the
project are presented at national and international scientific meetings and also through publication in peer
reviewed scientific journals.
Name of contact:
Guy B Marks
Email/Phone no. of contact:
guy.marks@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 457457
CIA Name: Dr J. Margaret Hughes
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $612,697
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Airway smooth muscle control of mast cells in asthmaAirway smooth muscle control of mast cells in asthma
Lay Description (from application):
Around 12% of Australians are asthmatic, with up to 25% of children affected. Thus it is a significant burden
for us and our healthcare system. Currently we treat asthma with corticosteroids to reduce airway
inflammation, otherwise the inflammation leads to thickened airways with increased amounts of smooth
muscle (ASM) that contracts too much and too easily. However more research is needed. Corticosteroids
sometimes stop working or have unwanted side effects, especially for children, and we still cannot prevent
asthma developing or cure it. We need to know more about the chemical signals which cause the pattern of
inflammation that is specific for asthma in order to cure it and prevent it developing. Recently, inflammatory
cells called mast cells (MC) have been found in increased numbers in the ASM layer of asthmatics compared
with bronchitics or healthy people. MC release mediators that contract the airways, induce mucous secretion
and promote further inflammation. We think the effects ASM cells and MC have on each other are central
factors in causing physical changes to the airways of asthmatics. In asthmatics we have identified a chemical
message (IP10) released in increased amounts by the ASM which attracts MC to it. We also have evidence that
ASM from people without asthma release factors that prevent IP10 and similar chemical messages from
working on MC. These two exciting findings demonstrate asthmatic ASM is different. We will investigate why
asthmatic ASM produces more IP10 and try to prevent each of the steps we identify with drugs that have very
specific actions. In addition, we will identify the factors released by non-asthmatic ASM that inhibit IP10 and
similar chemical messages from working. The additional knowledge gained by this research may lead to the
design of novel treatments to prevent asthma symptoms without side effects and lead to new strategies to
prevent asthma developing, especially in children.
Research achievements (from final report):
The smooth muscle cells in the breathing tubes (airways) of people with asthma are different to those from
people without asthma. There a more of cells, they are larger and they deposit large amounts of different matrix
proteins around themselves. They also have more activated mast cells in amongst them because they release
increased amounts of proteins like CXCL10 (IP10) which attracts the mast cells. These mast cells affect how
the smooth muscle cells behave. During this project we made several novel observations that may be of
significance in asthma: 1) we observed reduced activation of two signalling proteins involved in the muscle cell
production of CXCL10 and other factors that attract mast cells; 2) we identified four matrix proteins released in
much higher amounts by the muscle cells from people with asthma than without asthma and 3) we discovered a
protein CXCL1 that inhibits mast cell movement towards the airway smooth muscle and found it is released in
much greater amounts by the non-asthmatic airway smooth muscle cells. The reduced activation of the
signalling proteins in the asthmatic airway smooth muscle cells may underlie their altered production of
factors, including CXCL10, CXCL1 and the matrix proteins, that modulate mast cell accumulation within the
muscle bundles especially during periods of severe inflammation. Thus this project has increased our
understanding of why the airway smooth muscle is different in asthma and opened up new avenues for
developing strategies to prevent the signs and symptoms of the disease. Manuscripts of these findings are
currently being prepared (3) for/or are submitted (2) to peer reviewed journals. Other findings continuing on
from the previous project have already been published or are in press .
Expected future outcomes:
Now we need to determine 1) why the smooth muscle cells produce more matrix proteins and less CXCL1; 2)
whether the matrix proteins released in increased quantities are involved in the mast cells moving in amongst
the muscle cells and staying there and 3) how CXCL1 stops the mast cells moving to the muscle cells. Then we
will have new more specific ways to prevent them in asthma.
NHMRC Research Achievements - SUMMARY
Name of contact:
J Margaret Hughes
Email/Phone no. of contact:
margaret.hughes@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 464815
CIA Name: Dr Brian Oliver
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $270,710
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Repetitive viral infection accentuates airway wall remodellingRepetitive viral infection accentuates airway wall
remodelling
Lay Description (from application):
In the asthmatic lung structural changes or remodelling occur, which are thought to contribute to the abnormal
functioning of the airways. These remodelling events which occur in the asthmatic airway include increased
deposition of proteins which form the scaffolding of the airways (the extracellular matrix ECM proteins), and
an increased mass of bronchial smooth muscle cells. Many of these critical structural changes are not reversed
or prevented with current asthma therapy. Remodelling is an important process in both the development and
progression of asthma. The reason why remodelling occurs in the lungs of people with asthma is not known. It
is thought that persistent inflammation drives the remodelling process; however remodelling can perpetuate
inflammation, thereby creating a cyclic series of events. Furthermore we have shown that cells from nonasthmatic volunteers which are grown on asthmatic ECM change to become more like cells from asthmatic
subjects. Viruses which infect the lungs may play a role in the development of asthma, and in the increased
remodelling which is observed. Many common respiratory viruses are capable of infecting lung cells, eg
epithelial cells, which evokes an inflammatory response. I will investigate if viral infection can alter the
remodelling process, using lung cells isolated from asthmatic and non-asthmatic volunteers. Furthermore, I will
assess if current and novel treatments are effective in reducing the remodelling process. We have preliminary
evidence that infection of lung epithelial cells with rhinovirus (the common cold virus) alters the amount of
ECM deposited by these cells. I hypothesise that this process will be increased in cells from volunteers with
asthma compared to non-asthma. As current therapeutics are unlikely to be able to reverse these remodelling
events these experiments will enable the development of new therapeutics which can target this important
aspect of airway disease.
Research achievements (from final report):
The aeitology of airway remodelling in asthma is not known. We have shown that rhinvoirus infection alters
extracellula matrix deposition from bronchial epithelial cells, fibroblasts, and human airway smooth muscle
cells, and, furthermore, cell type specific responses were observed. Collectively these data, for the first time,
demonstrate that RV can alter ECM deposition and this may contribute to the remodelling observed in
respiratory diseases.
Expected future outcomes:
I will be able to use the information gained within this grant to produce other research papers
Name of contact:
Brian Oliver
Email/Phone no. of contact:
brian.oliver@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512301
CIA Name: Prof Judy Black
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $626,142
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Signal transduction in airway remodellingSignal transduction in airway remodelling
Lay Description (from application):
In the asthmatic lung structural changes, such as increased deposition of proteins which form the scaffolding
of the airways (the extracellular matrix proteins), and an increased mass of bronchial smooth muscle cells
occur. Many of these critical structural changes are not reversed or prevented with current asthma therapy,
thus we need to investigate, by using lung cells and tissues , why they happen and how we can prevent them.
Research achievements (from final report):
Asthma is one of the most common chronic diseases affecting the Australian population with a prevalence of
approximately 1 in 12. One of the major currently unsolved aspects of asthma pathology is airway remodelling.
This consists of an increase in the amount of airway smooth muscle, an increase in new blood vessel formation
and a thickening of the basement membrane which is situated beneath the epithelium. Because these changes
are not improved by current asthma therapy and because they contribute significantly to asthma symptoms it is
important to develop new more effective therapy. We have found in previous work on our human lung cells
that one of the pathways (the PI3 kinase pathway ) which could causing remodelling is upregulated in cells
derived from asthmatic volunteers when we compare them to cells taken from people without asthma. We
collaborated with Professor Peter Shepherd a researcher in Auckland, New Zealand who has developed
chemical compounds which inhibit the actions of specific members (isoforms) of the PI3 kinase family. We
have now discovered which isoforms are present in airway smooth muscle, fibroblasts and epithelial cells and
used the specific inhibitors to discover which PI3 kinase isoforms are responsible for the cellular changes
which constitute remodelling. We also found that one of the enzymes known as phosphodiesterases which
degrade cellular messengers which cause relaxation of airway smooth muscle is increased in asthma airway
smooth muscle cells. This could explain why response to asthma medication or "puffers" is sometimes less
than optimal and could indicate the need for additional therapy which inhibits the actions of these
phosphodiesterases.
Expected future outcomes:
As these pharmacological compounds become more refined and their actions more specific people with chronic
respiratory diseases such as asthma are likely to have more options to treat their disease and relieve their
symptoms.
Name of contact:
Judy Black
Email/Phone no. of contact:
judy.black@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512387
CIA Name: A/Pr Gregory King
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $382,539
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
How do thick airway walls affect airway hyperresponsiveness in asthma?How do thick airway walls affect
airway hyperresponsiveness in asthma?
Lay Description (from application):
Asthmatic airways narrow too easily, a characteristic called airway hyperresponsiveness (AHR). To
understand the cause of asthma we need to understand the cause of AHR. Thickened airway walls could
amplify airway narrowing and increase AHR. However, thick airway walls are also stiff, and stiff walls could
reduce narrowing and AHR. This project will examine the relationships between AHR and airway wall
thickness and stiffness during and after treatment that reduces airway wall thickness.
Research achievements (from final report):
This grant supported a study into the underlying abnormalities in the way in which airways function in asthma,
i.e. why asthmatic airways narrow excessively and close (a characteristic of asthmatic airways known as
airway hyperresponsiveness). We hypothesised that asthma caused airways to thicken and to become stiffer,
thus contributing to airway hyperresponsiveness. We used innovative technology to measure changes in the
mechanical function of the airways (forced oscillation measurement of airway stiffness) before and after
treatment with inhaled anti-inflammatory drugs, and high-resolution computed tomography (HRCT) to
measure stiffness. We found that airway walls were stiffer with increasing duration of asthma, and that
although treatment rendered them less stiff, neither stiffness or change in stiffness did not relate to airway
hyperresponsiveness. In the HRCT study, we showed the small airways (<2mm internal diameter) were more
responsive in terms of reduced stiffness, to bronchodilator inhalation. Further studies again using forced
oscillation technique showed that the reduced stiffness was most evident at low lung volumes. These series
findings show that the small conducting airways are likely an important region of responsiveness in asthma and
a cite of response to bronchodilator treatment. An important negative finding was that increased airway
stiffness in asthma did not contribute to airway hyperresponsiveness. These findings contribute to the
understanding of how airway hyperresponsiveness in asthma arises, although this is still incomplete.
Expected future outcomes:
The relationship between the mechanical function of small airways in asthma should be related to other asthma
outcomes, such as symptoms and asthma control.
Name of contact:
Greg King
Email/Phone no. of contact:
ggk@woolcock.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570856
CIA Name: A/Pr Alaina Ammit
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $461,528
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
MKP-1 as a novel anti-inflammatory strategy in asthma and airway remodellingMKP-1 as a novel antiinflammatory strategy in asthma and airway remodelling
Lay Description (from application):
Asthma is a chronic disorder where airways are remodelled, or thickened, resulting in poor lung function.
Airway remodelling is a consequence of long-term inflammation after multiple episodes of asthma. As the
current drugs to treat remodelling have side effects, the aim of this grant is to investigate a novel antiinflammatory strategy to reverse the development of airway remodelling by increasing the anti-inflammatory
protein - MKP-1.
Research achievements (from final report):
Asthma is a widespread chronic health problem responsible for the death and disability of many Australians.
Airway remodelling underlies asthma, but unfortunately, the pharmacotherapy currently available for
combating these diseases has limited success. With this grant, we gained a greater understanding of how to
control airway remodelling to be able to improve treatments for asthma. We increased our knowledge of the
mechanistic basis of asthma and elucidated novel molecular strategies and drug candidates based on exploiting
the MAPK-deactivator MKP-1 for future pharmacotherapeutic approaches to reduce and reverse airway
remodelling.
Expected future outcomes:
Further publications and novel anti-inflammatory strategies based on our increased understanding of MKP-1
will follow in future years.
Name of contact:
Alaina Ammit
Email/Phone no. of contact:
alaina.ammit@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570867
CIA Name: A/Pr Janette Burgess
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $317,076
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
The anti-inflammatory role of collagen IV in asthmaThe anti-inflammatory role of collagen IV in asthma
Lay Description (from application):
We have discovered that a protein, tumstatin, is missing from the lungs of people with asthma. We now have
exciting data showing, for the first time, that tumstatin can stop inflammation. If tumstatin is part of the system
that normally limits inflammation in the lungs its absence in asthma may be critical. In this grant we will
discover how tumstatin works to block inflammation and why it is absent in asthma. Our studies will provide
vital information about the role of tumstatin in the airways.
Research achievements (from final report):
We have discovered that a protein, tumstatin, is missing from the lungs of people with asthma. We have
discovered that tumstatin has unique properties, it does not regulate the inflammaotry response but leads to
deposition of matrix proteins in the airways . We have also characterised a profile of endogenous enzymes that
can degrade tumstatin. , If tumstatin is part of the system that normally limits the formation of excess blood
vessels in the lungs its absence in asthma may be critical. Our studies have provided essential information
about the role of tumstatin in the airways.
Expected future outcomes:
Repeated attacks of asthma result in structural changes in the lungs of people with asthma which contribute to
the worsening of lung function in these patients. Our work will enable the development of new drugs to reverse
or prevent these changes, which are resistant to current therapies.
Name of contact:
Janette Burgess
Email/Phone no. of contact:
janette.burgess@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570919
CIA Name: Prof Guy Marks
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $831,581
Start Year: 2009
End Year: 2014
Grant Type: NHMRC Project Grants
Title of research award:
Sex-related changes in asthma during the transition through puberty in the CAPS birth cohortSex-related
changes in asthma during the transition through puberty in the CAPS birth cohort
Lay Description (from application):
Early adolescence is a critical period in the life of people with asthma. Some children grow out of their asthma
and others acquire the disease for the first time. There are important sex differences in the pattern of change.
We believe these changes are related to the passage through puberty. This study will examine changes in the
features of asthma and allergy during this period and their relation to early life and current environmental
exposures.
Research achievements (from final report):
Of the original cohort of 616 children we have successfully follow up 370 (60%) at 11.5 years of age and 351
(57%) at 14 years of age. At the end of this project grant we still maitain contact with 429 (69.6%) which is
very good considering families enrolled in the study between 14 and 17 years ago and the study was initially
intended to run for 5 years only. , Results arising from this project have led to the publication of 52 peer
reviewed journal articles., We have collected evidence that shows that diet supplementation and house dust
mite allergen avoidance as implemented in this study did not prevent asthma or allergic symptoms. , The
funding of this project has allowed us to follow the children through the early stages of puberty where at the
end of 2013 our oldest child was 16.5 years and our youngest child was 14 years. We are continuing to collect
annual self-report of pubertal stage and also quarterly height which will provide information about transition
through the later stages of puberty. To completely address the project grant aims we need to continue to collect
data through to the end of puberty when children are 17 years of age.
Expected future outcomes:
With information from these children up to age 17 years we will be able to answer the main questions of this
project grant. Why do some children "grow out of asthma" while others develop it for the first time? What
early life and environmental factors are related to asthma remission or development during adolescence?
Name of contact:
Dr Brett Toelle
Email/Phone no. of contact:
brett.toelle@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 571053
CIA Name: A/Pr Helen Reddel
Admin Inst: University of Sydney
Main RFCD: Primary Health Care
Total funding: $460,821
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Improving asthma control: general practice strategies to optimise medication adherenceImproving asthma
control: general practice strategies to optimise medication adherence
Lay Description (from application):
Asthma is a major health problem for Australia. Many patients have frequent symptoms and need urgent health
care because they do not use a preventer inhaler regularly. This may be intentional e.g. fear of side-effects, andor unintentional e.g. forgetting. This real-life study will test two simple strategies for GPs to improve their
patients' use of preventer medications, to improve asthma control. Innovative technology will allow GPs to
tailor the approach to each patient during a normal visit.
Research achievements (from final report):
Despite the availability of effective preventer inhaler treatment for asthma, medication use in Australia remains
poor. This poor adherence is associated with worse asthma outcomes including symptoms, lung function and
health care utilisation. Asthma is mostly managed by GPs, who recognise adherence as an important problem,
but previous studies to improve adherence have used complex multi-component interventions that are not
feasible for delivery in primary care. This project tested tools designed to tackle issues which limit adherence
with preventer inhalers in patients with asthma, both life-style issues (such as forgetting medication), and
attitudinal barriers (concerns about side effects/necessity of medication). We investigated whether patients'
asthma control and medication adherence could be improved by (1) GP-led personalised adherence discussions,
(2) twice daily reminders for missed preventer doses plus internet-based adherence feedback or (3) both
discussions and reminders. These tools were compared to usual care. A key aim of the study was to provide
GPs with feasible, effective tools for supporting improved adherence in primary care.Data analysis is underway
and an abstract has been submitted for peer review to a international respiratory medicine conference. A media
release will be available once a manuscript has been accepted for publication in an international peer reviewed
journal.
Expected future outcomes:
If the analysis shows the study tools and strategies to be effective, they are likely to be recommended by
clinical practice guidelines for implementation to improve adherence in asthma, and to prompt studies of their
effectiveness in other chronic respiratory conditions.
Name of contact:
Assof. Prof. Helen Reddel
Email/Phone no. of contact:
helen.reddel@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 571098
CIA Name: Prof Judy Black
Admin Inst: University of Sydney
Main RFCD: Basic Pharmacology
Total funding: $794,642
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a respiratory cell biologist-pharmacologist investigating the cellular and molecular mechanisms of chronic
airways disease.
Research achievements (from final report):
Our work has focused on 3 different respiratory diseases- asthma, pulmonary fibrosis and
lymphangioleiomyomatosis (LAM). In asthma we have described the interaction of respiratory viruses with
human lung cells and found that they decrease the effectiveness of the beta receptor which is the target for beta
agonists used for the treatment of bronchoconstriction. We have continued to report how the airways of people
with asthma behave differently with respect to the supporting structure of the lung- the extracellular matrix
.The fact that we found that combined beta agonists and corticosteroid therapy does not prevent exxtracellular
matrix protein deposition in vitro has implications for the management of a number of chronic respiratory
diseases associated with fibrosis. In a clinical trial we investigated whether lowering the dose of inhaled
corticosteroids would be as effective against asthmatic inflammation and scarring of the airways. Importantly
we studied the levels of fibulin, an extracellular matrix protein which also circulates in the blood, in patients
with idiopathic pulmonary fibrosis -a disease of the lungs for which there is no effective treatment. We found
that patients who had a high level of fibulin in their serum experienced a more rapid worsening of their disease.
We conducted studies in LAM- a rare fatal disease of young women, characterised. by cystic destruction of the
lungs due to invasion of smooth muscle like LAM cells via lymph and blood. These cells multiply invade and
migrate through the lung and other organs. Although rapamycin, an immunosupressive drug can halt the
progress of the disease it is not wihout significant side effects and on its cessation, lung function declines just
as rapidly. Thus other treatments are necessary and we invstiegated the effects of doxycycline a drug wih few
side effects which has some efficacy in LAM patients in our cellular models of LAM. We found that
doxycycline inhibited migration of LAM cells.
Expected future outcomes:
In patients with IPF, measuring fibulin levels may tell us whether lung function will decline if these levels are
high and thus these patients will need accelerated management. In women with LAM combinations of durgs
such as doxycycline and members of the statin family with rapamycin derivatives, together with agents which
decrease lymphangiogenesis could prove promising in management.Prof
Name of contact:
Professor Judith Black
Email/Phone no. of contact:
judy.black@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 632793
CIA Name: A/Pr Gregory King
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $502,438
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Is asthma in the elderly a disease of the peripheral airways?Is asthma in the elderly a disease of the peripheral
airways?
Lay Description (from application):
Elderly asthmatics have poorer clinical outcomes compared with younger asthmatics. The reasons for this are
unclear but may involve age-related changes in the disease itself. In this project we aim to show that asthma in
the elderly is dominated by abnormalities of very small peripheral airways, in contrast to younger patients
where the abnormalities occur in larger airways. The results will provide the basis for new and better targeted
treatment strategies for asthma in the elderly.
Research achievements (from final report):
The study findings supported the hypothesis that asthma in the eldery differs from in younger patients by
affecting the airways towards the outside of the lung (small airways) and this may explain why asthma in older
patients is more difficul to treat and has different characteristics.
Expected future outcomes:
More detailed study on mechanisms of the differences so that new treatment targets can be developed.
Name of contact:
Dr Greg King
Email/Phone no. of contact:
ggk@woolcock.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 632830
CIA Name: Dr J. Margaret Hughes
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $623,764
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Mast cells - bystanders or instigators of airway remodelling in asthma?Mast cells - bystanders or instigators of
airway remodelling in asthma?
Lay Description (from application):
Current asthma treatments have little effect on changes to the breathing tubes in our lungs. The tubes are
thickened and stiffer, with more muscle, blood vessels, matrix and mucus. We propose that a particular
inflammatory cell, called a mast cell, causes these changes to the breathing tubes and we will find out how it
does that. Thus this project will establish why and how the changes to the breathing tubes happen in asthma
and reveal how best to target and reverse-prevent them in the future.
Research achievements (from final report):
The airways of people with asthma are thickened and the cells making up the structure of the airways behave
differently. There is more airway smooth muscle bulk because there are more muscle cells and they are bigger.
There are more blood vessels and mucus glands next to the muscle underneath the inner lining of the airway
and the lining itself is thicker and patchy. In all these areas immune cells called mast cells are found in
increased numbers and they are actively releasing products from their granules and producing more. We
investigated whether human lung mast cells were instigators of those structural changes in the airways or just
bystanders. We found mast cell products increased the amounts of matrix deposited by airway smooth muscle
cells and fibroblasts and increased fibroblast proliferation, thus contributing to thickening/fibrosis of the airway
wall. They also increased the levels of pro-inflammatory chemicals produced by those cells. As well, we
identified a specific mast cell product that stimulates new blood vessel formation. Mast cell products also
increased mucus production and increased wound closure by the cells from the lining of the airways. Both
processes are normally protective unless they become uncontrolled. This project has increased our
understanding of how the cells in the airways may interact to contribute to the changes that occur in asthma and
warrant follow-up investigation. This increased knowledge will inform the search for better therapies to reverse
/ prevent the structural changes and inflammation in the airways of people with asthma.
Expected future outcomes:
Mast cell serine proteases induced many pro-remodelling/inflammatory activities by airway structural cells.
Future studies investigating the efficacy of mast cell stabilisers / protease inhibitors on airway changes in
animal asthma models would establish the validity of those approaches to prevent changes / restore normal
airway structure and function in asthma.
Name of contact:
Dr J Margaret Hughes
Email/Phone no. of contact:
margaret.hughes@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1003263
CIA Name: Prof Judy Black
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $571,429
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Fibulin-a target for lung fibrosis?Fibulin-a target for lung fibrosis?
Lay Description (from application):
Although current medications are effective in the treatment of asthma, there remains a group of patients with
persistent disease and this is likely due to the presence of fibrosis. We have discovered that a novel protein fibulin is increased in the blood, lung fluid, cells and tissues of asthmatic patients. A number of other serious
lung diseases for which treatment is not available are also associated with fibrosis. We will investigate whether
fibulin is increased in these diseases and how to reverse or prevent its effects.
Research achievements (from final report):
Asthma, chronic obstructive pulmonary disease and pulmonary fibrosis are all characterised by fibrosis - the
deposition of structural matrix proteins which leads to stiffening of the lung and which is resistant to treatment.
We have discovered that fibulin, one of these proteins is particularly implicated in the development of fibrosis.
With our collaborators, we used animal models and cellular models of fibrotic lung disease to discover that
fibulin is increased in the blood lung fluid cells and tissues of people with lung disease. We also found that we
could decrease levels of fibulin and deposition of matrix proteins in our models of disease. Targeting fibulin
raises the possibility that there are therapeutic options - previously unavailable- for diseases associated with
lung fibrosis. ?????
Expected future outcomes:
Our results will be pursued with a particular emphasis on fibosis in idiopathic pulmonary fibrosis (IPF)- a
severe fibrotic lung disease with a view to halting progression that currently occurs.
Name of contact:
Professor Judith Black
Email/Phone no. of contact:
judy.black@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1003500
CIA Name: Prof Guy Marks
Admin Inst: University of Sydney
Main RFCD: Respiratory Diseases
Total funding: $319,714
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Research Fellowships
Title of research award:
Translating respiratory and environmental epidemiology into improved lung healthTranslating respiratory and
environmental epidemiology into improved lung health
Lay Description (from application):
Chronic respiratory disease, tuberculosis and the effects of air pollution are important health problems globally.
Evaluating current approaches to dealing with these problems and developing new approaches requires good
data. Over the next five years I will lead a number of studies addressing these issues, in Australia and
internationally, in order to provided the strongest possible evidence to underpin policy.
Research achievements (from final report):
The Fellowship was terminated early (after 3 years) because I gained a Senior Principal Research Fellowship.
During this three year period I completed a research project measuring the burden of COPD in Australia,
continued an RCT investigating the effectiveness of active case finding TB in household contacts of patients
with TB in Vietnam and commenced a new RCT of community-wide screening for TB in Vietnam. I also
gained funding to start two new CREs: in air pollution and in tuberculosis.
Expected future outcomes:
I expect to establish the role of novel interventions to improve global lung health.
Name of contact:
Guy Marks
Email/Phone no. of contact:
g.marks@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490057
CIA Name: Dr Fay Johnston
Admin Inst: University of Tasmania
Main RFCD: Epidemiology
Total funding: $172,393
Start Year: 2008
End Year: 2011
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Understanding the health effects of biomass smoke in Australian towns and citiesUnderstanding the health
effects of biomass smoke in Australian towns and cities
Lay Description (from application):
Wildfires have become more frequent and severe the world over and the health impacts of the associated air
pollution is a major gap in the current evidence. Working with lead agencies in air quality regulation, public
health and fire management I will examine and compare the health effects of air pollution from deliberate
burns, bushfires, wood heaters and other sources of air pollution. The research will focus on respiratory and
heart disease to inform public health and individual patient care.
Research achievements (from final report):
This project has: (1) Demonstrated commnity wide health impacts from landscape fire smoke, dust storms and
air pollution from wood heaters in Australia: (2) Made the first estimate of the mortality attributable to
landscape fire smoke at the global scale (3) Contributed to new public health policy for air quality in Australia;
and (4) contributed new evidence to the debates about the global impacts of tropical deforestation.
Expected future outcomes:
Our work continues to contribute to edvidence based guidelines and policies for the management of the air
quality impacts of planned burning, bushfires and smoke pollution from other sources such as wood heaters.
Name of contact:
Fay Johnston
Email/Phone no. of contact:
fayj@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 544943
CIA Name: Dr Julia Walters
Admin Inst: University of Tasmania
Main RFCD: Primary Health Care
Total funding: $354,381
Start Year: 2009
End Year: 2013
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Self-management support by trained health mentors for people with Chronic Obstructive Pulmonary Disease in
the communitySelf-management support by trained health mentors for people with Chronic Obstructive
Pulmonary Disease in the community
Lay Description (from application):
Chronic Obstructive Pulmonary Disease (COPD) is characterised by persisting limitation to airflow and is
usually caused by smoking. This disease significantly reduces quality of life and life expectancy. This
fellowship will support full assessment of a new model of community self-management support, health
mentoring by trained nurses, for people with COPD that aims to improve their quality of life, decrease health
care costs and empower patients to better manage their own disease.
Research achievements (from final report):
This fellowship grant supported work showing community health nursing workforce training is feasible and
effective for supporting chronic disease self-management by patients in the community. It resulted in high
quality evidence from a randomised controlled trial for the benefit of health mentoring on self-management in
chronic obstructive pulmonary disease of moderate severity. Changes in health behaviours that promote good
health and prevention of disease are supported by telephone-delivered health-mentoring. This has the potential
to reduce the burden of chronic disease.
Expected future outcomes:
Systems to deliver chronic disease self-management support for community based patients integrated into
primary care.
Name of contact:
Dr Julia Walters
Email/Phone no. of contact:
Julia.Walters@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 110238
CIA Name: Prof Wayne Thomas
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $203,297
Start Year: 2000
End Year: 2002
Grant Type: NHMRC Project Grants
Title of research award:
Mimotopes for the investigation and therapy of allergic diseaseMimotopes for the investigation and therapy of
allergic disease
Lay Description (from application):
10% of children now use regular asthma medication. The current treatments dampen allergic inflammation but
25% of asthmatic children, all under high medication, need multiple visits to the doctor, emergency treatment
or hospitalisation,. Immunotherapy has, since 1911, used repeated injections of allergens. The end result has
often been successful and lasting but the response has been unpredictable and requires years of multi-injection
treatment. The challenge is to develop effective, applicable immunotherapy which, like vaccines use few
injections. Mimotopes provide a new opportunity. Studying the parts of the allergens recognized by the
immune system (epitopes) can reveal important phenomena undetectable with whole allergens; and single
epitopes may be a powerful avenue to effective immunotherapy. The therapy can be targeted to a selected arm
of the immune system for maximal effect and the immediate side effects induced by cross linking antibodies
with two epitopes can be avoided. Allergens interact with two types of lymphocyte, the T and B cells. T-cell
epitopes can be easily studied because they comprise short regions of proteins which can be synthesized. B-cell
(and antibody) epitopes are shapes formed by the interaction of several parts of a protein which cannot be
represented by a simple sequence. The mimotope technology uses random peptides to obtain a shape which
mimics the B-cell epitope. Here mimotopes will be produced and used to study the common specificities
recognized in allergic responses to house dust mite allergens to develop new types of therapy. Importantly
recent information shows that B-cell epitopes can be used to modify both T and B-cell function.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 139020
CIA Name: Prof Patrick Holt
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $130,475
Start Year: 2001
End Year: 2001
Grant Type: NHMRC Project Grants
Title of research award:
Studies on the effects of RSV infection during infancy on aeroallergen-specific T-cell immunity and lung
functionStudies on the effects of RSV infection during infancy on aeroallergen-specific T-cell immunity and
lung function
Lay Description (from application):
Many infants who develop transient severe wheezing in association with respiratory infections, go on to
develop asthma which can persist throughout childhood and some times into adult life. It is not known whether
the respiratory infections are a direct cause of later asthma, or whether they simply function as "flag" which
identifies children who have a genetic predisposition to wheeze e.g. because they have abnormally narrow
airways. This project will compare the effects of respiratory infection in infants with the RSV virus, who
contract the disease at different ages, and who have varying levels of genetic risk for respiratory allergies. In
particular, it will examine the possibility that in certain cases, infection of genetically susceptible individuals
during early infancy will boost the development of allergies to airborne environmental allergens (such as house
dust mite) which are known to trigger asthma attacks in older children and adults.
Research achievements (from final report):
This project commenced in January 2001 and in January 2002 was rolled into Program Grant 211912. The
principal achievements at the time of termination of the grant (ie at the end of Year 1 of the project) were the
recruitment of a significant proportion of the study group, plus establishment of relevant lab methodology.
Expected future outcomes:
Elucidation of the relationship between severity of RSV infection in infancy and subsequent development of
asthma
Name of contact:
Patrick G Holt
Email/Phone no. of contact:
patrick@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 139024
CIA Name: Prof Peter Sly
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $577,040
Start Year: 2001
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Postviral wheezing in childhood: disregulation of airway tone?Postviral wheezing in childhood: disregulation
of airway tone?
Lay Description (from application):
Asthma is a very common childhood condition that is becoming increasingly more common. Wheezing is
common in infants and young children following viral infections and is often thought of as the first
manifestation of asthma. However, many children and infants who wheeze with viral infections appear to grow
out of asthma in their teenage years. Asthma that persists into adult life is usually associated with allergies to
common environmental allergens, such as house dust mite and grass pollens. However, many infants who
wheeze with viral infections, especially in the first year of life, do not develop allergies in later life, raising the
possibility that they did not have the same type of asthma as those whose symptoms persist. This project will
study the effects of viral infections on lung function to determine whether particular types of virus can have
detrimental effects of lung function lasting for years. We will also examine whether the age at which the
infection occurs and the severity of the infection influence the long-term outcome. The project involves
studying infants during the recovery phase of respiratory viral infections, older children years after documented
infections and experimental animal models that have been infected under controlled conditions. By
determining whether respiratory viral infections can have long-term effects on lung function that can mimic
asthma, we will advance our understanding of how asthma develops. In addition, specific treatment and
preventative strategies could then be developed to prevent these long-term abnormalities, instead of relying on
asthma medication (especially inhaled corticosteroids) as is the current practice. Preventative strategies could
include encouraging the development of specific vaccines.
Research achievements (from final report):
This project investigated mechanisms underlying the development of asthma and airway hyper-responsiveness
in animal models and human infants. A cohort of children requiring hospitalization for acute viral bronchiolitis
in the first year of life were recruited and have been followed. The asthma outcomes for these children will be
determined when they turn 5 years old. New animal models for studying the consquences of RSV infection
were developed along with new methods for measuring abnormalities in airway mechanics were developed.
Expected future outcomes:
An imporved understanding of how viral infections alter lung function and increase the risk of asthma.
Name of contact:
Peter D. Sly
Email/Phone no. of contact:
peters@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 139025
CIA Name: Prof Susan PRESCOTT
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $287,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Role of maternal dietary omega3 fatty acids in modulation of allergen-specific T cell responses in the
offspringRole of maternal dietary omega3 fatty acids in modulation of allergen-specific T cell responses in the
offspring
Lay Description (from application):
Environmental lifestyle changes are implicated in the concerning increase in allergic diseases such as asthma
and allergic diseases over the 25 years. Despite the enormous personal, social and economic cost, the exact
causes are not clear. Diet is one of the most important yet unstudied environmental exposures linked to the
recent increase in both asthma and allergic disease. Authorities in this area have recommended diet as
research priority in the search for allergy prevention strategies. Allergic diseases result from inappropriate
inflammatory immune responses to protein substances such as dust mite (allergens), and it now evident that
these patterns of immune responses are commonly initiated before birth. This study will address the influence
of maternal diet in pregnancy on the developing human immune system, and how it contributes to the
development of allergic immune responses in offspring. One of the most significant dietary changes associated
with increasing urbanisation is the increasing intake of pro-inflammatory omega-6 fatty acids (which may
promote allergic immune responses) and declining dietary levels of omega-3 fatty acids (which inhibit
inflammatory immune responses). Omega-3 fatty acids have beneficial effects in many inflammatory diseases,
and are important for healthy pregnancy. It is possible that maternal diets which are becoming increasingly
deficient in omega-3 fatty acids may prime the fetus to respond more readily to allergens, and increase the risk
of later allergic responses. This study will determine whether increasing dietary omega-3 fatty acids during
pregnancy using fish oil supplements, can alter immune responses to house dust mite and other allergens at
birth and later infancy. The findings will contribute to our understanding of the relationship between antenatal
nutrition and immune development and may lead to dietary recommendations as a cost effective, non invasive
strategy to help prevent allergic disease.
Research achievements (from final report):
The dramatic increase in asthma and allergic disease over the last 20-30 years has highlighted the urgent need
to identify associated environmental changes that may also be logical targets for disease prevention. Although
this is likely to be multifactorial, both epidemiological and experimental data also provide a plausible link
between these dietary changes and allergic diseases. It is logical that dietary exposures may have greater effects
during early development than once immune responses are established, and this study provided the first
evidence that n-3 PUFA may have significant effects in very early life before immune responses are fully
established. In a randomised double blind randomised placebo control trial, we demonstrated that maternal fish
oil supplementation in pregnancy resulted in significantly higher neonatal n-3 PUFA levels compared to the
control group. Infant cytokine responses were negatively correlated with n-3 PUFA levels and positively
correlated to n-6 PUFA levels (discussed in associated publications in more detail). A number of these
relationships were statistically significant. These observations suggest that n-3 PUFA have immunomodulatory
properties during early immune development. Although this previous study was designed to assess immune
outcomes (rather than clinical outcomes) we collected preliminary clinical data for the purposes of this
application. We observed a consistent trend for less allergic symptoms and sensitisation in the supplementation
group at 1 year of age. There has been strong international interest from the publications arising from this
work. Approximately 40% of infants in Australia and other developed countries develop allergic sensitisation.
If such a simple non-invasive strategy can reduce the risk (even slightly) or the severity of disease expression it
could have enormous impact in a global context at relatively little cost.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Our preliminary findings (which suggest that n-3 PUFA can modify early infant immune responses to
allergens) highlight the need to determine if this simple, non-invasive strategy has a role in allergy prevention.
This had lead to further successful NHMRC funding (2005-2007) to confirm these clinical effects
Name of contact:
A/Prof Susan Prescott
Email/Phone no. of contact:
susanp@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 139103
CIA Name: Prof Roy Goldie
Admin Inst: University of Western Australia
Main RFCD: Basic Pharmacology
Total funding: $421,528
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Airway virus infection, protease-activated receptors and microvascular permeabilityAirway virus infection,
protease-activated receptors and microvascular permeability
Lay Description (from application):
Asthma is an inflammatory airway disease which kills about 800 Australians each year and otherwise afflicts
millions of children and adults in all age groups. Respiratory tract viral infections trigger inflammation and
asthma. We believe that this is caused by the loss of naturally protective, bronchodilator and anti-inflammatory
substances such as prostaglandin E2 and increased production of asthma promoting substances such as
endothelins. Both of these substances are made by the epithelial lining cells of the bronchi where viruses grow.
This project will assess the influence of respiratory tract virus infection on epithelial mechanisms for the
production of PGE2 and endothelins. Respiratory viral infections are accompanied by airway inflammation and
thus by elevated microvascular permeability and oedema which exacerbates obstruction in asthma. We will
measure airway microvascular permeability changes during viral infection and assess the protective effect of
stimulating protease-activated receptors which increases PGE2 production. The impact of the PAR system on
the integrity of microvascular tissue and on epithelial endothelin production has not been previously
investigated. In addition, the influence of respiratory tract viral infection on PAR function in this system is also
unknown, but is potentially of great importance to our understanding of the behaviour and regulation of this
natural bronchoprotective pathway. This work may lead to the use of novel PAR activators as combined
bronchodilator-anti-inflammatory therapies in asthma.
Research achievements (from final report):
N/A
Expected future outcomes:
This research has opened the door to assessing the impact of changes in the fluid content of the airways in lung
disease on airflow patterns and on restricted breathing in asthma. This may alter the choice of drugs to be used
in asthma and COPD if it can be shown that reducing fluid induced airway swelling will improve restricted
breathing in asthma and COPD.
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 139173
CIA Name: Prof Peter Sly
Admin Inst: University of Western Australia
Main RFCD: Not Allocated
Total funding: $690,600
Start Year: 2001
End Year: 2005
Grant Type: Established Career Fellowships
Title of research award:
Postviral wheezing in childhood: disregulation of airway tone?Postviral wheezing in childhood: disregulation
of airway tone?
Lay Description (from application):
Not Available
Research achievements (from final report):
Development of techniques for studying differential gene expression in T-cells stimulated in-vitro, Expansion
of studies investigating Gene-Environment Interactions, Development of new techniques for measuring lung
volumes in mice and rats, Development of new models for studying influences of early life inflammatory
stimuli on lung growth and airway hyperresponsiveness in mice , Commencement of the first clinical trial of
primary prevention of asthma based on sound immunological theory, Immune Tolerance Network Protocol
ITN025AD sponsored by NIAID , Designation as a WHO Collaborating Centre for Research on Children's
Environmental Health. The Centre is expected to officially begin activities in late 2006., Optimal methods for
the early detection of lung disease in infants and young children with Cystic Fibrosis. in conjunction with the
Department of Respiratory Medicine at PMH and Drs. Philip Robinson and Colin Robertson from the
Department of Thoracic Medicine, Royal Children's Hospital, Melbourne
Expected future outcomes:
A major goal is to stimulate the resetting of the international public health agenda for control of asthma to
achieve a shift of emphasis from the current paradigm of treatment of established disease, towards the more
proactive approach of primary and secondary disease prevention in high-risk children
Name of contact:
Prof Peter Sly
Email/Phone no. of contact:
peters@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211906
CIA Name: Prof Howard Mitchell
Admin Inst: University of Western Australia
Main RFCD: Systems Physiology
Total funding: $301,320
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
AIRWAY STIFFNESS AND BRONCHIAL RESPONSIVENESSAIRWAY STIFFNESS AND BRONCHIAL
RESPONSIVENESS
Lay Description (from application):
The breathing difficulty experienced by asthmatics occurs because of excessive narrowing in the bronchial
tubes or airways. These airways are normally held open by the pressures in the chest during breathing. It is
possible that the excessive airway narrowing in asthma occurs because these pressures are no longer effective.
This may be due to changes in the airway stiffness which occurs during asthma. The project will involve
experts Canada and Australia who have developed new techniques which allow the airways to be seen so that
these changes can be measured.
Research achievements (from final report):
The causes of breathing difficulties in asthma are hotly debated. Several theories are under investigation in
basic and cliniacal research laboratories. One of the ideas is that the airway tubes narrow excessively because
they are no longer held open by the lung tissue, which surrounds and normally supports the airway. The
importance of this lung support even in healthy individuals is not known. This project has shown that
surrounding lung has much less effect on airway narrowing than previously thuoght, particularly in stiff
airways, as commonly present in the asthmatic lung. The significance of our findings is that excessive airway
narrowing in asthma is less likely, than previously thought, to be simply a result of the loss of support from the
surrounding lung. Additional causes of excessive airway narrowing must therefore be considered.
Expected future outcomes:
The study emphesises the importance of potential mechanisms which are responsible for airway narrowing in
asthma. It allows further experimental approaches to be used to pin point causes of the breathing difficulty.
Name of contact:
Howard Mitchell
Email/Phone no. of contact:
mitchell@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211912
CIA Name: Prof Peter Sly
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $7,822,981
Start Year: 2002
End Year: 2006
Grant Type: Programs
Title of research award:
Developmental Aspects of Respiratory inflammation, allergy and asthmaDevelopmental Aspects of
Respiratory inflammation, allergy and asthma
Lay Description (from application):
Not Available
Research achievements (from final report):
1. Development of techniques for studying differential gene expression in T-cells stimulated in-vitro. techniques developed have resulted in the discovery of many new genes related to T-cell activation Th-2
responses and expression of clinical asthma. The low-level stimulation of cells reveals a completely different
pattern of gene expression when compared to the conventional supra-maximal stimulation., 2. Expansion of
studies investigating Gene-Environmental Interactions - these studies are the first to elucidate the genetic basis
of the mechanisms responsible for the ill-effect of cigarette smoke in early life and led to a range of new
studies in 2006., 3. Development of new techniques for measuring lung volumes in mice and rats plethysmographic techniques for measuring absolute lung volumes in mices as young as 2 weeks old in the
absence of spontaneous breathing efforts.These techniques are now being used to produce more sensitive and
accurate models of human lung diseases., 4. Development of new models for studying influences of early life
inglammatory stimuli on lung growth and airway hyperresponsiveness in mice.- these include neonatal
sensitzation to allergen in the absence of adjuvant, allergen sensitization via the nasal route in the absence of
adjuvant, viral lower respiratory infections and ventilator-induces lung disease models. These modesl are being
used to investigate mechnaisms underlying humna lung disease and the impact of exposures to inflammatory
stimuili early in life on ling growth and development and on the induction of airway hyperresponsiveness., 5.
Progress in developing the first clinical trial of primary prevention of asthma based on sound immunological
theory - During 2006 we launched of the first true trial of primary prevention of asthma that will be based on
sound immunological theory. This trial, known as the Global Prevention of Asthma in Children (GPAC) in
funded by the Immune tolerance Network and US NIAID.
Expected future outcomes:
To gain a greater understanding of the mechanisms by which asthma develops with the intention of furhter
development of primary preventative strategies.
Name of contact:
Prof Peter Sly
Email/Phone no. of contact:
peters@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211942
CIA Name: Prof Susan PRESCOTT
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $195,990
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Fetomaternal immunological interactions in the aetiology of allergic disease.Fetomaternal immunological
interactions in the aetiology of allergic disease.
Lay Description (from application):
There is accumulating evidence that immune abnormalities that lead to allergy are present at birth, and may be
linked with maternal factors in pregnancy. This study examines how immune interactions between the fetus
and the mother during pregnancy predispose to allergic immune responses in the infant. Allergic diseases
result from inappropriate "Type 2" responses to the environment whereas "Type 1" response dominate immune
responses of nonallergic people. Type 2 immune responses are first initiated before birth when they are actually
normal for fetal survival. In normal infants maturation of Type 1 immune responses plays a central role in
"switching off" the Type 2 responses of fetal life. Allergic disease appears to be due to abnormal persistence of
this Type 2 response pattern beyond the newborn period. One of the most striking abnormalities in allergic
individuals is immature Type 1 function at birth. With rising rates of allergy, there is an urgent need to identify
how the balance of Type 1 and Type 2 responses is regulated during this early period. Maternal factors appear
to play a critical role. There is already evidence that Type 1 responses are lower in babies of allergic mothers
compared to babies of allergic fathers, suggesting direct effects of the mother in pregnancy. Although
pregnancy normally favours Type 2 immunity, there appears to be normal variation in the balance of Type 1
and Type 2 responses in pregnancy. We plan to determine if variations in this balance affect the fetal capacity
for Type 1 responses. We propose that minor degrees of tissue mismatch (present in all pregnancies) will
activate low grade Type 1 responses and enhance maturation of fetal Type 1 responses. We will determine if
allergic mothers (prone to stronger Type 2 responses) have less developed Type 1 responses in pregnancy and
if this plays a direct role in abnormal Type 1 responses observed in their babies.
Research achievements (from final report):
Aims and Rationale for the study: The aim of this study was to explore whether materno-fetal interactions can
influence immune development in pregnancy. We addressed the specific hypothesis that a gestational
environment where there is potentially reduced signal for fetal Th1 maturation (as seen at birth in infants of
atopic mothers) may contribute atopic risk additional to that conferred by maternal genetic factors alone., , Key
findings: We found that maternal responses to fetal antigens were related to fetal immune responses and
subsequent allergy. This novel observation suggests that events at the materno-fetal interface have an important
influence on early immune development. We have also been able to extend the scope of the study by using
samples from this cohort to further characterise early immune responses in relationship to subsequent allergic
disease , , Significance: The dramatic increase in allergic disease has highlighted the need to identify the
processes that underlie Th2 differentiation, and the pathways by which environmental factors could exert
influence. This study provides fundamental data for understanding of the "normal" spectrum of maternal-fetal
immune interactions. We have shown that alteration in the pregnancy cytokine milieu may have direct effects
on fetal immune development and affect subsequent immune responses. The findings also suggest that
materno-fetal interaction could contribute the protective effect of having older siblings (which has been
previously attributed to the "hygiene hypothesis"). Collectively these findings suggests that environmental
influences could exert effects by influencing interactions at the materno-fetal interface. Our work has
highlighted this as an important ongoing avenue of reseach. ,
Expected future outcomes:
We hope to identify new perinatal markers which may more accurately predict the development of allergic
disease., We plan to extend this work into microarray technology to examine early gene expression (in the fetus
and the placenta) which may give further insights into disease pathogenesis and prediction,
NHMRC Research Achievements - SUMMARY
Name of contact:
Prof Susan Prescott
Email/Phone no. of contact:
sprescott@meddent.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211986
CIA Name: A/Pr Peter Henry
Admin Inst: University of Western Australia
Main RFCD: Basic Pharmacology
Total funding: $376,980
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Influence of endothelin and protease-activated receptors on eosinophil trafficking in the airways of allergic
miceInfluence of endothelin and protease-activated receptors on eosinophil trafficking in the airways of
allergic mice
Lay Description (from application):
Asthma is a chronic inflammatory lung disease. This disease affects about 10% of the population, although its
incidence in primary school-age children is as high as 30% in some cities. People suffering from asthma have
very responsive (hyperresponsive) airways to substances which are usually innocuous. Many asthmatics are
allergic to substances such as pollens, animal dander and house dust, which causes the airways of the asthma
sufferer narrow, making breathing more difficult. The airways of asthma sufferers also become inflamed and
the resulting swelling of the airways and excess formation of mucous makes breathing difficult. Inflamed
asthmatic airways contain large numbers of cells called eosinophils, which move from the blood into the
airways. Substances released from the eosinophils are thought to damage the airways and cause airways
hyperresponsiveness. We have developed a mouse model of allergic inflammation which has many of the
hallmark features of asthma, including high numbers of eosinophils and hyperresponsive airways. We have
recently shown that these effects are inhibited by treatment of allergic mice with a drug called SB217242.
SB217242 inhibits the actions of endothelin, a peptide that is produced in elevated amounts in the airways of
asthma sufferers and which may produce many of the effects associated with asthma. We wish to investigate
the mechanisms through which SB217242 and drugs which stimulate novel protease-activated receptors
inhibits the increase in eosinophil numbers in the airways. We will investigate the possibility that these drugs
inhibit the migration of eosinophils from the blood into the airways, using a unique microscope that allows us
to visualize the movement of eosinophils into tissues such as the airways. These studies are likely to be of
considerable strategic value in determining the potential usefulness of these drugs in the treatment of asthma.
Research achievements (from final report):
Our research focuses on providing a better understanding of the mechanisms underlying asthma - a disease that
kills about 500 people each year in Australia and affects many thousands of others in this country, particularly
in the younger age groups. We are particularly interested in investigating ways of preventing or reversing the
airway obstruction that is a characteristic feature of asthma. Obstruction is often produced by specific chemical
mediators release during an asthma attack, which interact with other cell membrane proteins known as
"receptors" expressed on the surface of airway cells. We have investigated the role of two receptors which
appear to have opposing actions - the protease-activated receptor2 (PAR2) which opposes obstruction and
endothelin receptors which promotes obstruction. Our studies using animal models of asthma have clearly
demonstracted that drugs that block endothelin receptors and stimulate PAR2 significantly inhibit processes in
the airways that are likely to contribute to airway obstruction. These findings are of considerable strategic
value in that they provide 'proof of priciple' support for the postulate that these drugs can inhibit the
development of inflammatory cell recruitment and hyperresponsiveness in the allergen-driven diseases of the
airway.
Expected future outcomes:
Our hope is that these preclinical findings will stimulate future research of these molecules in the treatment of
human lung diseases.
Name of contact:
Dr Peter Henry
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
phenry@receptor.pharm.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 211988
CIA Name: Prof Matthew Knuiman
Admin Inst: University of Western Australia
Main RFCD: Epidemiology
Total funding: $115,110
Start Year: 2002
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Asthma, Lung Function, Snoring and Passive Smoking in BusseltonAsthma, Lung Function, Snoring and
Passive Smoking in Busselton
Lay Description (from application):
Respiratory diseases such as asthma, chronic obstructive airway disease, and sleep apnoea are common in the
community, and asthma is becoming more and more common. These diseases are a major cause of morbidity,
lost time from work, use of health and community resources and death. Using information collected by the
Busselton Health Studies between 1966 and 2000, we will investigate some new epidemiological aspects of
respiratory diseases. Some of the questions we will examine are: * How much more common has asthma
become in the Busselton population? Has the increase been more pronounced in some groups than in others (eg
younger people)? Have other respiratory diseases also become more common? * Is decline in FEV1 over time
a more useful measure of lung health than a single FEV1 measurement? How is decline in FEV1 related to age
and other factors such as asthma, smoking, chronic respiratory diseases and hay fever? * Do the following
put people at increased risk of sleep apnoea: overweight, recent weight gain, smoking, heavy alcohol intake,
respiratory illness, cardiovascular disease and use of sedatives? * Do non-smoking spouses of smokers suffer
more respiratory illness than spouses of non-smokers? We expect that results from this study will increase
our understanding of the causes and progression of respiratory diseases, and may eventually point to ways of
reducing the burden of these diseases in the community. Since all the information needed has already been
collected in the course of earlier health surveys, this study will be particularly cost-effective.
Research achievements (from final report):
This research has, for the first time using Australian data, demonstrated precisely how much more quickly lung
function declines (and chronic airflow obstruction develops) in smokers and asthmatics compared with nonsmoking non-asthmatics. It has also shown that the similarity in lung function between husband and wife is
primarily due to factors affecting choice of partner rather than sharing of common lifestyle, this ahs important
implication for family studies of obstructive lung diases. The research has also confirmed in an Australian
population that obesity and smoking are the principal reversible risk factors for snoring and witnessed
apnoeas..
Expected future outcomes:
The findings from this research will inform the effects to prevent and manage obstructive lung disease, asthma,
and sleep apnoea. The outstanding work on asthma trends will shed light on the explanation for the increasing
prevalence of asthma in Australia.
Name of contact:
Matthew Knuiman
Email/Phone no. of contact:
matthew@sph.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 212098
CIA Name: Dr Peter Franklin
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $252,365
Start Year: 2002
End Year: 2005
Grant Type: Early Career Fellowships (Australia)
Title of research award:
The effect of pollutants in the home on airway responsiveness & airway inflammation in infantsThe effect of
pollutants in the home on airway responsiveness & airway inflammation in infants
Lay Description (from application):
Not Available
Research achievements (from final report):
The aims of the research program were two-fold - investigate measures of lung function and airway
inflammation in infants and develop strategies for measuring exposure of infants to indoor air pollutants. Lung
function research concentrated on non-invasive measures of airway inflammation (exhaled nitric oxide (eNO)
and exhaled breath condensates (EBC)). We consolidated a method for measuring eNO in infants and
investigated its utility in different disease states. A method for collecting EBC in infants was developed,
however, more work is required to validate the various biomarkers in EBC. There is interest in eNO and EBC
for understanding airway disease and our work has been important in developing methodologies for measuring
these during the early stages of disease. These markers may also be useful in determining the impact of
exposure to environmental irritants in early life and can now be part of a battery of tests used in longitudinal
studies investigating the role of environmental exposures on the initiation of respiratory disease. For the second
aim a large study was undertaken to understand where young children spend most of their time and the impact
of the home environment on exposure to air pollution. This study found that young infants spend, on average,
less than 5% of their time outside and most time is inside at home. For important indoor pollutants, such as
formaldehyde, nitrogen dioxide and particulate matter, domestic levels seem to be a good indicator of personal
exposure. This data is important for the design of air pollution exposure studies.
Expected future outcomes:
The use of infant eNO for predicting the development of asthma and allergy is currently being investigated.
Infant eNO, but not EBC, will be part of future early life environmental exposure studies. Infant time-activity
and personal exposure data will be used for, as yet unfunded, longitudinal environmental exposure studies.
Name of contact:
Peter Franklin
Email/Phone no. of contact:
Peter.Franklin@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 254527
CIA Name: Prof Patrick Holt
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $782,250
Start Year: 2003
End Year: 2007
Grant Type: Established Career Fellowships
Title of research award:
Aetiology and pathogenesis of inflammatory respiratory diseasesAetiology and pathogenesis of inflammatory
respiratory diseases
Lay Description (from application):
Not Available
Research achievements (from final report):
My research work focuses on the causation and therapeutic control of asthma. The principal recent
achievements arising from this research are (i) elucidation of the role of airway wall dendritic cells in
triggering of the late phase asthma response, (ii) discovery of a range of new genes which control T-cell
responses to aeroallergens, (iii) development of a rational framework for asthma prevention strategies targeted
at "high risk" children, (iv) launch of the first international trial for primary prevention of allergy and asthma
by immunotherapy.
Expected future outcomes:
Shifting emphasis in international research on asthma from therapeutic control of established disease, towards
primary prevention of disease in "high risk" children.
Name of contact:
Patrick G. Holt
Email/Phone no. of contact:
patrick@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 254528
CIA Name: Prof Susan PRESCOTT
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $219,750
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Effects of enteric microflora on mucosal and systemic immune development in infants at risk of allergic
diseaseEffects of enteric microflora on mucosal and systemic immune development in infants at risk of allergic
disease
Lay Description (from application):
The increase in allergic diseases over the last 20-30 years has been attributed to an increased immunological
propensity to "Type-2" allergic immune responses in the postnatal period. It has been proposed that this may be
due to a relative deficiency of counter-regulatory "Type 1" immune responses in early life. Thus, there is
growing interest in factors that might affect Type 1 maturation in this early period. It has been proposed that
progressively "cleaner" societies may have more allergies because there is less stimulation of the Type 1
responses during immune development. Bacterial products provide important maturation signals to the
developing immune system, and may favour Type 1 responses. The largest early exposure to bacteria in occurs
in the human gut, which is colonised with bacteria soon after birth. These bacteria play an important role in
maintaining health, both in the protection from harmful bacteria, and in the development of food tolerance.
There is evidence that infants in cleaner sociaeties may have alterations in bowel flora. For many years
"probiotic" formulations (containing strains of these healthy bacteria) have been used safely to treat children
with gastroenteritis to reduce the duration of diarrhoea. More recently it has been suggested that these
formulations have a role in treating and even preventing allergic disease. Further research is needed to confirm
this, and to define the underlying immunological processes. This randomised double blind control study will
determine if supplementation with probiotic flora (in late pregnancy and in early infancy) can favourably
influence gut colonisation, alter subsequent immune development, and help prevent allergic disease in infants
at high risk (from allergic families).
Research achievements (from final report):
The aim of this study was to determine if early probiotic supplementation prevents allergic disease in high risk
infants. Newborns of allergic women (n=231) received either Lactobacillus acidophilus (LAVRI-A1) or
placebo daily for the first six months of life. Children were assessed for AD and other symptoms at 6 and 12
months and had allergen skin prick tests (SPT) at 12 months of age., , Results: 178 infants completed the
supplementation period. Those in the probiotic group showed significantly higher rates of Lactobacillus
colonisation). At six months, AD rates were similar in the probiotic and placebo groups and there were no
major differences in immune development. There was also no difference at 12 months, although the proportion
of children with SPT+AD was significantly higher in the probiotic group. At 12 months, the rate of
sensitisation was significantly higher in the probiotic group. The presence of culturable Lactobacilli or
Bifidobacterium in stools in the first month of life was not associated with the risk of subsequent sensitisation
or disease, however the presence of Lactobacillus at 6 months of age was associated with increased risk of
subsequent cows milk sensitisation., , Conclusions: Early probiotic supplementation with Lactobacillus
acidophilus did not reduce the risk of AD in high-risk infants and was associated with increased allergen
sensitisation in infants receiving supplements. The long-term significance of the increased rate of sensitisation
needs to be investigated in further studies., , Clinical Implications: These findings challenge the role of
probiotics in allergy prevention.
Expected future outcomes:
The findings are important in addressing premature public enthusiasm for the use of probiotics in allergy
prevention. Although microbial burden may be important for normal immune maturation, our findings suggest
that adding a single strain of probiotics as a dietary supplement is not the answer. This work will lead to the
development of more refined and targeted prevention strategies.
NHMRC Research Achievements - SUMMARY
Name of contact:
Prof Susan Prescott
Email/Phone no. of contact:
sprescott@meddent.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 254611
CIA Name: Prof Geoffrey Stewart
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $457,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
THE ROLE OFPROTEASES AND PROTEASE ACTIVATED RECEPTORS IN RESPIRATORY
EPITHELIAL CELL FUNCTION IN ASTHMATHE ROLE OFPROTEASES AND PROTEASE
ACTIVATED RECEPTORS IN RESPIRATORY EPITHELIAL CELL FUNCTION IN ASTHMA
Lay Description (from application):
The epithelium lines the airways and is, therefore, constantly exposed to a variety of exogenous antigens,
infectious agents and noxious stimuli. This tissue responds to such stimuli by secreting substances that help
counteract the insult while simultaneously initiating healing and repair. In this proposal, we will investigate the
role of a group of receptors present on the surface of the epithelium which monitor the area surrounding the
epithelium for the presence of enzymes which digest host tissue or pathogens. These receptors, known as PAR,
sense their suroundings by binding the protease, a process which then triggers the cell to respond in an
appropriate way by releasing cytokines and mediators. There are 4 PAR, each with different properties, and are
present on many cells of the body. However, little information about their role on epithelium exists. Although
we have shown them to be upregulated in the epithelium in the socio-economically important disease, asthma,
their function in this disease remains elusive. We will, therefore, initiate studies to define their role in
inflammation, healing and repair as this information may lead to a better understanding of their role in disease
which may then translate into better treatment.
Research achievements (from final report):
We determined the potential of the respiratory epithelium in the context of inflammation, resolution and repair
in diseases such as asthma and respiratory distress syndrome. We examined the endogenous and exogenous
proteases that have been implicated in the above disease and examined the role of a family of receptors
designated protease activated receptors (PAR) that are activated on exposure to such enzymes. Significant
findings from this study are that activation of PARs results in inflammatory mediator production associated
with asthma. Various other PAR-4 peptides have also been shown to induce cytokine release in an additive
fashion. These cleaved peptides were also able to induce cytokine release from human lung fibroblasts. This
suggests that the epithelial-mesenchymal unit plays a prominent role in regulating, orchestrating and localising
inflammation as well as being central to repair and remodelling processes. We also showed for the first time
that PAR agonist peptides were capable of stimulating a variety of non-cytokine related molecules from the
A549 cells, the release of which could have favorable or deleterious effects on asthma.The study of mediators
and their mechanisms of action may shed light on the underlying biochemistry of PAR-mediated events at
respiratory epithelial surfaces but also contribute to a greater understanding of inflammatory processes in
asthma.
Expected future outcomes:
It is anticipated that these studies will lead to an increased understanding of the role of mediators in asthma
with the potential to drive the development of novel therapeutic agents.
Name of contact:
Prof. Geoffrey Stewart
Email/Phone no. of contact:
head@bcs.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 303145
CIA Name: Prof Stephen Stick
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $263,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Developmental and cellular mechanisms involved in the pathological changes to the epithelium in
asthma.Developmental and cellular mechanisms involved in the pathological changes to the epithelium in
asthma.
Lay Description (from application):
A consensus has developed in recent years that asthma involves chronic airway inflammation superimposed
upon a background of airway remodelling. If untreated, these processes result in increased airway
responsiveness, variable airflow obstruction and ultimately a progressive decline in lung function). Recently
the role of the epithelium in the pathogenesis of asthma has been emphasised based upon observations
indicating that the epithelium can play an important role in airway inflammation and remodelling. However,
this paradigm has been developed using data accumulated almost exclusively from studies in adults.
Epidemiological studies suggest that airway remodelling might play a less significant role in the majority of
childhood asthma since most children with asthma have relatively minor symptoms, minimal disruption of lung
function and tend not to have symptoms that persist into adulthood. Clearly the relative importance of
inflammation and remodelling and the regulatory mechanisms involved are important factors to understand
particularly if new, effective prevention and therapeutic strategies are to be developed. For the first time in
children, the proposed project will allow the study of asthma mechanisms using target organ tissue (airway
epithelium) from a large unselected population. Primary cell samples recovered by bronchial brushing will be
analysed separately and also cultured in order to investigate critical elements of the pathogenesis of asthma.
Data collected from symptomatic children can be easily compared with that from healthy controls and also with
data from adults to determine age related factors that contribute to asthma. Furthermore, the establishment of a
repository of cultured epithelial cells from these children will provide a unique resource that will allow future
collaborations with scientists studying a variety of mechanisms in asthma & with the pharmaceutical industry.
Research achievements (from final report):
1. The first characterisation of epithelial function in primary cells from children with asthma., 2. First
demonstration of abnormal repair responses in epithelium from children with asthma., 3. Demonstration of the
important role of fibronectin in epithelial repair and deficiency in asthma., 4. Demonstration that Fibronectin
restores normal repair in asthmatic epithelium., 2.
Expected future outcomes:
N/A
Name of contact:
Stephen Stick
Email/Phone no. of contact:
Stephen.Stick@health.wa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 303161
CIA Name: Prof John Upham
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $254,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Effects of allergens on dendritic cell function in allergic asthmaEffects of allergens on dendritic cell function in
allergic asthma
Lay Description (from application):
In recent decades, there has been a nearly three-fold increase in the prevalence of allergic diseases such as
asthma. Although the reason these diseases have increased in prevalence remains unknown, we suspect the
way in which the immune system responds to foreign proteins in the environment may be very important in
determining whether an individual develops allergic disease or not. How and why individuals with allergic
asthma respond excessively and inappropriately to inhalation of a small range of seemingly innocuous proteins
(allergens) is a central question in respiratory medicine and allergy. We propose that investigating the way that
antigen presenting dendritic cells (DC) respond directly to allergens will shed important light on this issue, as
DC are fundamental to our ability to deal with foreign antigens and to generate an appropriate immune
response. The overall hypothesis underpinning this proposal is that allergens induce specific responses in DC
from individuals with allergic asthma, and that this contributes to the maintenance and amplification of allergic
tissue inflammation in this disease. Understanding the ways in which DC respond to clinically relevant
allergens will lead to significant progress in understanding the pathogenesis of allergic asthma. This project
was recommended for funding last year, but was relinquished when one of the previous co-investigators on last
year's grant was awarded a Program grant.
Research achievements (from final report):
How and why individuals with allergic asthma respond excessively and inappropriately to inhalation of a small
range of seemingly innocuous proteins (known as allergens) is a central question in respiratory medicine. This
study examined how dendritic cells regulate the way that the immune system reacts to allergens from house
dust mites. We showed that these allergens induce the expression of a unique and complex profile of genes in
dendritic cells from allergic individuals. Our studies focussed on a protein known as thrombomodulin. This
protein is usally associated with the regulation of blood clotting, but we showed for the first time that
thrombomodulin is highly expressed in dendritic cells from allergic people after exposure to house dust mite
allergens. This increase in thrombomodulin expression is not observed in dendritic cells from healthy people.
Moreover, thrombomodulin in dendritic cells altered the way that other immune cells such as lymphocytes
reacted to these allergens., In a second series of studies, we examined how lipoproteins and lipopetides derived
from common bacteria and which activate the Toll like receptor 2 could be used to turn off allergy in the test
tube. We showed that these Toll like receptor 2 activating lipoproteins and lipopeptides inhibited the allergic
response to house dust mite allergens in allergic subjects, without altering immune responses to other antigens.
The mechanism by which this occurred involved antigen presenting cells including monocytes and dendritic
cells.
Expected future outcomes:
These studies have provided new insight into the mechanisms leading to allergic asthma, and have provided the
foundation for developing new ways of treating allergies once we understand more about the mechanisms
involved.
Name of contact:
Professor John Upham
Email/Phone no. of contact:
j.upham@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 323204
CIA Name: Dr Wendy Oddy
Admin Inst: University of Western Australia
Main RFCD: Community Child Health
Total funding: $453,500
Start Year: 2005
End Year: 2009
Grant Type: Career Development Fellowships
Title of research award:
Nutritional influences on mental health and immune system development.Nutritional influences on mental
health and immune system development.
Lay Description (from application):
Not Available
Research achievements (from final report):
Interest in empirically derived dietary patterns has increased over the past decade. We have shown that
comparable dietary patterns may be obtained from a food frequency questionnaire and food record using
exploratory factor analysis. This supports the use of major dietary patterns identified using a FFQ in our
adolescent cohort., Dietary patterns have public health implications as they are a modifiable risk factor in
adolescent mental health. We showed behavioural scores were decreased with aspects of the healthy dietary
pattern specifically fruit and vegetable intake. We showed that higher behavioural scores (meaning poorer
behaviour) were associated with increased intake of the Western dietary pattern in particular takeaway foods,
red meat, confectionary and potato chips. , We found that high dietary glycemic carbohydrate was associated
with a higher prevalence of the metabolic syndrome in adolescents. However, relationships varied according to
the definition of Metabolic syndrome used, with waist circumference a potentially relevant factor., Higher
intakes of both omega-3, particularly long-chain, and omega-6 polyunsaturated fatty acids were significantly
associated with lower blood pressure in adolescent boys, but not girls. These results suggest that the
relationships between dietary fatty acid intake and blood pressure in adolescents may be moderated by gender.,
Our research shows that diets rich in wholegrains, fruit, vegetables and legumes are beneficial to the long-term
health of adolescents whereas diets high in red meat, processed meat, takeaway, refined foods, confectionary
and soft drinks are associated with increased risk for mental health problems and metabolic syndrome.
Expected future outcomes:
Nutrition has long-term programming effects on later health and disease and I am leading nutrition data
collection into the 21st year. Given the potential impact of dietary factors on metabolic syndrome, diabetes and
mental health risk this study provides a dataset unequalled world-wide for future studies.
Name of contact:
Wendy Oddy
Email/Phone no. of contact:
wendyo@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353532
CIA Name: Prof Arthur William (Bill) Musk
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $737,817
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
THE CHANGING PREVALENCE OF ASTHMA AND CHRONIC OBSTRUCTIVE AIRWAY DISEASE IN
AUSTRALIATHE CHANGING PREVALENCE OF ASTHMA AND CHRONIC OBSTRUCTIVE AIRWAY
DISEASE IN AUSTRALIA
Lay Description (from application):
Respiratory illnesses are common with asthma symptoms affecting up to 15% of adults and 30% of children in
the Australian community. Chronic obstructive pulmonary disease (COPD) is also common. The term
encompasses emphysema and bronchitis and is mainly due to cigarette smoking. Although COPD is less
common than asthma it causes more persistent disability especially in older people. Asthma is associated with
faster decline in lung function with age and may also ultimately cause COPD. A diagnosis of asthma has
become more common especially in children although this may be due to increased awareness and available
treatments. Less is known about changes in the prevalence of asthma and COPD in adults over the last 10
years. These airway diseases are associated with inflammation in the airways and changes in airway structure.
Tests of lung function and airway responsiveness have been used repeatedly in Busselton a coastal town in the
south west of Western Australia since 1966 to provide information on changes in airway structure (calibre).
Recently non invasive tests that can provide evidence of inflammation have been developed. Although
treatment of asthma can control symptoms and improve lung function, airway inflammation tends to persist.
The extent to which inflammation and abnormal structure are present in the airways of people in the
community who do not complain of respiratory symptoms is not known. This study will determine if the
frequency of asthma and COPD are actually increasing in the population of Busselton in comparison to
previous estimates over the past 35 years. It will determine the degree to which unrecognised airway
inflammation is present in the community and the best ways of detecting it. The results of the study will help
to look for causes of asthma, determine how big a problem airway inflammation is in the community, and how
it relates to abnormal airway structure, lung function, airway responsiveness and respiratory symptoms.
Research achievements (from final report):
Our presence in Busselton resulted in our being able to use the goodwill generated to take part in a further
study there (The Burden of Obstructive Lung Disease: BOLD) also funded by NH&MRC and commenced in
July 2007 immediately after the completion of the Busselton Health Survey. This study was in collaboration
with 4 other Australian centres and was completed in June 2008. Immediately since the BOLD study, we have
been conducting a Busselton Diabetes study in collaboration with Fremantle Hospital. Two manuscripts have
been accepted for publication in European Respirator Journal and Nature Genetics and 2 others are in
preparation., , We have trained our research assistants to collect a wide range of measurements such as FEV1
and FVC, eNO as well as conducting questionnaire survey. In addition, one of our senior research assistant,
Michael Hunter is now trained to assist in the analyses of the Sleep studies. He is also expected to become a
integral part of our next planned studies - the Healthy Ageing Study, involving all baby-boomers from
Busselton which will commence in 2010. The Busselton Health Study have become a more permanent fixture
of the town so that furture studies will be enhanced
Expected future outcomes:
As a result of this research, improved phenotypic definitions of asthma, COPD, and associated traits for genetic
association studies will benefit not only the Busselton population but also the general Australian community.
We plan further prevalence studies of respiratory disease which will benefit from the data collected in 20052007.
Name of contact:
Aw Musk
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
Bill.Musk@health.wa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353555
CIA Name: Prof Susan PRESCOTT
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $537,600
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Immunomodulatory effects of omega-3 polyunsaturated fatty acids : role in allergy prevention in
infancyImmunomodulatory effects of omega-3 polyunsaturated fatty acids : role in allergy prevention in
infancy
Lay Description (from application):
The dramatic increase in asthma and allergic disease over the last 20-30 years has highlighted the urgent need
to identify associated environmental changes that may also be logical targets for disease prevention. Although
this is likely to be multifactorial, one significant change during this period has been a progressive decline in the
intake of dietary anti-inflammatory n-3 polyunsaturated fats (PUFA) in Western diets, with a corresponding
increase in n-6 PUFA fatty acids. We recently showed for the first time that n-3 PUFA may have more
significant effects in very early life before immune responses are fully established. We confirmed that maternal
fish oil supplementation (n=40) resulted in significantly higher n-3 PUFA levels in newborns (compared to
those with no supplements, n=43), and this was related to reduced immune responses to allergens (such as
house dust mite, cat and egg). These observations suggest that n-3 PUFA can modify early immune
development. Although this previous study was designed to assess immune outcomes (rather than clinical
outcomes) we collected preliminary clinical data for the purposes of this application. We observed a consistent
trend for less allergic symptoms and sensitisation in the supplementation group. These observations clearly
warrant this proposed study to confirm these clinical effects, and to assess the mechanisms of action in
considerably more detail. In this proposed study we will compare the effects of fish oil (n=165) or placebo
(n=165) in early infancy (from 0-6 months of age). This much larger population will allow us to determine if
increasing dietary n-3 PUFA is a way of reducing the chance of allergy in families where there is a high genetic
risk. Approximately 40% of infants in Australia will go on to develop asthma or allergies. Strategies such as
this that reduce the risk (even slightly) or the severity of disease expression could have enormous impact in this
global context at relatively little cost.
Research achievements (from final report):
Fish oil supplementation for the first 6 months of life (650mg/day) achieved significant differences in n-3 and
n-6 PUFA levels in the supplemented infants compared with the placebo group, with significantly higher levels
of 22:6 n-3 DHA (p=0.011) and significantly lower 20:4n-6 AA (p=0.001) than the placebo group. , , Higher
levels of total n-3 PUFA at 6 months were associated with reduced risk of persistent respiratory symptoms such
as persistent and recurrent coughing (OR= 0.75; 95%CI 0.57-0.97; p=0.029). In contrast, higher levels of total
n-6 PUFA were associated with an increased risk of developing symptoms of eczema (OR= 1.13; 95%CI 1.011.26; p=0.037) at 6 months.This suggests that variations in n-3 and n-6 fatty acids levels at 6 months are
associated with altered risk of cutaneous and respiratory symptoms. Further follow-up of this cohort is
occurring at 12 months of age to determine the effects on allergy prevention., , In the coursse of this study we
have also idenitfied an novel early marker of allergic disease.Neonatal T-cell PKCzeta expression was lower in
children who had subsequent evidence of allergic disease at 1 year. It was also lower in children with
sensitization (positive skin prick test). Fish oil supplementation was associated with significantly higher
PKCzeta expression (P = .014), whereas most other isozymes were reduced by fish oil supplementation. This is
the first study to show that allergic disease is associated with altered expression of T-cell PKC isozymes in the
neonatal period. It has also demonstrated that fish oil can modulate expression of PKC isozymes in a
potentially favorable direction. , , , A further report will be provided by December 2009, when the final clinical
follow-up(of the main cohort, n=420) and further analysisof immune function has been completed.
Expected future outcomes:
1. Detailed effects of the fish oil supplementation on immune function has been performed at 6 months of age
and the data are currently being analysed (Dec 2009). , 2. Further clinical assessments will determine if the fish
NHMRC Research Achievements - SUMMARY
oil supplementation had any effect on the prevention of allergic disease. This be completed by October 2009
and the analysis completed for publication by December 2009.
Name of contact:
Prof Peter Le Souef
Email/Phone no. of contact:
plesouef@meddent.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353594
CIA Name: Dr Sunalene Devadason
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $326,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Distribution of monodisperse aerosols inhaled by children for determination of optimal therapeutic inhaler
formulationsDistribution of monodisperse aerosols inhaled by children for determination of optimal therapeutic
inhaler formulations
Lay Description (from application):
Inhalers are the primary form of treatment for asthma, allowing the delivery of lower doses of medication
directly to the lungs. Consistent daily use of these inhalers is often necessary to effectively control the
symptoms of asthma. Inhalers are now increasingly used to treat infants with lung problems. Many of these
inhalers are not designed for use by such young children, who may be unable to perform the breathing
techniques necessary for effective use of these inhalers. Not all the drug inhaled by patients will end up in the
lungs where it is needed; a large proportion is left in the mouth, throat and stomach. Our earlier studies have
shown that there is a large amount of variability in the amount of drug received by children using inhalers. We
intend to assess the important factors involved in improving the efficiency of inhaler therapy for children, such
as the size of the inhaled particles and the breathing pattern of the child. The results obtained from this study
will enable us to determine the best method of delivering these drugs to children so that they only receive the
lowest effective dose for treatment of the symptoms of asthma while minimising unwanted effects.
Research achievements (from final report):
There are a wide range of aerosol devices and formulations available for treatment of respiratory disease,
which may be used in combination with an even wider range of accessory devices. Very few of these are
actually suitable for children, particularly infants. It is extremely difficult to test all these device/ formulation
combinations in vivo in children of different ages. We have developed an ex vivo method of estimating drug
delivery to children so that suboptimal device/ formulation combinations may be eliminated prior to in vivo
testing. This methodology does not eliminate the need for in vivo paediatric studies, but does reduce the
number which may need to be performed. In addition, we have accumulated a database of over 200 paediatric
breathing traces from children of different ages, with and without significant respiratory disease, which can be
used for testing future devices.
Expected future outcomes:
Improved identification of optimal inhaler devices and inhalation techniques for children. Future research will
focus on aerosol deliver to term and preterm neonates.
Name of contact:
Sunalene Devadason
Email/Phone no. of contact:
sdevadason@meddent.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353642
CIA Name: A/Pr Peter Henry
Admin Inst: University of Western Australia
Main RFCD: Basic Pharmacology
Total funding: $469,500
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Protease-activated receptors as potential drug targets in allergic airways diseaseProtease-activated receptors as
potential drug targets in allergic airways disease
Lay Description (from application):
Asthma is a lung disease that kills about 700 Australians each year and causes widespread morbidity in our
community. For people with allergic asthma inhalation of allergens such as those contained in house dust
triggers an immune response that causes swelling of the airway wall, overproduction of mucus and bronchial
smooth muscle contraction. These effects lead to the narrowing of the airways that makes breathing more
difficult in people with asthma. Our research groups have been investigating a novel group of proteins, called
protease-activated receptors (PARs), and in an exciting development have found that substances that stimulate
PARs inhibit allergic airways inflammation in mice, which is a well-established animal model of allergic
asthma. This raises the possibility that PAR stimulants may in the future be developed as anti-asthma drugs.
However, there are many large gaps in our understanding of airway PARs that need to be filled before their use
as anti-asthma drugs can be contemplated. Thus, the current study will address many important questions: Do
PAR stimulants always improve allergic inflammation, or are there some doses or times of dosing that worsen
allergic inflammation? Stimulants of one PAR, called PAR2, improve allergic inflammation, but what about
stimulants of the three other PARs (PAR1, PAR3 and PAR4) that exist in the airways? How do PARs improve
allergic inflammation, and which substances and cells are involved? Are PAR stimulants also effective in
more complex animal models of allergic inflammation, such as those involving proteolytic allergens (e.g. Der
p1 from the house dust mite), respiratory tract viruses, and extended periods of allergen exposure (chronic
models) that better reflect the human disease allergic asthma? The answers to these and a range of other
questions will significantly improve our understanding of the potential utility of PAR stimulants in the
treatment of allergic airways disease.
Research achievements (from final report):
Our major objective was to test the hypothesis that drugs that stimulate Protease-Activated Receptors (PARs)
inhibit the development of allergic airways inflammation and airways hyperresponsiveness via the generation
of the bronchoprotective prostanoid prostaglandin E2 (PGE2). Specifically, we have established that SLIGRL a 6-amino acid peptide that selectively stimulates murine PAR2 - inhibits the development of pulmonary
eosinophilia in a mouse model of allergic airways inflammation. PAR2-mediated inhibition of eosinophilia was
inhibited by inhibitors of cyclooxygenase (COX), indicative of the involvement of COX-2-derived prostanoids,
such as PGE2, in this anti-inflammatory effect. Consistent with this, exogenous PGE2 and an EP2-receptorselective agonist produced similar effects. We also demonstrated that in anaesthetised, ventilated allergic mice,
SLIGRL inhibited methacholine-induced increases in airways resistance. Consistent with this bronchodilator
effect, SLIGRL induced pronounced relaxation responses in tracheal preparations obtained from allergic mice.
These bronchoprotective PAR2-mediated, PGE2-dependent effects were enhanced by inhibitors of the
prostaglandin transporter (PGT, which transports PGE2 away from its site of action) and prostaglandin
dehydrogenase (PGDH, which degrades and inactivates PGE2), which highlights the possibility that blockade
of these latter pathways may provide a means of augmenting bronchoprotective responses to PAR2-activating
compounds. Of particular relevance, and contrary to evidence from the literature, PAR2-mediated
bronchoprotective effects were not inhibited by the glucocorticoid compound dexamethasone. A potential
clinical outcome of these exciting findings is that PAR2 activators may be effective in glucocorticoid-treated
people with asthma.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
The findings of these preclinical studies indicate that PAR2 may be suitable drug target in future attempts to
reduce the inflammation and bronchoconstriction in obstructive airways diseases such as asthma. Future work
will focus on the development of drug-like molecules that can activate PAR2.
Name of contact:
Peter Henry
Email/Phone no. of contact:
Peter.Henry@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353649
Start Year: 2005
CIA Name: Dr Kate Brameld
End Year: 2007
Admin Inst: University of Western Australia
Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $246,000
Title of research award:
Population based estimates of MBS, PBS and hospital utilisation rates using prevalent chronic disease
denominatorsPopulation based estimates of MBS, PBS and hospital utilisation rates using prevalent chronic
disease denominators
Lay Description (from application):
This project will use hospital morbidity and mortality data from the WA Data Linkage System, linked to the
Medicare Benefits Scheme and Pharmaceutical Benefits Scheme databases to produce measures of disease
occurrence and health service utilisation within the Western Australian population according to indices of
social and geographical disadvantage. The first objective will involve establishing teams of clinicians and
researchers who will work together to develop and validate lists of MBS and PBS item numbers that are
indicative of specified chronic diseases. This information will then be used to identify patients with these
conditions from the MBS and PBS databases during the period 1990-2003 and this method of case
ascertainment will be compared with the use of the Hospital morbidity data system alone. Once groups of
patients have been identified, their utilisation rates of MBS, PBS and hospital services will be calculated. The
effect of social and geographical indices on the occurrence of disease and the utilisation of services will also be
studied. Trends over time in health status and health service utilisation are vital to the evidence-based planning
and evaluation of health services and to the provision of an equitable and accessible health service which is
based on the needs of the community. The work will represent the first time that the utilisation of Australian
MBS and PBS itemised services is measured in diagnostically defined groups of patients with chronic
diseases.Trends over time in health status and health service utilisation are vital to the evidence-based planning
and evaluation of health services and to the provision of an equitable and accessible health service which is
based on the needs of the community. The work will represent the first time that the utilisation of Australian
MBS and PBS itemised services is measured in diagnostically defined groups of patients with chronic diseases.
Research achievements (from final report):
The aim of this project was to use the Western Australian Data Linkage System (WADLS) and the crossjurisdictional linkage to the Medicare Benefits Scheme (MBS) and the Pharmaceutical Benefit Scheme (PBS)
to study the prevalence of selected chronic diseases in WA and to measure utilisation rates of MBS and PBS
items for these conditions.This data would then inform health service planning. The project has identified a
number of issues with regards the successful use of MBS and PBS data for record linkage in a research setting.
Expected future outcomes:
The data in the current state are not suitable for the work we originally planned. If the data situation is resolved
we aim to produce and publish data on the incidence, prevalence and health service utilisation of glaucoma in
Western Australia
Name of contact:
Kate Brameld
Email/Phone no. of contact:
kate.brameld@health.wa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 403915
CIA Name: Prof Howard Mitchell
Admin Inst: University of Western Australia
Main RFCD: Systems Physiology
Total funding: $355,015
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Intrinsic response of airways to cyclical dilation and elongation in breathingIntrinsic response of airways to
cyclical dilation and elongation in breathing
Lay Description (from application):
Variations in lung pressures during breathing produce cyclical expansion of the airway tubes. These respiratory
movements provide one of the most powerful protective mechanisms for the lung. The protective mechanism
fails in asthma so that cyclical expansion of the airway tubes can make breathing more difficult. Current
belief is that protective and harmful effects of lung expansion occur by either relaxation or contraction of the
muscles lining the airway tubes. Findings from this laboratory suggest that the above dogma needs
reconsideration. The project will utilize a novel model of the lung to enable us to determine the mechanisms
producing both the protective effect, and in asthmatics the harmful effects of cyclical lung expansion. Once
the part of the lung that 'fails' in this aspect of asthma has been detected then therapeutic strategies can be put in
place to reverse the defect.
Research achievements (from final report):
Work from the project has shown firstly that cyclical stress and strain during breathing markedly suppresses
airway responsiveness, as assessed from airway provocation. The broad significance is that different patterns of
airway responsiveness seen in disease and health can be directly explained by the behaviour of airways and
airway smooth muscle in its natural mechanical environment. The strain required to reduce responsiveness was
further defined in a subsequent study. A major advance was showing the overriding importance of airway wall
stiffness to airway responsiveness; stiffness from the activated airway smooth muscle is by far the most
important source of stiffness, implicating it in disease . The importance of the elastic properties of the airway
wall to airway responsiveness had not been defined before. Dynamic strain in breathing also contributes to
bronchodilation produced by relaxants including the relievers used in asthma. We described a powerful
softening action of these inhibitor drugs on airway stiffness, which we have hypothesized contributed to their
bronchodilation potency. Experiments with nerve stimulation (inhibitory and excitatory) indicated that
breathing strains act directly on airway smooth muscle and not the nerves. Investigations were carried out in
airways from immature animals, which exhibit hyperresponsiveness, in order to determine whether age- or
responsiveness- related effects modulate the response of the airway to dynamic strain. They did not.
Expected future outcomes:
Conceptually, the major advance has been identifying the importance of stress and strain in breathing to airway
responsiveness and the importance of airway smooth muscle stiffness to hyperresponsiveness seen in asthma.
Name of contact:
Prof Howard Mitchell
Email/Phone no. of contact:
mitchell@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 403928
Start Year: 2006
CIA Name: Prof Cashel D'Arcy Holman
End Year: 2009
Admin Inst: University of Western Australia
Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $1,077,767
Title of research award:
Chronic Disease Outcomes and Enhanced Primary Care in Seniors: A Cross-Jurisdictional Linkage
ProjectChronic Disease Outcomes and Enhanced Primary Care in Seniors: A Cross-Jurisdictional Linkage
Project
Lay Description (from application):
This project will provide evidence on how best to use the efforts of Australian GPs to obtain better outcomes in
patients aged 65+ years who suffer from chronic diseases such as diabetes, heart disease and high blood
pressure, asthma and emphysema, seizures and stomach disorders. It will also examine the best way that GP
visits can promote healthier ageing in all older seniors, aged 75+ years. For each disease and in older seniors,
the study will be able to detect which of the following factors are the most important for better patient health:
(i) seeing a GP more times, (ii) seeing a GP at more even intervals, (iii) seeing the same GP, or (iv) seeing a GP
with a lot of experience in chronic diseases. Separate investigations will be made in older people living in
hostels and nursing homes, because their needs may be different. The study will also evaluate the benefits of a
major change that occurred to Medicare in 1999, when GPs were paid to perform health assessments and to
prepare health plans (with other health workers) for patients with chronic health problems. The results will
enable this important initiative to be further improved. The study will use a unique and new Australian
research facility, which has brought together health data on the entire population of WA from both the State
and Commonwealth levels, including information on Medicare use, pharmaceuticals, hospital stays and deaths.
The facility works in such a way as to preserve patient and GP privacy. A strong feature of this research will
be the degree of involvement of a representative and voluntary group of older Australian patients who attend
GP clinics, and the GPs themselves, in advising the researchers on what's important to consumers and GPs.
Research achievements (from final report):
Using the cross-jurisdictional facility of the WA Data Linkage System, linking all Medicare and PBS data for
WA in 1990-2006 with all inpatient episodes and deaths for people >65 years, the project was successful in
separating the the effects of intensity and regularity of general practitioner visits on a number of ambulatory
care sensitive chronic diseases., An important and consistent resultof this research has been the demonstration
in patients with type II diabetes, chronic respiratory conditions, chronic cardiac conditions and epilepsy that
more favourable patient outcomes (eg survival, avoidance of hospitalisation and slower disease progression)
are achieved when visits to the GP follow a regular,periodic pattern, as distinct from the total frequency of GP
visits., The study has provided strong evidence of the importance of primary health care based on a proactice
chornic disease management model rather than a reactive sickness response model., The project has also made
an important contribution to the development of new data linkage research methods, infrastrcuture and has
been one of two recent NHMRC research projects (with 403929) that have led the nation in best industry
practice in community participation in research.
Expected future outcomes:
In addition to publications already in print or in press, a number of manuscripts are under consideration and
others will be submitted.
Name of contact:
Prof C. D'arcy J. Holman
Email/Phone no. of contact:
dholman@meddent.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458502
CIA Name: Prof Susan PRESCOTT
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $463,328
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
The ontogeny of TLR mediated innate immune function in normal and atopic childrenThe ontogeny of TLR
mediated innate immune function in normal and atopic children
Lay Description (from application):
Bacteria are first recognised by the immune system though primitive innate immune pathways which are
highly conserved through evolution. The activation of these pathways is critical for the maturation of the
immune system. This may explain the rise in immune diseases with cleaner environments (and less innate
immune activation). We speculate that functional differences (as a result of environmental or genetic factors)
are implicated in the rising rates of allergic disease. This is the first study to document normal maturation of
these innate pathways in early childhood, and to compare this in allergic and nonallergic children. We will do
this using existing samples collected as part of previous cohort studies. This study is the logical next step in the
quest to define allergy pathogenesis. Whatever the outcome, the findings will be of enormous significance. A
better understanding of the development of these pathways is also likely to contribute to more avenues for
better-targeted treatment and prevention.
Research achievements (from final report):
For the first time we have mapped the normal development of innate immune development and showed striking
differences in children who develop allergic disease . Specifically, Non-allergic children show progressive and
significant age-related increases in innate cytokine responses (IL-1β, IL-6, TNFα, IL-10) to virtually all TLR
ligands. This innate maturation corresponds with a parallel rise in adaptive Th1-(IFNγ) responses to allergens
and mitogens. In contrast, allergic children show exaggerated innate responses at birth (P<0 01) but a relative
decline with age thereafter, so that by age 5, TLR responses are attenuated compared with non-allergics (P<0
05). This early hyper-responsiveness in allergics fails to translate to a corresponding maturation of Th1function, which remains attenuated relative to non-allergics, but is associated with a characteristic agedependent increase in allergen-specific Th2 responses (P<0 01). Our findings suggest significant differences in
the developmental trajectory of innate immune function in children who develop allergic disease that may
contribute to the recognised differences in postnatal adaptive T cell immunity.
Expected future outcomes:
This is the basis for a new NHMRC application to further explore novel mechanisms. WE HAVE NEW
PRELIMINARY DATA FROM THIS COHORT WHICH SUGGESTS NEW GENETIC MECHANISMS.
Name of contact:
Prof Susan Prescott
Email/Phone no. of contact:
sprescott @meddent.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458512
CIA Name: Prof Prue Hart
Admin Inst: University of Western Australia
Main RFCD: Cellular Immunology
Total funding: $820,332
Start Year: 2007
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a cellular immunologist interested in the study of cytokines and other regulatory molecules in
inflammatory and immune responses. One key area relates to the effect on sunlight on cell-mediated immunity.
Research achievements (from final report):
During my fellowship I have increased awareness of the positive benefits of moderate sun exposure for optimal
immune health of Australians. This has been achieved by published scientific papers and reviews, delivery of
scientific lectures both nationally and internationally, and also by liaison with members of the Cancer Council
and delivery of public lectures detailing the benefits of moderate sun exposure. This may occur by both
increased vitamin D levels, but also by vitamin D-independent effects on immunity. Together with my team, I
have identified a new pathway by which exposure to the UV wavelengths of sunlight can down-regulate
immune responses at sites distant to the skin site exposed to sunlight. Further, the indirect effects of skin UV
exposure on cells in the bone marrow support the long-lived effects of sun exposure. My studies have
incorporated analyses of vitamin D and measures of incidence of immune, respiratory, neurodevelopmental and
metabolic diseases in large cohort studies that have followed the development of Western Australians for over
23 years. A greater awareness of the benefits versus the harm of moderate sun exposure will allow Australians
to better personally determine their pattern of sun exposure. Greater knowledge of the pathway of UV-induced
immunoregulation by effects on cells in the bone marrow will allow adoption of new immunotherapeutic
approaches to control chronic immune diseases, such as multiple sclerosis.
Expected future outcomes:
With greater knowledge of the benefits versus the risks of moderate sun exposure, we may better advise
Australians of their choices for vitamin D supplementation and sunlight exposure. With knowledge of
pathways involved, more advanced immunotherapies for the chronic immune diseases affected by latitude and
sunlight may be developed.
Name of contact:
Prue Hart
Email/Phone no. of contact:
prueh@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458513
CIA Name: Prof Peter Sly
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $7,169,609
Start Year: 2007
End Year: 2011
Grant Type: Programs
Title of research award:
Developmental aspects of respiratory inflammation, allergy and asthmaDevelopmental aspects of respiratory
inflammation, allergy and asthma
Lay Description (from application):
Asthma develops as a complex series of interactions between genetic susceptibility and environmental
exposures occurring in early life.
While many children grow out of asthma others do not and develop the chronic form of the disease that persists
into adult life. Our
research involves understanding why some susceptible children develop asthma and why this becomes chronic
in some. We will
undertake studies in children to find out how and why this occurs. A major part of our studies involve
longitudinal studies in cohorts of
children recruited before birth. Having the ability to study children as they grow and develop conditions such
as allergies and asthma
allows us to understand why these conditions occur and allow us to predict which children are likely to develop
them. Our research
Program also has a solid focus on Translational Research, in which we will use the findings from our basic
science studies to develop
and test new methods of preventing and of treating asthma. These studies will include new methods for
preventing the development of
allergies, preventing the damage done to the lungs by severe viral respiratory infections in early life and better
methods of treating
established allergic asthma by improving immunotherapy techniques. By its very nature, primary prevention of
disease in young
children is controversial and raises some interesting questions. As part of this Program we intend to initiate
consultation and debate in
public, academic, regulatory and industry circles. An important role for our Program is shifting the current
emphasis away from treatment
of established disease towards preventing disease occurring. This is the best way to decrease the health, social
and economic burden of
chronic diseases such as asthma.
Research achievements (from final report):
Major findings from the program include:, o
Demonstration that risk for
development of asthma that persists into the school years in associated with the combination of severe lower
respiratory tract infections and allergic sensitization to indoor allergens, during the first 2-3 years of life;, o
Identification of specific interactions
between inflammatory pathways triggered during immune responses to respiratory viruses and aeroallergens,
which lead to severe respiratory symptoms that can include asthma exacerbations;, o
Identification of
an important role for host immunity to respiratory mucosal dwelling bacteria in resistance to development of
asthma;, o
Demonstration of developmental
deficiencies in innate immune function(s) that are associated with asthma susceptibility., These findings
contribute to the growing evidence that early treatment of asthma, targeting mechanisms associated with
respiratory allergies and infections during the preschool years, have potential for primary prevention of asthma.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
In the near future we expect a variety of novel clinical trial initiatives aimed at asthma prevention will be
tested, which specifically target respiratory infection and respiratory allergy in young children who are at high
risk of asthma development.
Name of contact:
Prof Patrick G Holt
Email/Phone no. of contact:
patrick@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458543
CIA Name: Prof Bruce Robinson
Admin Inst: University of Western Australia
Excellence
Main RFCD: Respiratory Diseases
Total funding: $2,007,200
Start Year: 2007
End Year: 2013
Grant Type: Centre of Clinical Research
Title of research award:
Centre of Research Excellence in Pulmonary and Environmental Medicine.Centre of Research Excellence in
Pulmonary and Environmental Medicine.
Lay Description (from application):
This Centre will study inhalational lung diseases, ie diseases caused by substances such as asbestos, cigarette
smoke, air pollutants and allergens. Australia has of the highest incidences in the world of at least 2 of the
diseases to be studied, asbestos- and allergen-induced lung diseases. These two alone are estimated to cost the
Australian economy over $100 million -yr and $1 billion respectively in direct health costs plus loss of
productivity and compensation. Furthermore COPD on of our other major areas of interest is the 4th leading
cause of death in males and conservatively costs the economy over one billion dollars per year as well as being
the leading cause of disability in the elderly. It is predicted that COPD will be the 4th most common disease
worldwide by 2020. As such this area of study is important for Australia and internationally and any advances
will deliver major economic and health benefits. We will study the role of blood and sputum tests in the
diagnosis, monitoring, screening and management of lung diseases caused by asbestos, cigarette smoke, air
pollutants and allergens ie. mesothelioma, asthma, COPD and lung cancer. We will apply modern DNA 'gene
chip' methods to study the pathogenesis of these diseases and help us to identify new treatment targets. This
will also be used to guide genetic searches for polymorphism's, spliced variants and DNA
modification(epigentics) in COPD and lung cancer. Genetic studies of sensitivity to air pollution will be used
to define at risk patients We will also evaluate how the method of cell death that occurs during some therapies
eg. in cancer and allergy-asthma, might alter how the body responds and thus help us develop novel therapeutic
strategies for these diseases. This research program should lead to new tests and treatments and at the same
time promote the training of a new generation of young researchers in this field and so ensure that the work
continues long term
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Prof Bruce Robinson
Email/Phone no. of contact:
bruce.robinson@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458546
CIA Name: Prof Patrick Holt
Admin Inst: University of Western Australia
Main RFCD: Cellular Immunology
Total funding: $713,058
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of T-cell activation in the airway mucosa of rats expressing low versus high IgE responder
phenotypeRegulation of T-cell activation in the airway mucosa of rats expressing low versus high IgE
responder phenotype
Lay Description (from application):
We have established an experimental rat model of allergic airways inflammation which mimics human asthma.
Interactions occurring between airway mucosal dendritic cells and CD4+ Th2 (effector) cell populations are
responsible for the late phase response (LPR) component of asthma exacerbations, including airways
hyperresponsiveness (AHR). We have previously demonstrated that termination of the LPR and prevention of
its continual recurrence in the face of ongoing aeroallergen challenge is established via the induction of a state
of dynamic equilibrium, mediated by local T regulatory cells (Treg) which act to functionally silence local Th2
memory (effector) cells. Maintenance of protective Treg activity is dependent upon continuing allergen
exposure as cessation of exposure leads to waning of Treg numbers and function and release of mucosal
allergen specific Th2 cells from control. These studies have primarily involved low IgE responder (LR) PVG
rats ("normals" or "nonatopics"). The present study will focus on elucidating the control of Th2 dependent
immune responses to inhaled antigen in high IgE responder (HR) BN rats ("atopics"). Studying these two
strains in parallel enables a comparison between the extremes of the spectrum of susceptibility to both the
induction and the expression of Th2 immunity in the airways. A more detailed understanding of the cellular
interactions occurring within the airway mucosa and draining lymph nodes and the mechanisms responsible for
the maintenance of immunological homeostasis within the airways will provide new insights into the
pathogenesis of inflammatory airway diseases such as atopic asthma. This will enable further development and
possibly illuminate other avenues of intervention for more effective therapeutic strategies used in the control of
asthma, which is the long term goal of this research.
Research achievements (from final report):
o
Established the principle that
duration of allergic asthma exacerbations can be shortened via oral administration of microbial derived
immuno-stimulants. These stimulants act to boost T regulatory cell activity (cells which are able to control
disease) in the airway mucosa via stimulation of T regulatory cells generated in the gastrointestinal tract, that
migrate to the airways., o
Determined that tissue specific
microenvironmental factors modulate antigen uptake functions of airway mucosal dentritic cells, which can be
linked with disease expression. Reduced uptake by immunogenic DC populations associated with responses
leading to persistent disease., o
Determined that dysregulated T
regulatory cell responses (function, migration and number in airway tissue) are linked to severity of disease., o
The data indicates potential areas for
therapeutic manipulation. Disease expression can be reversed/ inhibited by modulation of T regulatory cell
populations and AMDC function (by altering antigen dose). , o
Our data offers support for
understanding mechanisms associated with successful allergen specific immunotherapy regimens.
Expected future outcomes:
Future publications delineating roles of AMDC subsets in development of allergic asthma should help identify
other potential pathways involved in the control of immunological homeostasis in the airways.
Name of contact:
N/A
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 458562
CIA Name: Dr Debra Turner
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $425,088
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Allergen-sensitzation and environmental exposures in early life interact synergistically to alter lung
growthAllergen-sensitzation and environmental exposures in early life interact synergistically to alter lung
growth
Lay Description (from application):
Asthma develops as the result of complex interactions between genetic susceptibilities and environmental
exposures. Approximately 40% of 6-year-old children in Perth are sensitized to inhaled allergens, however,
only half of these have asthma. Allergic sensitization per se is therefore insufficient for the development of
persistent asthma. A "second hit", associated with lung inflammation in early life, increases this risk several
fold. This "second hit" could come from viral infection or from other inflammatory stimuli such as exposure to
cigarette smoke, air pollutants and vehicle exhaust emissions. The timing of this second hit may well be
important, particularly if it is early while the lungs are still growing and developing. The aim of this project is
to examine interactions between allergen sensitization and exposure to environmental hazards in early life
using a mouse model of allergic inflammation. We will test the hypothesis that "the combination of allergic
sensitization and viral infections in early life alter lung growth, airway function and airway
hyperresponsiveness, however, exposure to air pollutants can not provide the 'second hit" required to induce
persistent asthma". Determining the role viral infection and environmental pollution have early in life may
provide us with a strategy for intervention that could prevent life-long changes in respiratory function and
airway hyperresponsiveness.
Research achievements (from final report):
Approximately 40% of 6 year old children in Western Australia are sensitised to inhaled allergens and yet only
half of them go on to develop asthma - the question is why? This project directly tested the idea that allergen
sensitisation is not sufficient for the developmenrt of persistent asthma and that a "second hit" such as a viral
infection or environmental exposure is required. We have shown that a severe viral infection (influenza) in
early life is capable of altering long term lung function. We also found that viral infection in early life can alter
inflammatory responses that we have shown to be critical in the development of the lung dysfunction
associated with asthma. These findings have not only progressed our understanding of the development of
asthma, they also provide critical data that will assist in identifying children at risk of developing the disease so
that we can intervene prior to the onset of the irreversible lung damage.
Expected future outcomes:
These studies have provided key information that can be used to direct clinical studies aimed at identifying
children at high risk for develpoing asthma with a view to intervening prior to the onset of persistent and
irreversible lung damage.
Name of contact:
Dr Graeme Zosky
Email/Phone no. of contact:
graemez@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458612
CIA Name: Prof Prue Hart
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $496,447
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Asthma prevention and treatment using UVB radiation-induced immunomodulationAsthma prevention and
treatment using UVB radiation-induced immunomodulation
Lay Description (from application):
The prevalence of asthma is increasing despite the adoption of modern expensive drugs. Our studies suggest
that exposure of skin to an erythemal dose of the wavelengths of UVB radiation found in sunlight can suppress
responses to allergens encountered in the airways. We are requesting support to study the mechanisms in mice
by which exposure to UVB radiation on their shaved backs can reduce inflammation in the airway mucosa
upon allergen exposure. Whole body immunomodulatory effects of UVB radiation have been previously
described but have not been scientifically linked with asthma development. This is a very new and novel
research area which supports century-old anecdotal reports that holidays at beach and mountain resorts
associated with increased UVB exposure are beneficial in asthma treatment. This is a proof of principle study.
If we can confirm that UVB is immunomodulatory and better understand the mechanisms by which UVB
suppresses inflammation in the airways, we will investigate the potential of non-carcinogenic, UVB-induced,
skin-derived intermediary molecules to have the same regulatory effects.
Research achievements (from final report):
The economic burdens of asthma are significant, where >1% of health expenditure in 2004-05 was devoted to
asthma. Further 1 in 10 Australians suffer from asthma. Exposure to ultraviolet (UV) radiation is one of the
most important environmental influences on human health and is particularly important for Australians who
live in a sun-drenched country. Exposure to the UV radiation, even amounts of sunlight that do not cause a
sunburn, can affect your immune system and the way that you handle immune challenges from foreign
organisms, or in the case of asthma, immune allergens. In this application, we established several models of
asthma in mice and investigated how exposure to UV light reduced the symptoms and markers of asthma. We
investigated how UV irradiation delivered to shaved skin could signal to the airways for reduced asthma
outcomes. In this project and contrary to our initial proposal, we showed that regulatory cells were not induced
in the airways by UV-exposure. Instead, we demonstrated that UV exposure reduced the way our immune cells
handled the asthma-causing allergens such that there was a reduced inflammatory response and fewer immune
cells attracted to the airways. Less immunological memory was induced in the UV-exposed animals and
therefore they responded to a lesser degree upon further exposures to allergens. UV-irradiation of mice with
already established immunological memory to asthma-causing allergens was also beneficial. These studies are
significant as a positive latitude for allergic asthma has just been reported (populations living further from the
equator have a higher incidence of asthma). We are continuing to search for the mechanisms involved. Our
studies with UV-induced vitamin D3 are giving us promising clues.
Expected future outcomes:
With the increasing incidence of asthma world-wide, new therapeutic approaches are required. Exposure to UV
irradiation, and UV-induced vitamin D3, may benefit asthma outcomes. In the future, we must determine the
right balance between sun exposure and vitamin D supplementation for treatment of asthma, and the
mechanisms involved.
Name of contact:
Prue Hart
Email/Phone no. of contact:
prueh@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458668
Start Year: 2007
CIA Name: Prof Billie Wilma Giles-Corti
End Year: 2012
Admin Inst: University of Western Australia
Grant Type: Capacity
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $2,194,516
Title of research award:
The impact of urban design on physical and mental health building capacity for research across the life
courseThe impact of urban design on physical and mental health building capacity for research across the life
course
Lay Description (from application):
In the last decade there has been growing recognition that the urban environment influences health. The design
of neighborhoods and public open space design as well as transport planning is associated with levels of
walking, cycling and use of public transport, as well as the sense of community, positive mental health,
depression and asthma. Low-density, automobile dependent suburbs discourage the use of non-motorized
forms of transport and public transport use, thereby reducing physical activity and opportunities for casual
contacts between neighbors. Nevertheless, how to optimize urban environment to meet the needs of different
population groups (eg. Children and young people, older adults, as well as the general public) has been largely
unexplored. While more walkable neighborhoods (i.e., those characterized by higher density, mixed use
planning and enhanced connectivity) may encourage able-bodied adults to do more working, the impact on
children, young people and older adults is unknown. For example, adults generally report there is more traffic
in more walkable areas. Exposure to traffic decreases the likelihood of children walking. In addition, higher
levels of traffic increase traffic pollution, thereby increasing the likelihood of asthma. Moreover, while some
research suggests that social capital or sense of community is higher in more walkable neighborhoods; other
research suggests that living on a busy road decreases one’s social networks. Thus, it is likely that there is an
optimum level of walkability that encourages sense of community. The proposed research will build upon and
strengthen and extensive program of research examining the impact of the urban environment on adults, by
adding programs of work with children and older adults. It will build our group’s capacity for research in this
area, by building expertise within the whole team for appropriate qualitative, statistical and geo-spatial methods
which will assist our team to work in this complex, multi-disciplinary area. With input from consumers,
practitioners and policy-makers a major focus of this applied research program will be designing research that
can be translated into policy and practice with the aim of creating urban environments that promote good
health.
Research achievements (from final report):
The CBG funding facilitated establishment of the multi-disciplinary Centre for the Built Environment and
Health at UWA, with a focus on undertaking interdisciplinary policy-relevant research aimed at enhancing
built environments across the life course. In 2012, CBEH was successfully reviewed by UWA. Since 2007, it
has supported 8 post-doctoral fellows (five of whom have attracted independent fellowship funding; and two of
whom now have academic positions); three research associates, 24 research students (13 of whom have
completed (one PhD with distinction) and three of which are under review). Importantly the Centre has funded
staff providing technical support in Geographic Information Systems which has helped train a team of
interdisciplinary researchers and postgraduate students in mixed methods: qualitative, quantitative and GIS.
Since 2007, the team has had 126 publications (114 peer reviewed). The Centre is overseen by a multi-sector
Advisory Board which meets quarterly and this is facilitating our research translation (RT) activities. In this
Centre, RT is not an 'add on': it is embedded into all projects from the outset. Thus, our research is directly
influencing policy and practice. The Centre is recognised internationally for its unique links with policymakers and practitioners. Since its establishment, CBEH has hosted visits national and international scholars
including from Harvard, UBC, UC San Diego, Pennington Medical Centre, and the Universities of Graz, East
Anglia, Ghent and Southern Denmark. Team members have active collaborations with researchers across
Australia, and the USA, UK and Europe.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
, CBEH has a number of self-funded post-doctoral fellows and strong links with established research groups. It
has two-year Healthway funding to focus on translating research undertaken in the past five years into policy
and practice. A CRE with University of Melbourne's Place, Health and Liveability Program is currently under
review.
Name of contact:
Professor Billie Giles-Corti
Email/Phone no. of contact:
b.giles-corti@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458689
CIA Name: Prof Peter Henry
Admin Inst: University of Western Australia
Main RFCD: Basic Pharmacology
Total funding: $421,690
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
How anti-inflammatory drugs differentially affect the bronchoprotective signalling of Protease-Activated
Receptor-2How anti-inflammatory drugs differentially affect the bronchoprotective signalling of ProteaseActivated Receptor-2
Lay Description (from application):
Asthma contributes significantly to the burden of ill health and impaired quality of life in Australian
communities, and for many measures of asthma, Australia has amongst the highest prevalence when compared
with other countries. Furthermore, there is evidence that the prevalence of asthma has increased during the
latter part of the 20th century. There is currently no cure for asthma, and the need for better asthma therapies
through the discovery of novel targets for drug development has never been more acute. PAR2 is a receptor
that is located on the surface of many cell types in the respiratory tract, including the epithelial cells that line
the airway tubes. When PAR2 is stimulated it causes the epithelial cells to produce and release large amounts
of PGE2 (prostaglandin E2). PGE2 released from epithelial cells then binds to other proteins such as the
prostanoid EP2 receptor located on smooth muscle cells. This causes the airway smooth muscle cells to relax.
Drugs that cause airway smooth muscle cells to relax - called bronchodilators - make breathing easier, and are
often used during an asthma attack to relieve bronchoconstriction. It also appears that activation of the PPP
axis inhibits airway wall swelling (that is, has anti-inflammatory actions). Thus, drugs that activate the PPP
axis may be beneficial in the treatment of asthma by reducing airway sweeling and producing smooth muscle
relaxation. Thus, we we are investigating ways of optimally stimulating the PAR2-PGE2-prostanoid EP2
receptor axis (the PPP axis), as a means of develeping novel treatments for asthma.
Research achievements (from final report):
, Asthma kills about 700 people each year in Australia and affects many thousands of others to the point where
it is in epidemic proportions in this country, particularly in younger age groups. Our primary research focus is
to develop a greater understanding of the inflammatory and obstructive processes that occur in the airways in
response to a variety of stimuli including respiratory tract viruses, airborne allergens, bacterial products and
environmental toxins, and to investigate the role of specific chemical mediators in these diseases. Some of
these mediators are relatively small proteins, which induce changes in the function(s) of the tissues comprising
the bronchial airway system in the lung. Such mediators interact with other cell membrane proteins (receptors)
expressed on the surface of airway cells and this interaction triggers the change in cell function. The potential
role of protease-activated receptors (PARs) in the treatment of airway disease is a major focus of our current
work. One PAR, called PAR-2 appears to have an important bronchoprotective role by promoting antiinflammatory processes within the airways. In this project we have looked at how the PAR-2 system is
modulated by disease and by drugs, and how the PAR-2 system can be targetted to produce beneficial effects in
diseased airways. Of particular interest we have discovered that activation of PAR-2 may be bronchoprotective
in airway diseases promoted by allergens and bacterial products, and that this bronchoprotective effect is not
compromised by drugs such as corticosteroids which are the mainstay controller treatment for asthma.
Expected future outcomes:
It is likely that the beneficial effects of PAR-2 will extend beyond respiratory diseases induced by allergens
and bacterial products, and future investigations into the potential for targetting these receptors in airway
disease induced by viruses and environmental toxins are clearly warranted.
Name of contact:
Professor Peter Henry
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
Peter.Henry@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458690
CIA Name: Prof Geoffrey Stewart
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $562,427
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
PROTEASE ACTIVATED RECEPTORS PRESENT ON TYPE II PNEUMOCYTES PLAY AN
IMPORTANT ROLE IN PULMONARY SURFACTANT PRODUCTIONPROTEASE ACTIVATED
RECEPTORS PRESENT ON TYPE II PNEUMOCYTES PLAY AN IMPORTANT ROLE IN PULMONARY
SURFACTANT PRODUCTION
Lay Description (from application):
Lung surfactant comprises both lipids and proteins and is secreted by alveolar type II cells into the liquid lining
the air-tissue interface. These monolayers stabilise the alveoli, decrease the work of breathing, prevent oedema,
and assist in the clearance of foreign particles from the epithelial lining. In addition to this homeostatic role in
respiration, there is evidence linking surfactant with removal of harmful microbes and allergy and asthma.
Various stimuli are known to control surfactant production to maintain normal, healthy lung function but with
microbes and allergen, where inflammation is common, the role of pro-inflammatory proteases and protease
activated receptors (PAR) in their biology has not been investigated. Our preliminary findings now show,
however, that they are involved. In this proposal, we will determine their importance in surfactant production
both in vitro and in vivo. The possibility that proteases and their receptors play a role in surfactant production
has not been previously described but if shown to play a role in production, we will have identified a novel
pathway that will aid our understanding of the mechanisms of surfactant release and, possibly, lung
development. Thus, it is anticipated that results from this study may contribute to a significant reduction in
morbidity associated with the above mentioned diseases, resulting in reduction in the cost of health care. Social
benefits obtained from study this would be improved health as a result of the application of the findings to
patients who currently lead a life heavy dependant on medical interventions.
Research achievements (from final report):
Lung surfactant is produced by alveolar type II epithelial cells and is indispensable for lung function but failure
to secrete, or abnormalities in its composition may lead to respiratory distress syndrome in both adults and
children. Physiological stimuli such as stretch, biochemical agonists and second messengers stimulate
surfactant secretion and involves one or more cellular protein kinases. In addition, a number of G-protein
coupled receptors also trigger surfactant secretion including adrenergic, prostaglandin, leukotriene and gastrinreleasing peptide receptors, as well as purinoceptor subtypes. The studies supported by this project grant now
show that a group of protease activated receptors (PAR), also members of the G-protein coupled receptor
family, may also be involved in surfactant release. These receptors are activated by proteases such as thrombin
and trypsin, and we showed that pneumocytes treated with them produced surfactant and involved the receptors
PAR-1, PAR-2 and PAR-4. In non-pneumocyte cells, little if any surfactant was produced and when two of the
receptors were simultaneously activated, additive effects were seen but not when they were combined with
other known activators of surfactant secretion. The activation process involved phospholipase C, intracellular
calcium and cyclic AMP. Combined, these data indicate that in protease-rich environments, proteases may
stimulate surfactant and surfactant protein release as part of a defensive mechanism. In addition to these
findings we also demonstrated that type II pneumocytes may also activate the kallikrein-kinin system, and that
novel organic compounds based on the naturally occurring chalcones stimulate prostaglandin production which
may stimulate these cells to produce surfactant.
Expected future outcomes:
The findings from this study are expected to help us understand the role of proteases in the secretion of
surfactant and surfactant proteins and their role in normal homeostasis and innate immunity.
Name of contact:
Professor G.A. Stewart
NHMRC Research Achievements - SUMMARY
Prof. G. A. Stewart
Email/Phone no. of contact:
geoff.stewart@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458692
CIA Name: Prof Geoffrey Stewart
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $518,210
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
HOUSE DUST MITES, BACTERIA AND ASTHMA: THE POTENTIAL MODULATORY ROLE OF
GRAM-POSITIVE BACTERIAL PAMPSHOUSE DUST MITES, BACTERIA AND ASTHMA: THE
POTENTIAL MODULATORY ROLE OF GRAM-POSITIVE BACTERIAL PAMPS
Lay Description (from application):
Asthma continues to be a socio-economically important disease with an increasing prevalence. In this regard,
allergy to the house dust mite appears to predispose children to the development of the disease although the
reasons are unclear. Recently, we discovered and characterised a bacteriolytic enzyme which had previously
only been described in pathogenic bacteria, particularly Mycobacteria. In an attempt to determine the origin of
the lytic enzyme, we demonstrated that mites also contained a diverse array of Gram-positive bacteria in
contrast to Gram-negative bacteria within their guts. Interestingly, the same spectrum of bacterial species were
found in carpet and mattress dust from children with asthma. A variety of data suggest exposure to products
from Gram-positive organisms may enhance allergic diseases including asthma. In contrast, exposure to
products from Gram-negative bacteria is thought to be protective for asthma development. The reasons for the
association between Gram-positive bacteria and asthma have not been explored in detail but one potential
mechanism that will be explored in this application is the the role of the cell wall constituents which demarcate
Gram-positive organisms from Gram-negative organisms as well as sectreted products. The underlying
mechanisms involved are likely to reflect a differential ability of the two types of organisms to stimulate the
release of divergent immunomodulatory cytokines from cells known to play a role in asthma such as epithelial
cells, fibroblasts, T cells and dendritic cells. Data from such studies are likely to greatly increase our
understanding of the development of asthma and, therefore, contibute to the development of new treatment
modalities with consequent benefit to the community.
Research achievements (from final report):
, Our objectives were to test the hypotheses that house dust and house dust mites contain a range of Gram+ve
cocci and rods whose secreted products and cell wall constituents have the potential to modulate the cells
comprising the epithelial mesenchymal trophic unit in the lung as well as inflammatory cells. This modulation
may contribute to the inflammatory response observed in allergic disease and, therefore, play a role in the
pathology of asthma. We have previously identified a 14 kDa bacteriolytic enzyme in D. pteronyssinus and
have now identified almost identical sequences in the tropical dust mite, Blomia tropicalis as well as in
Dermatophagoides farinae. We also examined mite genomic libraries and the data indicate that this enzyme
may be produced by an endosymbiotic bacterial species since no introns were observed in mite-derived
sequences. Similarly, we detected the gene coding for the lytic enzyme in at least two species of Bacillus.
Recent addditions to the data bases show that the 14K enzyme also demonstrates high homology with P60
proteins from fungal species indicating that endosymbiotic fungi may also be present in mites. We
demonstrated bacteriolytic activity in both house dust and mattresses. Various lytic bands were identified in
these dusts, and nine of the twelve samples contained a 14K band corresponding to the mite enzyme indicating
that it is prevalent in the environment. Although lytic enzymes were detected in the bacterial excretory
products, none corresponded with the 14K band but some were similar in size to those seen in endosymbiotic
species.
Expected future outcomes:
The findings from this study are expected to help us understand the role of mite, and bacterial products from
Gram-positive bacterial species on respiratory epithelial cell function. In addition, it will help in understanding
endosymbiosis in house dust mites.
Name of contact:
NHMRC Research Achievements - SUMMARY
Professor G.A. Stewart
Prof. G. A. Stewart
Email/Phone no. of contact:
geoff.stewart@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 463909
Start Year: 2007
CIA Name: A/Pr Guicheng Zhang
End Year: 2011
Admin Inst: University of Western Australia
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Environmental and Occupational Health and Safety
Total funding: $282,008
Title of research award:
A study on interactions between indoor exposure and genetic polymorphisms in asthma using established
cohortsA study on interactions between indoor exposure and genetic polymorphisms in asthma using
established cohorts
Lay Description (from application):
Not Available
Research achievements (from final report):
Asthma has been a National Health Priority Area in Australia since 1999. Asthma and other allergic conditions
collectively affect 1 in 5 Australians and cost more than $7.8 billion/yr. Consistent with this priority, the early
career fellowship program investigated gene by environment interactions on the development of asthma and
allergy in several established asthma cohorts in Perth. Important gene-environment interactions have been
identified in the fellowship studies including interactions between smoking/passive smoking and B2AR and
GST genes and interactions between "Western or Eastern environment/lifestyles" and innate immunity-related
genes regarding the development of asthma and allergy. We also reviewed asthma genetic studies and
highlighted the opportunity and challenges in asthma genetics in the era of genome-wide association studies.
During the fellowship period, more than twenty papers have been published in peer-reviewed international
journals and several grants have been awarded supporting the fellowship research activities including a
NHMRC project grant, two asthma foundation (Western Australia) grants and two University of Western
Australia small grants. , This fellowship project has provided valuable data for understanding the interactions
between common domestic environmental exposures and the commonly identified asthma candidate genes on
the development of atopic phenotypes and lung function maturation in children. As environmental
modifications and dietary interventions during pregnancy, infancy and early childhood are being investigated
for the prevention of allergic disorders, the findings from the fellowship study will be important in guiding
prevention practices and therapeutic decisions in managing allergic diseases in children.
Expected future outcomes:
In the future we plan to further invetigate gene-environment interactions on the development of asthma and
allergy to facilitate the development of specific preventive and management strategies of asthma and allergic
conditions in children.
Name of contact:
Guicheng Zhang
Email/Phone no. of contact:
gczhang@meddent.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513701
CIA Name: Prof Patrick Holt
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $780,307
Start Year: 2008
End Year: 2012
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am an immunologist studying mechanisms of development of allergy
and asthma with the aim of developing new approaches to disease
prevention.
Research achievements (from final report):
Major Achievements:, - Description of a network of interacting genes responsible for allergic responses;, Discovery of the mechanisms by which virus infections trigger severe asthma in children which has led to
trialling of a new therapy for asthma prevention;, - Development of a new approach to screening childhood
vaccines for safety;, - Discovery of "anti-inflammatory" immune responses to bacteria that protects against
asthma;, - Identification of a defect in the mechanisms that control immunological surveillance for airborne
allergens in the airways, which predisposes to asthma susceptibility.
Expected future outcomes:
N/A
Name of contact:
Prof Patrick Holt
Email/Phone no. of contact:
patrick@ichr.uwa.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 513709
CIA Name: Prof Susan Prescott
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $557,939
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
T cell PKC expression as a novel neonatal predictor and modulator of allergic disease.T cell PKC expression as
a novel neonatal predictor and modulator of allergic disease.
Lay Description (from application):
This application will further assess the role of a novel biological predictor of allergic disease, which appears
more accurate than any previous marker (based on preliminary data). This is highly relevant to development of
predictive tools that could be ultimately used in clinical practice. We will also assess this marker as a potential
target for disease prevention, as our preliminary data also indicates that it can be modified by an early
intervention aimed at preventing allergic disease.
Research achievements (from final report):
, We developed a new method for measuring a neonatal marker that can predict allergic disease. Allergic
children (particularly those with eczema) had significantly lower levels of a particular immune marker (T-cell
PKCz expression) at birth than nonallergic children. This was a more predicitive measure of which newborns
are likely to develop allergic disease than relying on family history alone. This marker also predicted the
capacity for the immune cells (T cells) to make the immune mediators (cytokines) that suppress allergy, and
these infants were more likely to produce allergic immune responses to allergens by 6 months of age. This
suggests that T cell PKCz levels might be a useful screening marker to help predict allergic disease.
Expected future outcomes:
, It is hoped that this method might be commercially developed to screen for allergic disease.
Name of contact:
Susan Prescott
Email/Phone no. of contact:
susan.prescott@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513769
CIA Name: Prof Arthur Musk
Admin Inst: University of Western Australia
Main RFCD: Epidemiology
Total funding: $220,292
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
I am a salaried-full time Physician in Respiratory Medicine at a major teaching hospital with postgraduate
training, research experience and qualifications in clinical medicine and the epidemiology of occupational and
environmental lung diseases and cance
Research achievements (from final report):
I have been able to devote at least 30% of my time as a salaried respiratory physician to research activities
including:Chairperson of the Busselton Population Research Institute;Chairperson of the WA Mesothelioma
Registry;Co-convenor of the Occupational Respiratory Epidemiology Group UWA;CI Burden of Obstructive
Lung Disease (BOLD) study (NH&MRC); - An international multi-centre collaboration of the ddistrubution
and determinants of obstructive lung disease in older adults.CI Busselton Healthy Aging Study; (NH&MRC) A comprehensive multi-disciplinary health assessment of "baby boomers" demonstrating determinants of
healthy functioning in older adults.CI Diagnostic Markers for Malignant Mesothelioma and other Respiratory
Diseases; (NH&MRC) - Collaboration with Professor Jenette Creaney investigating serum markers for
malignant mesothelioma.CI Centre of Research Excellence in Pulmonary & Environmental Medicine;
(NH&MRC) - collaboration with Professor BWSR Robinson and others demonstrating the mechanisms of
asbestos-related diseases (especially mesothelioma).CI Genetic Understanding of Asbestos-Related Diseases;
(NH&MRC/NCARD) - a GWAS for mesothelioma risk in collaboration with the UWA Dept of Genetics &
Biostatistics (Professor Lyle Palmer replaced by Professor Eric Moses) demonstrating associations between
SNPs and mesothelioma incidence.CI Dust-related health issues in WA miners; Insurance Commission of WA
- Epidemiology of pneumoconiosis in WA.CI Effect of N-acetylcysteine supplementation on oxidation status
and alveolar inflammation in people exposed to asbestos: a double-blind randomised clinical trial; Dust Disease
Board of NSW.CI Lung function decline in asbestos exposed individuals. Sir Charles Gairdner Hospital
Research Institute.CI Transfer RNA Derived Fragments as diagnostic and molecular targets for malignant
mesothelioma therapy. Sir Charles Gairdner Hospital Research Institute.
Expected future outcomes:
Projects are ongoing and I will continue to work on them in my own time.
Name of contact:
Dr A W (Bill) Musk
Email/Phone no. of contact:
bill.musk@health.wa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513842
CIA Name: Dr Peter McFawn
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $281,037
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Response of Human Airways to Deep Inflation in Health and DiseaseResponse of Human Airways to Deep
Inflation in Health and Disease
Lay Description (from application):
The trachea and bronchi contain muscle that when it contracts narrows the air passages and makes it harder to
breath. In healthy people taking a deep breath relaxes this airway muscle and improved breathing. However, in
people who suffer from asthma and chronic airflow obstruction deep breaths do not have the normal relaxing
actions on airway contraction. This study will use lung removed as part of surgery for lung cancer to study how
the relaxing actions of deep breathing work in human airways.
Research achievements (from final report):
The most significant result from the study was both unexpected and very predictable. Originally the study was
intended to focus on Chronic Obstructive Pulmonary Disease (COPD) but we were also able to recruit and
study some asthmatic patients undergoing surgery for lung cancer treatment. In those patients we showed for
the first time that increased smooth muscle mass produced more airway narrowing a long expected but hard to
prove result. The main aim of the study though was to identify how the bronchodilatimg affect of a deep
inhalation fails in obstructive disease. In healthy humans taking a deep breath in is an effective way of
reversing airway muscle contraction but not for asthmatics of COPD patients. Our work with lung samples
from patients undergoing surgery for lung cancer treatment has shown that the failure of stretch to
bronchodilate the airways is not due to changes in the airway itself. For COPD that leads to the conclusion that
emphysema these patiens suffer from is likely preventing the deep breaths from stretching the airway in the
first place. We have also found evidence for smoking history changing the structure and mechanical properties
of bronchi. Patients who had smoked more had stiffer airways and more matrix proteins around their airway
smooth muscle cells. We had expected that changes like those might explain the poor bronchodilation response
of people with COPD to deep breaths but the data so far have not found the connection to prove that
hypothesis.
Expected future outcomes:
The results from asthma patients are exciting but limited because only a few of the people study had asthma.
Assuming our asthmatics are typical then it appears the increased airway narrowing in asthma can be attributed
to increased airway muscle with no change in the character of that muscle.
Name of contact:
Peter Mcfawn
Email/Phone no. of contact:
peter.mcfawn@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513854
CIA Name: Prof Peter Eastwood
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $408,367
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Bronchoscopic applications of anatomical optical coherence tomography.Bronchoscopic applications of
anatomical optical coherence tomography.
Lay Description (from application):
This research proposal aims to investigate the potential utility of a novel, Australian designed dianostic laser
system. A tube positioned in the lungs takes real-time images of the shape and size inside the airways. This
can have both clinical and research benefits. It may help doctors choose the right size hardware when opening
up cancerous airways and it will help us understand disease mechanisms of lung diseases by studying parts of
the airways not previously able to be measured.
Research achievements (from final report):
This project proposed to use a novel technique called anatomical optical coherence tomography (aOCT),
recently developed by ourselves, to measeure the internal airway dimensions to characterise airway stenoses in
lung canceer and to examine local variations in airway wall compliance, , The studies found that airway
images, both 2- and 3-dimentional, could be derived using aOCT and that measurements from these images
could help improve the selection of airway stents in the management of endobronchial lung cancer., , Studies
were also perfomed that demonstrated the ability for aOCT to measure regional airway wall compliance
characteristics in a population of healthy subjects and in subjects with asthma, emphysema and bronchiectasis.
Expected future outcomes:
This work has demonstrated the feasibility of using aOCT to assist interventional bronchoscopists performing
airway recanalisation procedures for obstructing lung cancers and as a tool for obtaining physiological
measurements of airway wall mechanical properties.
Name of contact:
Winthrop Prof Peter Eastwood
Email/Phone no. of contact:
Peter.Eastwood@health.wa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513921
CIA Name: Dr Peter Noble
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $287,321
Start Year: 2008
End Year: 2011
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Regulation of pulmonary responsiveness by chronic mechanical strain and its role in obstructive lung
diseaseRegulation of pulmonary responsiveness by chronic mechanical strain and its role in obstructive lung
disease
Lay Description (from application):
The pressures required to breathe place a continuous but varying mechanical strain on airway passages and
lung tissue. This mechanical strain may protect the airway from collapsing, however, this protection is deficient
in lung diseases such as asthma. This project considers the possibility that abnormal mechanical strain
occurring in lung disease predisposes the individual to debilitating and potentially life-threatening airflow
obstruction.
Research achievements (from final report):
The principle aim of the project was to better understand the mechanism(s) producing airway
hyperresponsiveness (exaggerated narrowing of airway passages) in obstructive disease. A major outcome of
the project was the development of an approach to study human airways outside the lung in custom built organ
bath chambers which preserve the tissue. By recruiting patients who were undergoing lung surgery to remove
pulmonary neoplasms, we utilised airway tissue that would be otherwise discarded (i.e. a longitudinal segment
of airway). Our first published study on airway segments reports new data on airway narrowing and shows that
pressures generated during tidal breathing do not significantly alter airway narrowing capacity. In contrast,
deep inspiration produces a considerable short-term expansion of the airway which can explain the beneficial
response to a normal deep inspiration observed in humans. An abnormal response to deep inspiration may in
part contribute to the development of airway hyperresponsiveness and our most recent data (unpublished)
suggests that airways from asthmatic individuals have a reduced response to deep inspiration. However, there
are other factors that likely contribute to airway hyperresponsiveness and our data suggests that airways from
subjects with asthma and chronic obstructive pulmonary disease have an inherent increased capacity to narrow.
Expected future outcomes:
The tissue collection and organ bath system provides a great opportunity to finally pinpoint the mechanisms of
airway hyperresponsiveness and future experiments will focus on identifying the structural and/or mechanical
abnormalities which give rise to airway hyperresponsiveness observed at the level of the whole airway (i.e. in
airway segments).
Name of contact:
Assistant Professor Peter Noble
Email/Phone no. of contact:
peter.noble@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572501
CIA Name: Prof Meri Tulic
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $387,490
Start Year: 2009
End Year: 2012
Grant Type: Career Development Fellowships
Title of research award:
Ontogeny of Toll (TLR) function in normal and allergic children: the impact of microbial-rich
environmentsOntogeny of Toll (TLR) function in normal and allergic children: the impact of microbial-rich
environments
Lay Description (from application):
Reduced exposure to bacteria during early life has become a leading candidate to explain the escalating rate of
allergic disease. Despite this, the development and maturation of the pathways involved in normal recognition
of bacteria in children has not been explored. In this proposal we set out to address this critical shortcoming in
both normal and allergic children. Mapping normal maturation of such pathways will help us to identify better
early markers of allergic disease.
Research achievements (from final report):
Despite intense interest in how bacteria can modify allergy, the normal maturation of innate and regulatory
function has never been documented. I was the driving force behind novel NHMRC funded studies
characterizing, for the first time, the longitudinal development of innate and regulatory responses over the first
5 years of life; showing key differences already exist at birth and before development of allergic disease.
Maturation of innate immunity was studied by measuring longitudinally toll-like receptor (TLR) expression
and peripheral blood cytokine responses to TLR agonists. Results have shown striking differences in trajectory
of innate and adaptive immune function development between allergic and non-allergic children, with allergics
having exaggerated innate responses at birth but delayed maturation of their adaptive immunity. Our
observation directly challenged notions that allergic disease was preceded by reduced capacity for innate
immune responses but rather suggests that dysregulated inflammatory responses might have a role to play in
abnormal T-cell development. To study maturation and function of regulatory T cells (Tregs) with age was a
technical challenge as its difficult to isolate sufficient number of these rare cells from the small volumes of
blood we get from children. Using thymic tissue as rich source, we have detected Tregs in neonatal thymus,
shown that they have strong suppressive function, and that in allergic children their maturation is delayed.
Together, these studies are fundamental to understanding the early events that lead to immune dysregulation in
infancy, which may predispose to allergic disease. Although relatively recent, these papers published in highimpact journals are highly cited and have received much international recognition.
Expected future outcomes:
These findings were of great interest to a wide audience as they provided fundamental information that is an
essential prelude to any immunomodulatory therapies using microbial products.
Name of contact:
Meri Tulic
Email/Phone no. of contact:
Meri.Tulic@unice.fr
NHMRC Research Achievements - SUMMARY
Grant ID: 572503
CIA Name: Prof Susan Prescott
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $436,469
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Research Fellowships
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
I am a paediatric allergist and immunologist investigating pathways involved in normal immune development
and how these differs in infants who develop allergic disease.
Research achievements (from final report):
This is a career development award and allowed me to reach the top level of my field internationally. I am now
regularly invited for Keynote and Plenary Lectures at leading international meetings, including the American
and European Academies or Allergy Aathma and immunology, the World Allergy Organisation (WAO) and
many national societies globally. , , I established and lead the International Inflammation Network (inFLAME) within the Worldwide Universities Network (WUN), including over 135 experts (from >30
institutions) across multiple fields, all with an interest in 'early life' interactions that predispose to a range of
inflammatory noncommunicable diseases (NCDs). , , I also established and lead (as elected President) the
developmental Origins of Health and Disease (DOHaD) Society in Australia and New Zealand. We held the
inaugural meeting in April 2014 focusing on the early origins of Obesity and NCDs. , , I was the 2013 recipient
of The Salvaggio Memorial Lectureship, a prestigious American award recognizing my 'outstanding service to
the specialty and science of allergy and immunology'. , I have >200 career publications, collectively cited
>7495, with 103 during the funding period (since 2009). 18 have been cited >100 times and 2 have reached
classical status, cited 838 (Lancet) and 714 (J I) times respectively. My H-Index is 49. , I have raised >$13
million as CI, mostly through consistent NHMRC success (10 grants as CIA including 2 fellowships). In 2010
my research was recognised in the NHMRC '10 of the best' with numerous awards and fellowships., I have 8
completed PhD students as primary supervisor (and 5 current PhD students). I am on the WAO Board of
Directors an a number of other international committees, 4 Editorial Boards of international journals, with
extensive peer review activities. My leadership through DOHaD and in-FLAME builds capacity though
interdisciplinary collaborations, and provides career development for early and mid career researchers.
Expected future outcomes:
Through my leadership we are developing multicenter trials including the 'Origins Program' to favourably
influence fetal programming and subsequent NCD risk through early internvention (RCTs). This addresses a
number of major health issues, namely growing susceptibility to obesity, metabolic, cardiovascular,
neurological, allergic diseases and other NCDs. This is highly translational in nature.
Name of contact:
Prof Susan Prescott
Email/Phone no. of contact:
susan.prescott@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572616
CIA Name: Prof Graham Hall
Admin Inst: University of Western Australia
Main RFCD: Respiratory Diseases
Total funding: $635,093
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Impact of exposure to air pollutants during the prenatal period on lung function in infancyImpact of exposure
to air pollutants during the prenatal period on lung function in infancy
Lay Description (from application):
The lungs undergo rapid development both before birth and in the early years of life and therefore may be
susceptible to the impacts of exposure to environmental pollutants. Poor lung function in early childhood may
increase the risk for respiratory disease in later life. This study will investigate if exposure to air pollution,
indoors and outdoors, before birth significantly affects lung function and the respiratory health of young
children.
Research achievements (from final report):
There have been limited studies that explore the relationship between a mother's exposure to indoor air
pollution and a baby's development during pregnancy, particularly of the lungs. Pregnant women and young
infants spend a large proportion of their time indoors which coincides with a critical period of lung
development. It is possible that exposure to these pollutants in the indoor environment may have a significant
impact on respiratory health, particularly in childhood. Indoor air pollution was low in this study. However, our
results suggest increased early life exposure to some indoor environmental pollutants has the potential to
adversely influence fetal growth and early life lung function. However, these results were not consistent and do
not allow definitive conclusions to be drawn. This study may inform health policies designed to reduce the
environmental impacts on health
Expected future outcomes:
Work in this area is ongoing, specifically the impact of indoor air pollution and early life respiratory
symptoms. Other pollutants, including outdoor pollutants assessed as part of the larger Peel cohort study are
being investigated with the outcomes of this study.
Name of contact:
Prof Graham Hall
Email/Phone no. of contact:
Graham.Hall@telethonkids.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572689
CIA Name: Prof Wayne Thomas
Admin Inst: University of Western Australia
Main RFCD: Allergy
Total funding: $246,478
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Immunity to colonising bacteria of the respiratory tract in atopic and non-atopic childrenImmunity to
colonising bacteria of the respiratory tract in atopic and non-atopic children
Lay Description (from application):
Evidence that seemingly harmless and common bacterial infections have a role, in the development of allergic
disease has been uncovered. The development of immune responses to these microbes will be studied in
children with and without allergy to inhalant allergens.
Research achievements (from final report):
Children under three who, later in life, develop allergy to the inhaled house dust mite allergen and asthma have
a widespread delay in the development of immunity to the common bacteria that inhabit the nose and upper
lining of the respiratory tract. This shows that they have aberations of immunity in addition to the deviation of
their immune responses to become allergic to otherwise harmless constituents of the house dust mite and they
occur before the allergy becomes evident. The main benefit is that it provides an avenue to investigate
differences in the early immune responses of people who become asthmatic before they become allergic and
asthmatic. Since this is first demonstration of the delayed immunity it not known if it just applies to bacteria
but defective antibacterial immunity and increased infection could have a direct role in the development of
disease and be a target for early treatment.
Expected future outcomes:
, The aberant immunity is found for different bacteria investigations will target differences in the immune
responses (shown by asthmatics) common to the bacteria and the genetics of people who make these different
responses. Since one of the new anti-bacterial vaccines has a bacterial protein similar to the ones studied here
the responses to the vaccine and its effect on asthma can be studied.
Name of contact:
Professor Wayne Thomas
Email/Phone no. of contact:
wayne@ichr.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 115080
CIA Name: Dr Philip Hodgkin
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Cellular Immunology
Total funding: $729,158
Start Year: 2000
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Testing a new theory of Immune regulationTesting a new theory of Immune regulation
Lay Description (from application):
The immune system plays an important role in protecting us from infectious diseases. To do this it regulates a
series of cell types that must decide upon an appropriate course. In general, this response is successful and
protective. However, occasionally the cells make an inappropriate decision leading to problems. For example,
allergies are an incorrect response against pollens and dust mites. Similarly, autoimmune disease such as
diabetes and multiple sclerosis result from inappropriate attack upon our own tissues. Despite the clear
importance of immune regulation for health, the complexity of its behaviour has made it difficult to predict and
control. In this research program a new theory of immune regulation with clear implications for rational
intervention and beneficial manipulation of the immune system will be developed.
Research achievements (from final report):
The new theory of immune regulation tested here was that many important immune regulatory decisions are
taken 'automatically' as cells divide. This theory has to a large extent been verified and consolidated and is
widely accepted. Due to the success of the theory a suite of new quantitative methods have been developed,
published and widely adopted by the immunological community. These methods have been used to examine
the quantitative control of cell behaviour by a large range of cytokines in both mouse and human cells and form
the foundation for the extension of the work into a new NHMRC program.
Expected future outcomes:
Software based on the new theory that can be used to analyse lymphocyte signal integratoin and simulate
immune processes
Name of contact:
Phil Hodgkin
Email/Phone no. of contact:
Hodgkin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 305538
Start Year: 2004
CIA Name: Dr Ian Street
End Year: 2004
Admin Inst: Walter and Eliza Hall Institute
Grant Type: NHMRC Development Grants
Main RFCD: Therapies and Therapeutic Technology
Total funding: $99,750
Title of research award:
Development fo a novel treatment for asthma: the identification of lead small molecule antagonists of the IL13/IL-13 reDevelopment fo a novel treatment for asthma: the identification of lead small molecule antagonists
of the IL-13/IL-13 re
Lay Description (from application):
In developed countries Asthma ranks among the most common chronic illnesses. Over two million Australians
now have this condition and the cost to our community is estimated to be in excess of $720 million per annum.
In 1996 researchers at The Walter & Eliza Hall Institute discovered a new member of the cytokine receptor
family, IL-13Ra1, which further research has strongly implicated in the pathology of this disease. The main
goal of the proposed research is to discover small molecule antagonists of IL-13Ra1 and to identify those
suitable for development as novel asthma therapeutics.
Research achievements (from final report):
In developed countries Asthma ranks among the most common chronic illnesses. Over two million Australians
now have this condition and the cost to our community is estimated to be in excess of AUD$720 million pa. A
wide range of prophylactic and symptom relieving medications are currently available for the treatment of
asthma. These include corticosteroids, mast cell stabilisers, antihistamines and bronchodilators. In general these
drugs do not target the mechanisms that underlie disease progression, they are in some cases associated with
significant side-effects, and their efficacy decreases with use over an extended period. Studies using genetically
modified animals have strongly inferred a role for the cytokine, IL-13, in the fundamental pathology of asthma.
Therefore small molecules (chemicals) or proteins such as antibodies that can specifically block the interaction
of IL-13 with its receptor have the potential to become novel asthma therapies. Indentification of small
molecule antagonists of the IL-13/IL-13 receptor interaction is therefore one of the first steps in translating the
outcomes from a basic research program towards the discovery and marketing of a new medicine.
Expected future outcomes:
N/A
Name of contact:
Ian Street
Email/Phone no. of contact:
istreet@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 356210
CIA Name: Dr Philip Hodgkin
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Cellular Immunology
Total funding: $651,750
Start Year: 2005
End Year: 2009
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
My research goal is to develop a quantitative description of immune regulation within a logical framework.
During this Fellowship I have progressed toward this goal by formulating new theoretical ideas that advance
our knowledge of the immune system. This is particularly important as the immune response is extremely
complex and grantpromising results for disease treatments from animal models are often difficult to translate to
new clinical therapies. My experimental work has revealed surprising regularity and underlying order in
lymphocyte proliferation and differentiation. Most importantly, the data are consistent with independent
'stochastic' machinery controlling proliferation, survival and differentiation. This discovery has the potential to
greatly simplify our understanding of the source of cellular heterogeneity and the coding of complex behaviour.
Further, a mathematical scheme can be developed to describe all possible behaviours. This scheme I have
called the "cellular calculus". These concepts and experimental methods have been published in highly rated
journals and represent the conceptual foundation for future work. Thus, my research has identified weaknesses
in our current knowledge of the immune system and replaced them with a foundation that can exploit new
developments in computer modelling and systems biology. These methods forge a new platform with which we
can revisit complex problems in immunology, particularly the causes of autoimmune disease, allergies and
subtle immunodeficiencies.
Expected future outcomes:
Theoretical and experimental platforms developed during my Fellowship are now being applied to analysis of
complex diseases of the immune response, including autoimmune diseases, allergies and immunodeficiencies.
The methods promise more efficient diagnosis of genetic susceptibilities, rational design of vaccines and useful
predictive immune simulation software for the scientific community.
Name of contact:
Philip D. Hodgkin
Email/Phone no. of contact:
hodgkin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 406691
CIA Name: Dr Jonathan Baell
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Clinical Chemistry
Total funding: $122,750
Start Year: 2006
End Year: 2006
Grant Type: NHMRC Development Grants
Title of research award:
Development of Novel Small Molecule Antagonists of IL-13 as New and Better AsthmaDevelopment of Novel
Small Molecule Antagonists of IL-13 as New and Better Asthma
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
We analysed a number of chemicals that appeared to block the interaction of IL-13 with its receptor and which
could be useful for the treatment of asthma. Most of these chemicals were found to be non-selective but one
class appears to display a good relationship between structure and activity
Expected future outcomes:
With further development, these compounds could be made more potent to be ultimately candidates for
preclinical development as asthma therapeutics.
Name of contact:
Jonathan Baell
Email/Phone no. of contact:
jbaell@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 461201
CIA Name: Prof Ken Shortman
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Cellular Immunology
Total funding: $927,557
Start Year: 2007
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am an immunologist determining the development and function of the dendritic cell system, including its role
in autoimmunity and resistance to infection.
Research achievements (from final report):
The specialised immunological functions of dendritic cell (DC) subtypes have been clarified and related to
their state of development or activation. The pathway of development of individual DC subtypes as part of
haematopoiesis has been mapped and precursors identified. The novel DC surface molecules Clec9A and
Clec12A, common to mice and humans, have been identified and antibodies against them developed as
research reagents. Clec9A was shown to be a dead cell recognition molecule and its ligand identified as a
normal cellular component, filamentous actin. Targeting antigens to Clec9A in vivo was shown to be an
exceptionally effective way of enhancing immune responses; strong antibody responses were generated even in
the absence of adjuvants. This is being evaluated as an approach to improving the efficiency of vaccines.
Expected future outcomes:
A detailed mapping of the haematopoietic pathways to DC development. Improved efficiency of novel
vaccines for infectious diseases.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 461232
Start Year: 2007
CIA Name: Dr Sandra Nicholson
End Year: 2009
Admin Inst: Walter and Eliza Hall Institute
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $405,940
Title of research award:
Investigating the physiological and biochemical role of SOCS5 in the immune systemInvestigating the
physiological and biochemical role of SOCS5 in the immune system
Lay Description (from application):
Asthma affects millions of people worldwide and is a complex inflammatory disease of the lung. Asthma
manifests as recurrent episodes of wheezing, breathlessness, chest tightening, and coughing. Three key proteins
called; interleukin 4 (IL-4), interleukin 13 (IL-13) and interleukin 5 (IL-5) are produced by a subset of white
blood cells (T helper cells; Th2) and are thought to be responsible for the asthma response. Normally these
proteins act to coordinate the body s immune defence against parasite infection. In other words, asthma is
thought to arise through inappropriate IL-4 and IL-13 activity in the absence of a parasite infection. Extra IL-13
is commonly found in the lungs of asthmatics and is thought to help trigger asthma attacks. IL-13 is a validated
target for drugs that could be used in the treatment of asthma. The SOCS genes were discovered in our
laboratory and by genetically deleting the genes in mice we have demonstrated a critical role for SOCS1,
SOCS2 and SOCS3 in regulating the immune response and the action of growth hormone. My hypothesis is
that SOCS5 is an important physiologic regulator of the asthma response. This proposal will investigate the
basic biochemical processes underlying the regulation of IL-4 and IL-13 action and the relationship to
development of asthma and immune disease. I plan to induce asthma attacks in mice that lack the genes for
SOCS4 and SOCS5. If the severity of the attacks is greater in the absence of these proteins this will indicate
that SOCS4 and/or SOCS5 are important negative regulators of IL-4 and IL-13. This has the potential to open
up a completely new strategy for the development of drugs that could be used in the prevention and treatment
of asthma.
Research achievements (from final report):
Asthma is an inflammatory disease of the lung affecting millions of people worldwide. It is largely mediated by
two T helper type 2 (Th2) cytokines, interleukin 4 (IL-4) and interleukin 13 (IL-13). The aim of this project
was to determine whether SOCS5 was a physiological regulator of IL-4 and/or IL-13 signalling and the Th2
cytokine response underlying allergic asthma. The project also aimed to investigate the biochemical basis for
SOCS5 inhibition of IL-4 signalling. We have clearly defined the functional domains in SOCS5 and shown that
forced expression of SOCS5 inhibits JAK kinase activity. We have extensively examined IL-4 signalling in
SOCS5-deficient cells in vitro and in vivo, using a mouse athma model and found no change in IL-4 responses.
Despite this we have compelling evidence that SOCS5 interacts with two of the JAK kinases, JAK1 and JAK3,
which are associated with IL-4 and other cytokines that signal through the IL-2 receptor common gamma
chain. In contrast to published work, SOCS5 does not appear to function (in IL-4 signalling) as a classical
negative regulator of responses post-ligand activation of the receptor complex. We are excited by the concept
that SOCS5 function may represent a novel mode of action for SOCS regulation of JAK activity.
Expected future outcomes:
We are now exploring the significance of the SOCS5/JAK interaction.
Name of contact:
Sandra Nicholson
Email/Phone no. of contact:
snicholson@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 461240
CIA Name: Dr Philip Hodgkin
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Cellular Immunology
Total funding: $447,210
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Evaluating the T cell calculusEvaluating the T cell calculus
Lay Description (from application):
The immune system plays an important role in protecting us from infectious diseases. To do this it regulates a
series of cell types that must decide upon an appropriate course. In general, this response is successful and
protective. However, occasionally the cells make an inappropriate decision leading to problems. For example,
allergies are an incorrect response against pollens and dust mites. Similarly, autoimmune disease such as
diabetes and multiple sclerosis result from inappropriate attack upon our own tissues. Despite the clear
importance of immune regulation for health, the number of different cell types involved and the complexity of
their behaviour has made it difficult to predict and control the response. In this research program a new theory
of immune regulation enables the reduction of the complex system to separate components that can be
modelled by computer to predict the outcome. An improved predictive framework promises to have a major
effect on our understanding and ability to control immune related diseases.
Research achievements (from final report):
The aims of this collaborative, multicentre grant were as follows:, 1.
To directly measure the 'calculus' of
signal addition and subtraction that dictates the rates of population growth, death and differentiation. 2.
Link models of T-cell growth and survival to simulated T-cell populations with a range of affinities for antigen,
to explore the implications of individual cell division and differentiation profiles on clonal outgrowth, epitope
dominance effector cell numbers and generation of memory in vivo. 3. Develop visualisation and analysis
software that can incorporate different modelling options and allow experimentalists to easily evaluate data in
relation to mathematical models., Significant progress in the theoretical and mathematical description of
cellular differentiation was achieved. Two streams of modelling were pursued to accommodate the data. One
adopts the ODE framework and assumes rates of change associated with cellular events. This approach is
relatively easy to calculate and construct. The second approach builds upon the 'cyton' model (PNAS 2007,
104:5032). This framework incorporates an age structure into the models and attempts to directly incorporate
experimental features into rules of cell operation. Application of these models to T-cell differentiation has been
achieved and published. Software for data evaluation has been developed and is currently available to
download for free from the WEHI website. Further software is under development and is being prepared for an
interactive web interface. Additional experimental work on the integration of antigen and cytokine signals on
T-cell division and death is significantly advanced and being prepared for publication.
Expected future outcomes:
The software is well advanced and will be available on the web for download. A generalised cyton theory and
model is being readied for publication. The combination of software, theory and experimental advances
allowed us to improve clonal selection theory and monitor autoimmunity, atopy and immunodeficiency with a
new paradigm.
Name of contact:
Philip D Hodgkin
Email/Phone no. of contact:
hodgkin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 461288
Start Year: 2007
CIA Name: Dr Kate Jeffrey
End Year: 2010
Admin Inst: Walter and Eliza Hall Institute
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $377,409
Title of research award:
Investigating the roles of DUSPs and p38 MAPK isoforms in immune responsesInvestigating the roles of
DUSPs and p38 MAPK isoforms in immune responses
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Here we describe the first chemical inhibitor of epigenetic reader enzymes that suppresses inflammatory gene
expression and sepsis in vivo. We identified an essential regulator of inflammatory gene expression,
successfully identified a chemical compound inhibitor targeting the important protein domain and convincingly
demonstrated its function in preventing inflammatory responses in vivo. This small molecule inhibitor is now
in clinical trials with GlaxoSmithKline.
Expected future outcomes:
Targeting epigenetic enzymes to control gene expression during immune responses
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 516705
Start Year: 2008
CIA Name: Dr Sandra Nicholson
End Year: 2013
Admin Inst: Walter and Eliza Hall Institute
Grant Type: NHMRC Research Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $690,502
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a protein biochemist investigating how SOCS box proteins regulate intracellular signal transduction.
Research achievements (from final report):
Viral infections such as influenza cause profound morbidity and mortality and remain a significant global
health issue. The innate immune system presents the first line of defense against infectious viral and bacterial
pathogens. We have been interested in understanding how the host response is regulated and the consequences
of excessive inflammatory signalling the so-called "cytokine storm". The suppressors of cytokine signalling
SOCS box proteins are classic examples of negative regulators that control cytokine signalling and the
inflammatory response. In particular we have investigated the physiological role of two lesser known SOCS
proteins SOCS4 and SOCS5. Our interests have extended to another protein family the SPSB proteins and the
central role of a protein-protein interaction domain called a SPRY or B30.2 domain. This project has
significantly enhanced our understanding of how these intracellular proteins regulate the host response to
infectious and inflammatory disease. The findings have been published in high impact scientific journals and
presented at a variety of national and international meetings. The project has also contributed to the training of
several PhD and Honours students.
Expected future outcomes:
Understanding the structural details of the intracellular protein complexes involved in the host response to
infection and the physiological consequences of enhancing this response will provide an opportunity for the
development of new anti-viral therapies.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 516786
CIA Name: Dr Kirsten Fairfax
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Cellular Immunology
Total funding: $419,738
Start Year: 2008
End Year: 2014
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
The investigation of Immune Function in mice deficient in RNA-binding molecules.The investigation of
Immune Function in mice deficient in RNA-binding molecules.
Lay Description (from application):
Our immune system is delicately balanced between fighting off bugs and destroying infected cells yet
protecting healthy cells within the body. The ways in which the immune system responds to attack is regulated
by certain genes within the body. This project is focussing on cutting edge research that describes a newly
identified way of fine-tuning the immune system. We are studying RNA-binding molecules that can bind to
and block genes involved in immune function.
Research achievements (from final report):
This fellowship spanned work across a few different but related fields. We were able to advance knowledge of
how B cells function and get activated. These findings have broad implications as all vaccines currently used in
the Australian Immunisation Schedule elicit B cell responses and understanding how we can optimise B cell
responses will enable us to provide the best protection for our population with the least intervention. We also
uncovered a molecule that is critical to plasma cell survival that could be targeted in people with myeloma. We
also showed for the first time that an RNA-binding protein HuR can mediate B cell responses. In so doing we
uncovered novel metabolic requirements for activated B cells. We also demonstrated the role of IL-10 in
regulating miR-155 expression levels in B cells. We showed the importance of B1b cells and CD19 signalling
in a mouse model of systemic lupus erythrematosus. And finally in another model of systemic lupus
erythematosus we showed the importance of the tyrosine kinase Lyn and disregulated STAT signalling for
plasmacytosis in these mice.
Expected future outcomes:
This work as a body contributes to our understanding of B cell biology and provides research suggesting three
different lead compounds Mcl-1 CD19 and Lyn are of potential commercial interest for myeloma Systemic
Lupus Erythematosus and plasmacytosis respectively.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 516791
CIA Name: Dr Joanna Groom
Admin Inst: Walter and Eliza Hall Institute
Main RFCD: Cellular Immunology
Total funding: $342,384
Start Year: 2008
End Year: 2013
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Chemokine mediated collaboration between T cells and dendritic cells during inflammationChemokine
mediated collaboration between T cells and dendritic cells during inflammation
Lay Description (from application):
The immune system protects us from foreign pathogens by using multiple immune cell types. Immune cells
need to migrate and interact with each other in order to function properly. When immune cells fail to migrate
appropriately, autoimmune diseases or immunodeficiency may develop. By understanding the molecules
regulating their migration, we can promote or inhibit immune cell function.
Research achievements (from final report):
My research focused on defining the role of interactions and location of immune cells, during the initial stages
of an immune response. Chemokines are cytokines that direct the migration of immune cells. I primarily
investigated one chemokine system, CXCR3. My work revealed unexpected roles for CXCR3 during T cell
effector and memory function and highlight the therapeutic potential of activating this chemokine system for
targeted vaccine strategies, and to re-establish immune activation in chronic infectious disease and cancer., For
this work, I generated a novel mouse to track the expression of the chemokine ligands for CXCR3, using
distinct reporter fluorescent proteins. This novel tool offers unique possibilities to screen for new pathways that
regulate productive and over exuberant immune responses, to discover novel therapeutic targets for infectious
and autoimmune diseases., During the Australian portion of this fellowship, I extended my work on the
CXCR3 system to investigate the receptors transcriptional regulation during viral infection. In addition, I
investigated intestinal immune responses, which have interesting transcriptional parallels with T cells. This
work is relevant to the understanding of intestinal homeostasis and has potential for development of
therapeutics for intestinal diseases such as Colitis.
Expected future outcomes:
My current work continues to investigate the role and regulation of CXCR3 during immune responses and
identify and develop novel therapeutic targets for vaccine development and treatments for infectious and
autoimmune diseases.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au