University of Exeter Medical School Self-funded PhD project
proposals
The University of Exeter Medical School PhD Competition 2014 is now closed. However, the attached
projects are potentially available for self-funded students.
Projects may be held on either a full-time (3 years) or part-time (6 years) basis. Successful applicants will
pursue a project within one of the principal research themes of the Medical School - a) Diabetes,
Cardiovascular and Ageing; b) Neuroscience; c) Environment and Human Health or d) Health Research.
Candidates are invited to discuss project areas informally with potential supervisors and to indicate in their
application which of the theme areas (and within these, which projects) are of most interest. Appointees will
work with the relevant supervisor(s) to develop proposals fully for approval prior to registration.
Contact UEMS Graduate Research in the first instance for more detail:
UEMS-GraduateResearch@ex.ac.uk
How to apply
Applications are invited from suitably qualified graduates, 2:1 or above, in a suitable scientific
discipline. Non UK candidates must also have IELTS [International English Language Testing
System] score of 7 and above (or equivalent qualification).
Please send a CV, Covering letter (outlining your academic interests, prior research experience and
theme and research projects of interest and reasons for wishing to undertake the project) and
copies of transcripts of degrees/awards to UEMS Graduate Research
UEMS-GraduateResearch@ex.ac.uk
1
The potential PhD projects are listed below in alphabetical order according to the lead
named supervisor
ANDERSON
UEMS Internal PhD studentship – proposed title and idea
From Rob Anderson, June 2014
How does health promotion become sustainable and get embedded within schools?
Within public health there is a sizeable research literature on the effectiveness and
implementation of health promotion in schools, but most of this focuses on the initial
implementation of new programmes under ‘research conditions’. As part of the NIHR School
for Public Health Research, UEMS researchers have recently conducted a review of the
implementation (including feasibility and sustainability) of health promotion in schools
(Pearson et al, 2013). This produced a detailed synthesis of evidence about what factors
and contexts are important for preparing for implementing a programme in schools, and for
the phase of the first implementation. There was much less evidence about the longer term
sustainability (or ‘embedding’) of health promotion in UK schools, or how health promotion
programmes adapt and evolve in order to be acceptable and sustainable in the longer term.
This PhD will yield a much-needed evidence base on how and why some health promotion
programmes and activities continue and become an accepted ‘part of school life’, while
others seem to disappear after the funding and trials have finished. It will do this through a
mixed-methods approach, and an overarching theoretical framework such as May’s
Normalisation Process Theory, and potentially also complexity theory to design and conduct:
(a) a theory-driven review of international evidence about embedding health promotion in
schools (b) a cross-sectional sample survey of schools and their long-sustained health
promotion activities, and (c) qualitative follow-up case studies of schools who have been
involved in a number of (completed) NIHR-funded and other large-scale trials of health
promotion in schools, purposively sampling stories of both success and failure at sustaining
the original health programme (both ‘early abondoners’ and ‘ongoing adapters’ etc..)
Pearson, M., Chilton, R., Buckley Woods, H., Wyatt, K., Ford, T., Abraham, C., & Anderson,
R. (2013) Implementing health promotion programmes in schools: A realist systematic
review of research and experience in the UK. Exeter: PenTAG, NIHR School for Public
Health Research
Lead Supervisor: Associate Professor Rob Anderson (PenTAG, IHR, UEMS) R.Anderson@exeter.ac.uk
2nd supervisor: Dr Mark Pearson (PenTAG, IHR, UEMS) - Mark.Pearson@exeter.ac.uk
3rd supervisor: Dr Katrina Wyatt or Dr Tamsin Ford (IHR, UEMS) or Dr Chris Bonell
(Institute of Education, UCL, London)
2
ANDERSON/PEARSON/STEIN
Scaling-up evidence-based health and social care service re-design: Conceptual
development and application
Supervisory team: Rob Anderson, Mark Pearson, and Ken Stein
Service re-design to improve the quality and safety of health and social care services whilst
reducing costs is a key service delivery priority. UEMS researchers are contributing to
knowledge about how to implement evidence-based improvements in areas such as the
integrated care of frail older people (Pearson et al. 2013), shared care in long-term
conditions (Hardwick et al. 2013), and the delivery of health promotion in schools (Pearson
et al. 2014). Many frameworks, such as PARIHS, RE-AIM, Normalisation Process Theory,
and the Consolidated Framework for Implementation Research, have been proposed to
structure investigation and understanding of complex implementation processes. However,
there is a paucity of critical reflection on the utility of these frameworks in relation to scalingup evidence-based service changes from local to regional level. This PhD research will draw
on existing collaborations between UEMS researchers, healthcare practitioners and
managers. It will develop, test and refine an implementation framework that conceptualises
scaling-up processes in the provision of integrated care services which cross sectoral
boundaries such as acute and community care. Developing advanced research skills in
theory-driven review and case study methodology, the candidate will design and conduct a
coherent programme of research involving, as appropriate, network or organisational
ethnography, theory-driven evaluation, and/or discourse analysis of primary and/or
secondary data.
Hardwick, R., Pearson, M., Byng, R. Anderson, R. (2013) The effectiveness and cost
effectiveness of shared care for long term conditions: A realist review. Systematic
Reviews 2: 12
Pearson, M., Hunt, H., Cooper, C., Shepperd, S., Pawson, R., & Anderson, R. (2013)
Intermediate care: a realist review and conceptual framework. Final report. NIHR Service
Delivery and Organisation Programme.
Pearson, M., Chilton, R., Buckley Woods, H., Wyatt, K., Ford, T., Abraham, C., & Anderson,
R. (2014) Implementing health promotion programmes in schools: A realist systematic
review of research and experience in the UK. Exeter: PenTAG, NIHR School for Public
Health Research
3
ANDERSON/THOMPSON COON/PEARSON
Barriers and facilitators to the implementation of person-centred care in care homes
Supervisory team): Rob Anderson, Jo Thompson Coon and Mark Pearson
The uptake of evidence-based person-centred care within nursing homes is variable.
Aspects of care where this has been noted include routine nutrition screening on admission,
appropriate prescribing of antipsychotic medications to individuals with dementia (Thompson
Coon, 2014), management of medications to reduce poly-pharmacy, infection control and
mealtime interventions to improve nutritional status (Abbott, 2013; Whear 2014). Internal
(e.g. resident, clinician and care home characteristics) and external (e.g. regulation,
development of guidelines) factors have been shown to influence change but the
relationships are not uniform. The impact of organisational culture in this context is not well
understood.
This PhD will seek to i) develop an explanatory framework of what is hindering and
facilitating the implementation of person-centred care in care homes at the individual,
organisation and system levels through realist review, ii) develop an implementation plan or
simple intervention specific to an aspect of care taking into consideration organisational
structure/culture, and iii) conduct a feasibility study to test and evaluate the impact of the
implementation plan. The focus of the work and methods employed will be refined in light of
emerging findings but may include using the Promoting Action on the Implementation of
Research in Health Services (PARIHS) framework, an intervention mapping approach and
qualitative interviews. The project will involve the collaboration of stakeholders (e.g.
residents, families, care home staff and owners, GPs etc.) at all levels and in all stages to
enable co-ownership of the findings.
Thompson Coon J, Abbott R, Rogers M, Whear R, Pearson S, Lang I, Cartmell N, Stein K.
Interventions to reduce inappropriate prescribing of antipsychotic medications in people with
dementia resident in care homes: A systematic review J Am Med Dir Assoc (under peer
review).
Abbott RA, Whear R, Thompson-Coon J, Ukoumunne OC, Rogers M, Bethel A, Hemsley A,
Stein K. Effectiveness of mealtime interventions on nutritional outcomes for the elderly living
in residential care: A systematic review and meta-analysis. Ageing Res Rev. 2013
Sep;12(4):967-81
Whear R, Abbott R, Thompson-Coon J, Bethel A, Rogers M, Hemsley A, Stahl-Timmins W,
Stein K. Effectiveness of mealtime interventions on behavior symptoms of people with
dementia living in care homes: a systematic review.J Am Med Dir Assoc. 2014
Mar;15(3):185-93.
.
4
CHILTON/JOURDAIN
The maintenance of healthy neuronal function by regulation of plasma membrane and
cell shape
Supervisors: Dr. John Chilton (UEMS)
Dr. Isabelle Jourdain (CLES)
Defects in neuronal polarity or growth lead to neuronal death, brain atrophy and dementia
but the underlying causes of degeneration remain obscure. Our strategy is to describe how
a healthy neuron acquires and maintains its intricate, functional shape, apply this new
knowledge to prevent the morphological changes leading to cell death and thus reverse
disease processes.
Neuronal morphology and axon guidance are the result of complex interplay between the
cytoskeleton and the cell membrane. Actin tracks are believed to deliver secretory vesicles
to specific areas of the cell surface thereby controlling lipid and protein composition of the
plasma membrane. Recent evidence indicates that the membrane in turn regulates the actin
cytoskeleton but how this occurs is not understood.
You will tackle this question by exploiting the experimental power of the fission yeast S.
pombe in conjunction with vertebrate neuronal cultures. The exocytic and actin machineries
are highly conserved across evolution and many mechanisms that control cell shape are
identical between species and cell types. Using a range of genetic, biochemical and
fluorescent imaging techniques you will use yeast to identify the partners of the exocytic
system in actin organisation and apply the conclusions to vertebrate neurons. These data
will provide novel insights into the mechanisms of a range of human neurological disorders.
References:
Bloom & Morgan (2011) Mol. Cell. Neurosci. 48:339-348
Jourdain et al. (2012) Traffic 13:1481-1495
Tojima et al. (2014) J. Neurosci. 34:7165-7178
5
CORY
Giles Cory – University of Exeter Medical School
2014 – Internal Ph.D studentship summary
Making the Message Stick – mRNA localisation tells cells where to go.
Technological developments in science are allowing us to ask new questions about the
organisation and control of cellular behaviour. Next-generation sequencing can quantify the
copy number of each mRNA transcript within a cell, providing huge amounts of information
on cellular regulation and function.
We have refined this technique to quantify the mRNA transcripts present at different
locations within a cell, generating an unbiased catalogue of messages ‘delivered’ to a
specific address. Our particular focus has been to identify a sub-population of mRNAs
enriched at sites of cell/matrix adhesions. These adhesive sites are crucial controllers of cell
migration and invasion –processes acquired by aggressive cancers cells enabling them to
colonise secondary tissues. By understanding how, where and when this mRNA localisation
occurs we are hoping to highlight possible therapeutic targets to combat the spread of
tumours around the body.
The Ph.D project will use methods such as fluorescent microscopy (confocal and TIRF),
genetic manipulation, cell culture and quantitative PCR to define the components of the
mRNA targeting mechanism and elucidate their role in cell adhesion and migration.
Further reading
mRNA localization: gene expression in the spatial dimension.
Martin KC, Ephrussi A. Cell. 2009 Feb 20;136(4):719-30.
http://www.ncbi.nlm.nih.gov/pubmed/19239891
6
CROSBY/CHILTON/DAWE
Characterisation of genetic and molecular changes causing hereditary spastic
paraplegia
Supervisors: Prof. Andrew Crosby (UEMS)
Dr. John Chilton (UEMS)
Dr. Helen Dawe (CLES)
The hereditary spastic paraplegias (HSPs) are a large group of motor neurone
diseases causing weakness and disability of the lower limbs, although many other
neurological as well as non-neurological features may be present. In Exeter we have found
10 new genes that may cause this condition, providing important new insight into the causes
of the disease and identifying potential new treatment options for some forms. Two of these
genes were discovered as part of an ongoing investigation of inherited disease amongst the
Amish communities of Ohio, USA (see www.WOHproject.org). The first of these genes is
‘maspardin’ responsible for Mast syndrome, in which the HSP is associated with an early
onset form of dementia. The second gene is ‘spartin’, in which the HSP is associated with
difficulties with speaking, and poorly coordinated movement. While various cellular roles for
spartin have been proposed, the function of maspardin remains entirely unknown. This
project aims to investigate the role of spartin and in particular maspardin, to enable us to
consider new possible treatment therapies. This project will use a range of cellular studies
including modern fluorescent imaging approaches, to understand the function of these
molecules. It will also use a range of cutting edge genetic techniques to investigate other
related forms of HSP in order to find new genes that may cause these motor neurone
disorders. A trip to the Amish community to visit patients with these conditions may also be
possible as part of the ongoing community genetic program.
References:
Patel et al. (2002). Nat. Genet. 31(4):347-8
Simpson et al. (2003) Am. J. Hum. Genet. 73:1147-1156
Noreau et al. (2014) Exp. Cell Res. 325:18-26
7
DICKENS/WATKINS/WINYARD
Exploring mechanisms by which inflammatory processes influence mood among
people with chronic physical illness: a PhD proposal.
Supervisors: Chris Dickens (UoEMS), Ed Watkins (UoE Psychology) and Paul
Winyard (UoEMS)
Up to one quarter of individuals with chronic physical illness may also suffer from
depression, compared to 2 to 3% in the general population. Such depression in people with
chronic physical illness is important as it adds to the symptom load and disability of the
affected individual, but also predicts worse medical outcomes, such as increased morbidity
and mortality. The causes of such depression in the physically ill are multi-factorial, though
recently there has been growing interest in the role of inflammation and inflammatory
mediators in contributing to the development of depression in those with physical illness.
Observational and experimental studies have shown that increases in inflammation are
associated with increases in depression. Furthermore, clinical administration of Interferon
alpha (IFN-α), which greatly increase level of inflammatory mediators, is associated with
development of major depression up to one third of patients, which can lead to
discontinuation of the treatment or even suicide, but which is preventable in many by pretreatment with antidepressants. A number of mechanisms have been proposed to explain
the links between inflammation and the development of depression, though it remains
unclear i) who is most at risk from inflammation associated depression, ii) which components
of the inflammatory response are associated with the development of depression and iii) the
mechanisms by which increases in inflammation / inflammatory mediators influence
psychological processing to result in depression. This PhD would be suitable for a student
interested in science at the interface between physiology and psychology. Findings from this
PhD could help identify which people with inflammatory disease are at greatest risk of
developing depression, which in turn could lead to the development of novel interventions to
reduce depression and improve medical outcomes. More importantly, findings of this PhD
could elucidate basic mechanisms underlying the natural history of depression in the
population at large.
1) Poole, L. Dickens, C. Steptoe, A. The puzzle of depression and acute coronary
syndrome: Reviewing the role of acute inflammation. J Psychosom Res. Aug 2011;
71(2): 61–68.
2) Miller AH. Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral
changes: psychoneuroimmunology at the translational interface. Brain Behav Immun
2009;23:149-158.
8
EGGLETON/GUTOWSKI/SMERDON/MICHALAK
Project Title: The role of calnexin in T-cell trafficking across the blood-brain barrier in
multiple sclerosis disorders in vitro and in vivo
Applicants: Paul Eggleton (UEMS), Nick Gutowski (UEMS, UK), Gary Smerdon (DDRC
Healthcare, UK) & Marek Michalak (UEMS and Edmonton, Canada).
Proinflammatory T-cells in MS patients cross the blood-brain barrier (BBB) becoming
sensitized by as yet unknown mechanisms to proteins specific to myelinating
oligodendrocytes within the central nervous system (CNS) 1. Our immunopathology groups
in Exeter and Canada study the function of endoplasmic reticulum chaperones including
calnexin (CNX) 2. Our combined data implicates a role for CNX in MS, as we have shown
CNX-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) and
observed that CNX protein is over-expressed in MS patient brains. The tissue location and
inflammatory phenotype of T-cells isolated from CNX-deficient mice differ from wild-type
EAE mice. We will investigate changes in the expression of key molecules involved in T-cell
tissue distribution in the context of CNX deficiency in mice and overexpression in MS
patients. As CNX deficiency may alter adhesion or trafficking of T-cells to the CNS, we shall
identify differences in the adhesion/target molecules on the surface of T-cells from wild-type
and CNX-deficient mice and from human T-cells in which CNX has been deleted in vitro.
Finally we will study in vitro and in vivo trafficking of T-cells across brain endothelial cells,
and investigate oxidative stress treatments that alter CNX expression and how that effects Tcell trafficking. The candidate will get the opportunity to study in Canada.
Refs:
1. Holley J, Bremer E, Kendall AC, De Bruyn M, Helfrich W, Tarr JM, Newcombe J,
Gutowski NJ & Eggleton P. CD20+ inflammatory T-cells are present in blood and
brain of multiple sclerosis patients and can be selectively targeted for apoptotic
elimination. Multiple sclerosis and related disorders 2014 (In Press)
2. Kraus A, Groenendyk J, Bedard K, Baldwin TA, Krause KH, Dubois-Dauphin M Dyck
J, Rosenbaum EE, Korngut L, Colley NJ, Gosgnach S, Zochodne D, Todd K, Agellon
LB & Michalak M. Calnexin deficiency leads to dysmyelination. J Biol Chem
2010;285:18928-38.
9
GARSIDE/GWERNAN-JONES/BRITTEN
Meta-study: transforming qualitative research synthesis for evidence-based practice
Ruth Garside, Senior Lecturer in Evidence Synthesis, ECEHH; Ruth Gwernan-Jones,
Associate Research Fellow, PenTAG; Nicky Britten, Professor of Applied Healthcare
Research UEMS.
There's nothing so practical as good theory (Lewin, 1951)
Outline
This PhD will apply an innovative method of evidence synthesis for qualitative
research, meta-study, to two case studies and explore with researchers and policy makers
how this method impacts on the reviews’ reliability, utility and value.(1)
Evidence-based practice is the cornerstone of medical decision-making. Systematic
reviews are at the top of the evidence hierarchy. Systematic reviews of qualitative research
evidence are gaining increasing credence to complement reviews of effectiveness based on
quantitative trial data. Qualitative evidence syntheses can provide information about how to
implement interventions successfully, the socio-cultural contexts which may impact on
effectiveness for different people or in a given locality, as well as how different people
experience conditions, their treatment and services. Methods for the review and synthesis of
qualitative research evidence are still in development, but standard practice involves
methods such as thematic analysis or meta-ethnography. In such approaches the themes
and concepts across research projects on a shared topic are brought together to produce a
synthesised account that encompasses all the existing studies.(2) These methods have
been influenced by approaches to systematic review for quantitative evidence, and do not
fully take account of the variability in theoretical and methodological approach taken across
qualitative research traditions. Typically then, existing synthesised accounts pay more
attention to the findings of the studies than the epistemological and ontological frameworks
that produce these findings. Meta-study explicitly addresses this lack.
The candidate will explore how findings from two existing syntheses, undertaken by
the supervisors and produced using synthesis methods currently established as standard,
would be transformed by the additional application of meta-method and meta-theory (steps
in meta-study). This represents the further development of a sophisticated method of
synthesis of qualitative research that has, thus far, been little used by researchers.
The candidate will appraise the resultant meta-studies through seeking feedback
from researchers (systematic reviewers and qualitative researchers from different
disciplines) and policy-makers (both within healthcare and other arenas where systematic
review methods are less commonly applied), about the value and utility of the meta-studies
in transforming understanding of a phenomenon and producing policy relevant findings.
1.
Paterson B, Thorne S, Canam C, Jillings C. Meta-study of qualitative health
research: a practical guide to meta-analysis and meta-synthesis. Brink P, editor. Thousand
Oaks, California: Sage Publications; 2001.
2.
Noblit GW, Hare RD. Meta-Ethnography: Synthesizing qualitative studies. London
(England): Sage Publications Ltd; 1988.
10
GOODING/SHORE
Classifying diabetic retinopathy using an integrated approach
Supervisors: Dr Kim Gooding and Professor Angela Shore
Diabetes related eye problems, known as diabetic retinopathy (DR), is the leading cause of
blindness in the working age population in the western world. Dysfunction of the small blood
vessels at the back of the eye (retina): excessive leakiness (haemorrhages / macular
oedema) and ischaemic (impaired blood flow / oxygen delivery) changes, are primary
contributing factors to the development and progression of DR.
DR is currently diagnosed and monitored by grading colour retinal photographs for vascular
morphological abnormalities eg microaneurysms, haemorrhages and cotton wool spots.
However, the current screening grading scale isn’t always effective in identifying patients
with early signs for clinical significant macular oedema (back of the eye becomes swollen
due to fluid accumulation) or fast progressing, proliferative DR, both of which are sight
threatening if untreated. What is needed is a more robust method to diagnose individuals at
most risk of future complications and to do this early in the progress of retinopathy so
treatments can be instigated. The student will investigate whether classifying DR in relation
to its underlying pathology (eg ischaemic vs leakiness) may be a more effective method of
identifying patients ‘at risk’ of sight threatening complications. To achieve this they will use
an integrated approach by, for example, implementing new software to provide novel
information about how individual vessel abnormalities (microaneurysms) develop and
regress over time (this is important as currently we simply count the number at a given time
which is the result of how many microaneurysms are created and how many have been
“healed”, individuals with many microaneuryms because they are not being “healed” may
require completely different treatment to those with many microaneuryms who are also
“healing” many), measuring the thickness of the macula and assess which components
contribute to changes in thickness and exploring risk of diabetic retinopathy/ change of retina
measurements with a combination of genotype and biomarker information including
recruiting patients by genotype where appropriate. Many resources are already available to
enable the student to make excellent progress in their studies. These include the ongoing
large, EU funded multi-centre SUMMIT study in which retina, genotype and biomarker data
are available from 3 years ago and are now being repeated; over 20 years of clinical retinal
photographs, and the Exeter 10, 000 bioresource of volunteers ready for recruit by genotype
studies. The project will offer the student opportunities to train in experimental medicine
research with particular emphasis in eye physiology and pathophysiology, epidemiology,
bioinformatics and to an excellent understanding of the diagnostic framework needed to
create new genomic/biomarker/imaging diagnostic tools.
11
GOODWIN/ABBOTT/TARRANT
Proposed PhD Title: Mealtime interventions and the health, quality of life and wellbeing of older people in residential care
Supervisors: Dr Rebecca Abbott, Dr Vicki Goodwin, Dr Mark Tarrant
Malnutrition is one of the greatest threats to the health, wellbeing and autonomy of older
adults, particularly those living in care homes. Older individuals identified at risk of
malnutrition have poorer quality of life, are more likely to be admitted to hospital, and are at
increased risk of mortality. Furthermore, mealtimes have a critical socio-cultural role in care;
‘enjoying food and being able to eat food’ are central to the UK Government’s nutrition action
plan. Whilst the need to improve nutrition of older people living in care has long been
recognised, how this can best be achieved and whether (and which) interventions are
successful in reducing morbidity and improving well-being is less understood. The proposed
PhD will build on the findings from two of our recent reviews1,2 which suggest that simple
changes to the mealtime environment, such as provision of real food snacks, the style of
food service, seating arrangements (group or alone),the playing of music and the ambience
of the dining room can significantly impact resident health and well-being. These findings,
however, need to be supported by controlled, pragmatic studies that take into consideration
care home policies and staffing.
References:
1
Abbott RA, Whear R et al Effectiveness of mealtime interventions on nutritional outcomes
for the elderly living in residential care: A systematic review and meta-analysis. Ageing
Research Reviews, 2013; 12: 967-981
2
Whear R, Abbott RA et al. Effectiveness of mealtime interventions on behaviour symptoms
of people with dementia living in care homes: A systematic review. Journal of the American
Medical Directors Association, 2014; 15: 185-193
For further information please contact Dr Mark Tarrant (m.tarrant@exeter.ac.uk); Dr Vicki
Goodwin (V.Goodwin@exeter.ac.uk) or Dr Rebecca Abbott (R.A.Abbott@exeter.ac.uk)
12
GREEN
Director of Studies/Supervisor – Prof Colin Green, Health Economics
Supervisory Team TBC
PhD Topic
The development of methods to model Alzheimer’s dementia (AD) over time for use in
health technology assessment (HTA).
The current methods available for modelling AD progression offer useful insights but all have
limitations. The main concerns, raised in previous reviews, are on model structure. One of
the key limitations with current methods is on the limited characterization of disease
progression through use of a narrow description of the natural history of AD (e.g. using
broad categories for cognitive function), and on the use of a limited number of health states
to capture events related to disease progression over time (e.g. moving into full-time care
setting). Advances are needed in the methods available to model disease progression in AD
in order to capture the effects of AD on people’s lives and to quantify the influence of health
technologies on the experience of AD. Proposals/plans here (for this PhD) include
development of a descriptive system for AD using the key symptomatic domains of the
condition, including cognition, function (ADLs) and behaviour/mood, and methods to predict
disease progression through this descriptive system over time. A model-based framework
for assessment of AD progression over time, and related costs and outcomes, will be
developed. Such a model-based approach, using a descriptive system for AD, is expected
to be sensitive to change in both symptomatic and disease modifying effects, and is
expected to be able to support HTA, and the conduct of economic evaluation of health care
interventions (such as those evaluations undertaken by NICE).
13
GREEN/SPENCER/MEDINA-LARA
Comparing generic and condition-specific preference-based (QALY) measures of
health-related quality-of-life
This PhD will investigate health outcomes assessment in the context of health technology
decision-making. Two prominent approaches for estimating health state values used in
quality-adjusted life years (QALYs) will be compared. QALYs are a health outcome measure,
commonly used in health policy settings, which incorporate both length and quality of life,
with quality of life (health state values) estimated using preference-based measures. Such
preference-based measures can be either generic or condition-specific. The most widely
used generic preference-based measure, the EQ-5D, uses a simple descriptive system
covering five dimensions of health, and it has been criticised for its limited applicability to
certain conditions. This has led to consideration of the effect on health state values of adding
‘bolt-on’ dimensions to the EQ-5D descriptive system (such as vision or fatigue) (Longworth
et al., 2013). However, there has been little, if any, consideration of the impact of the loss of
dimension information when estimating health state values, as can occur with movements
between generic and condition-specific measures. This PhD will explore the impact of
information gain/loss on estimating health state values (Spencer et al., 2014) and the
reasons for differences between generic and condition-specific measures. The PhD findings
will have implications for the assessment of competing treatments in health technology
assessments, as differences in health state values derived from generic/condition-specific
measures can affect the decision to accept treatment (Rowen et al., 2012). Moreover, it will
help to explain the additional contribution that condition-specific measures have in priority
areas such as Multiple Sclerosis. The PhD will build on existing high quality health outcomes
research already being undertaken within UEMS in the disease area of MS (Hawton et al.,
2013), and will utilise data available to the Health Economics Group from the South West
Impact of MS (SWIMS) longitudinal, a large (n=approx. 1,500) cohort study of people with
MS.
HAWTON, A., SHEARER, J., GOODWIN, E. & GREEN, C. 2013. Squinting through layers of
fog: Assessing the cost effectiveness of treatments for multiple sclerosis. Applied Health
Economics and Health Policy, 11, 331–341.
LONGWORTH, L., YANG, Y., ROWEN, D., TSUCHIYA, A., YOUNG, T. & BRAZIER, J.
2013. Development and valuation of a vision bolt-on to EQ-5D. Health Economists' Study
Group conference, University of Exeter. Exeter
ROWEN, D., YOUNG, T., BRAZIER, J. & GAUGRIS, S. 2012. Comparison of generic,
condition-specific, and mapped health state utility values for multiple myeloma cancer. Value
in Health, 15, 1059-1068.
SPENCER, A., ROBINSON, A., PINTO-PRADES, J-L., Exploring differences between
generic health states values derived using time trade off methods and choice based
methods. iHEA conference Dublin 2014.
Lead Supervisor: Colin Green. Supervisors: Anne Spencer and Antonieta Medina-Lara.
14
HARRIES/GALLOWAY
Does Bisphenol A (BPA) cause human disease through epigenetic mechanisms?
Lorna Harries and Tamara Galloway.
Epigenetic modifications to our genome (DNA methylation, miRNA gene regulation and
histone alterations) are now known to form a key interface between our genes, the
environment and human health.
This has particular importance for exposure to
environmental chemicals, to which we all have near ubiquitous exposure, where exciting
new data on human health effects are now emerging. Bisphenol A (BPA), for example, a
synthetic oestrogenic compound widely used in food packaging has been shown to be
causally-linked with disruption of cardiovascular and metabolic function. Despite these
advances, the underlying mechanisms that lead to these associations are largely unclear.
We have recently demonstrated that the effects of BPA on metabolism may act via changes
to the expression of estrogen-responsive genes such as the estrogen-related receptor alpha
(ESRRA
function [1, 2]. In this studentship, we aim to examine the precise epigenetic mechanisms by
which BPA may cause these effects. We will assess the effects of BPA on epigenetic
regulation of gene expression at the level of a) DNA methylation and b) small RNA (miRNA)
expression with a particular focus on genes involved in cardiac function, obesity or type 2
diabetes. Finally, we will assess the potential for population-level dietary intervention to
reduce BPA exposure to levels which would be unlikely to cause health effects. This project
will provide a robust and varied programme for a student resulting in highly employable
skills, and delivering enhanced understanding of wider significance.
1.
2.
Melzer, D., et al., Bisphenol A exposure is associated with in vivo estrogenic gene
expression in adults. Environmental health perspectives, 2011. 119(12): p. 1788-93.
Cipelli, R., et al., Bisphenol A modulates the expression of Estrogen-Related
Receptor-alpha in T-Cells. Reproduction, 2013.
For further information please contact Dr Harries (L.W.Harries@exeter.ac.uk)
15
HENLEY/LIN/LLEWELLYN
Title: A unifying approach to quantifying bias in sensitivity analysis for treatment effects
Research area: Health statistics
Director of studies: Professor William Henley
Other supervisors: Dr Nan Lin, Dr David Llewellyn
Project outline: This is an exciting opportunity to contribute to developing statistical
methodology for quantifying bias when estimating the effectiveness of medical interventions.
Risk of bias due to uncertainty about untestable assumption is common in both
observational studies and randomised controlled trials. Complete control for the risk of bias
is unlikely in practice, but its impact can be estimated by means of sensitivity analyses (Lin,
Logan and Henley, 2013). The aim of this project is to develop a unifying approach for
sensitivity analysis, facilitate efficient implementation and make the proposed approach
accessible. The unifying approach will make it possible to systematically integrate the
assessment of bias into conventional analyses for a range of statistical models (including
logistic regression, survival analysis, Poisson regression, meta analysis) for both
randomized and non-randomized studies. Application of these methods will help facilitate
better research planning, reporting and decision making. The studentship is linked to a
project funded by the MRC Methodology Research Panel and forms part of a growing
programme of work on sensitivity analysis methods.
References
Lin NX, Logan S, Henley WE (2013). Bias and sensitivity analysis when estimating
treatment effects from the Cox model with omitted covariates. Biometrics 69: 850-60.
16
HENLEY/RODGERS/MELZER
Title: Quasi-experimental methods for pharmacovigilance
Research area: Health statistics
Director of studies: Professor William Henley
Other supervisors: Dr Lauren Rodgers, Professor David Melzer
Project outline: Pharamacovigilance studies involving post-marketing surveillance of new
drugs play a vital role in ensuring that patients receive safe treatments. One increasingly
important approach is to study adverse drug reactions using longitudinal data from electronic
health record systems. However, a major challenge in making use of these data is the
problem of confounding by selective prescribing based on indication, severity, or prognosis
(The European Network of Centres for Pharmacoepidemiology and Pharamcovigilance
(ENCePP), 2013). In many cases the sources of confounding are unmeasured, preventing
adoption of standard adjustment methods to remove bias. The prior event rate ratio (PERR)
method (Tannen, Weiner, & Xie, 2009), and other recent developments in quasiexperimental analytic methods, offer a promising strategy for addressing unmeasured
confounding in observational studies. This project will seek to extend and apply the PERR
method to establish a framework for reducing confounding bias in drug safety studies. Given
the range of adverse events that may be attributable to drug treatment, the PERR model will
be extended to include competing risk events. Another important consideration, reflecting
the need for long-term monitoring of drug safety events, will be exploring the performance of
the PERR method in the presence of time dependent confounding. The project will make
use of data from large-scale clinical databases, together with biologically realistic
simulations, to evaluate methodological developments. This studentship will be based in the
health statistics (Prof Henley, Dr Rodgers) and epidemiology (Prof Melzer) research groups,
and will benefit from growing links with industrial partners.
References
Tannen, R. L., Weiner, M. G., & Xie, D. W. (2009). Use of primary care electronic medical
record database in drug efficacy research on cardiovascular outcomes: comparison of
database and randomised controlled trial findings. British Medical Journal, 338.
doi:ARTN b81 DOI 10.1136/bmj.b81
The European Network of Centres for Pharmacoepidemiology and Pharamcovigilance
(ENCePP). (2013). Guide on Methodological Standards in Pharmacoepidemiology
(Revision 2).
17
KOS/GOODING
Diabetes and Microvascular function
Supervisors: Dr Katarina Kos (lead supervisor), Dr Kim Gooding (co-supervisor)
Obesity is associated with cardiovascular disease and the development of Type 2 diabetes.
With increasing weight gain fat/adipose tissue is prone to become compromised with
limitation of its capacity to store fat. A diversion of fat storage from adipose tissue to nonadipose tissue such as liver, muscle, heart and perivascular fat (which is also known as
ectopic fat) occurs with increasing dysfunction of adipose tissue. There is increasing
evidence that ectopic fat is pro-inflammatory and may be causing structural and functional
harm to surrounding tissues, for example blood vessels [1]. In previous studies we
demonstrated altered vascular function in obese individuals compared to lean individuals.
Type 2 diabetes, preceded by insulin resistance, is also associated with vascular
dysfunction, which contributes to the development of diabetes related complications in the
eyes, kidney and heart. As obesity is closely associated with type 2 diabetes it is difficult to
distinguish the vascular impairment resulting from diabetes from obesity. Exciting new
evidence suggests that microvascular function improves with drastic weight loss such as in
obese subjects after bariatric surgery however not in subjects with diabetes [2].
The overall objective of this project is thus to test the hypothesis that
Microvascular impairment is a result of diabetes rather than obesity.
This studentship will have the opportunity to take a patient to bench side approach with the
student performing vascular assessments with state of the art microvascular laser Dopplers
in human clinical studies as well as learning molecular biological techniques.
References:
1. Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ
Res. 2005 May 13;96(9):939-49.
2. Martín-Rodríguez JF,et al. Effect of bariatric surgery on microvascular dysfunction
associated to metabolic syndrome: a 12-month prospective study. Int J Obes (Lond).
2014.28. doi: 10.1038/ijo.2014.15.
18
KOS/WINLOVE/SCOTTON
Multi-photon image analysis and adipose tissue mechanics in diabetes
Supervisors: Dr Katarina Kos (lead supervisor), Professor Peter Winlove and Dr Chris
Scotton (co-supervisors)
Obesity is associated with considerable metabolic complications, including diabetes. This is
derived in part from an increasing dysregulation of fat/adipose tissue and limitation of its
capacity to store fat. A diversion of fat storage from adipose tissue to non-adipose tissue
such as liver, muscle, heart and perivascular fat (also known as ectopic fat) occurs with
increasing dysfunction of adipose tissue. Type 2 diabetes is one of the complications of
obesity, whereby insulin resistance results from overfeeding-induced changes affecting
adipose tissue. This includes inflammation, and dysregulation of the extracellular matrix
(ECM) composition - with an increase in the content of structural proteins such as fibrillar
collagens [1,2]. The ECM in obese individuals therefore differs from that in lean subjects,
with the presence of fat fibrosis (akin to excessive scarring of the adipose tissue). As a group
we have a track record in investigating adipose tissue mechanics and function; we are able
to assess fibrillar collagen content and ECM composition, plus the regulation of gene
expression (mRNA and protein level) which relates to biomechanical properties [3]. The
purpose of this study is to increase the understanding of changes in mechanical properties
of fat tissue in diabetes and how a change in ECM structure of subjects with diabetes affects
the storage function of adipose tissue, using cutting-edge multiphoton imaging microscopy
and in vitro cell biology. Identification of the pathogenic processes which affect the ECM
fibrillar structure of adipose tissue will aid development of therapies for diabetes treatment
and its prevention.
The objectives of this study are therefore:
 To compare the composition of ECM and the mechanical coupling between cells and
matrix of subjects with/ without diabetes with novel biophysical techniques
(multiphoton microscopy and CARS)
 To determine the role of adipose ECM in fatty acid uptake and its storage
References:
1. Spencer M et al. J Clin Endocrinol Metab. 2011;96(12):E1990-8.
2. Tam CS et al. Diabetes. 2010;59(9):2164-70.
3. Alkhouli N et al. AJP 2013. 305(12):E1427-35.
19
MELZER
ANALYSIS PATIENT RECORD DATA TO EVALUATE CLINICAL EFFECTIVENESS OF
TREATMENTS
Director of Studies: Prof David Melzer
Large-scale clinical record databases offer novel opportunities to examine the effects of
treatment in groups who are seldom included in clinical trials. This project will use primary
care clinical records linked to hospital episode and mortality data on over a million older
patients. We will apply emerging statistical approaches including instrumental variables
analysis and the prior event rate ratio approach (Tannen et al, BMJ 2009) to estimate likely
effects of interventions in clinically important groups. Areas of particular interest include
cardiovascular prevention and psychotropic drugs in older patients. This studentship will
build on statistical, epidemiological or computational skills and will be based in the
epidemiology (Prof Melzer) and medical statistics (Prof Henley) research groups. For further
information contact Prof Melzer at D.Melzer@exeter.ac.uk
Ref: Tannen RL, Weiner MG, Xie D. Use of primary care electronic medical record database
in drug efficacy research on cardiovascular outcomes: comparison of database and
randomised controlled trial findings. BMJ. 2009;338:b81.
20
MELZER
GENOME WIDE EXPRESSION STUDIES IN HUMAN POPULATIONS
Director of Studies: Prof David Melzer
The Melzer and Harries groups at UEMS have recently identified novel gene expression
markers of key phenotypes of human ageing, by analysing transcriptome wide array data in
human cohort studies. By studying gene expression in human blood we can identify
promising biomarkers and gain mechanistic insight into diseases and traits relevant to
ageing. Working with the Framingham Heart Study and the CHARGE collaboration, we
currently lead the international meta-analyses of transcriptome wide data on muscle strength
and other phenotypes of ageing. In this studentship we will explore gene expression
signatures related to dynamic changes in phenotypes over time. We will also analyse data
on the white cell subtype origins of key expression markers in blood. This studentship will
build on bioinformatic, statistics or epidemiology skills and will be based in the epidemiology
group (Prof Melzer) and molecular genetics (Dr Lorna Harries). . For further information
contact Prof Melzer at D.Melzer@exeter.ac.uk
REF: Harries LW, Hernandez D, Henley W, Wood AR, Holly AC, Bradley-Smith RM,
Yaghootkar H, Dutta A, Murray A, Frayling TM, Guralnik JM, Bandinelli S, Singleton A,
Ferrucci L, Melzer D. Human aging is characterized by focused changes in gene expression
and deregulation of alternative splicing. Aging Cell. 2011 Oct;10(5):868-78. PMID: 21668623
21
MORGAN/RUSSELL
Role of STAT transcription factors in diabetes pathogenesis
Professor Noel G Morgan & Dr Mark A Russell
In both type 1 and type 2 diabetes, the pancreatic islet is exposed to a complex milieu of
cytokines. Pro-inflammatory cytokines within this milieu (e.g. IL-6) can reduce pancreatic βcell viability, whereas anti-inflammatory cytokines (e.g. IL-4, IL-13) are cytoprotective1, 2.
Understanding the molecular mechanisms by which these proteins impact on β-cell viability
(and function) may uncover novel pathways to therapeutically target in diabetes.
Our laboratory focusses on STAT family transcription factors which likely underpin many of
the effects described above. We are particularly interested in STAT3 (activated by IL-6) and
STAT6 (activated by IL-4 and IL-13) and are dissecting their roles in regulating β-cell viability
and also examining whether they are altered in diabetes. Furthermore, we are functionally
investigating novel rare mutations within the STAT3 gene which are implicated in early
diabetes onset. To achieve these goals, our approach is to use a combination of cuttingedge molecular biological techniques in cell-based model systems alongside the use of more
conventional histological methods in a unique bank of human tissue samples.
1.
Russell MA, Cooper AC, Dhayal S, Morgan NG. Differential effects of interleukin-13
and interleukin-6 on Jak/STAT signaling and cell viability in pancreatic beta-cells. Islets
2013; 5.
2.
Kaminski A, Welters HJ, Kaminski ER, Morgan NG. Human and rodent pancreatic
beta-cells express IL-4 receptors and IL-4 protects against beta-cell apoptosis by activation
of the PI3K and JAK/STAT pathways. Biosci Rep 2010; 30:169-75.
22
MUJICA-MOTA/MELZER/HENLEY
Title: Evaluating the costs and health benefits of medical treatments used by older
adults in routine practice
Director of Studies: Ruben E Mujica-Mota
Supervisor: David Melzer
Supervisor: William Henley (TBC)
The recent availability of large clinical record datasets has created the opportunity to use
observational data from routine health care use and practice to evaluate the costs and health
outcomes (markers) of commonly used medical treatments. Studies using such data may
add to the evidence base generated from traditional experimental studies (i.e. randomised
controlled trials (RCTs)), which are internally valid sources of treatment effects but often of
limited generalizability to the relevant patient population, thus resulting in improved medical
decisions in the NHS. Established methods of observational data analysis used in labour
and education policies or programmes (Angrist and Pischke 2008) are increasingly being
applied to the evaluation of health programmes and interventions. These include quasiexperimental methods of evaluation that employ ‘natural experiments’ arising from variations
in the way patients are managed to produce treatment effect estimates that may be free from
confounding and apply to a broader population than that included in RCTs. This PhD
programme seeks to evaluate the strengths and weaknesses of natural experiment methods
to assess the economic costs and health outcomes of treatments in older adults (aged 65+)
and it is intended to inform methodological practice on using administrative observational
data for health care economic evaluation. The prospective student will gain experience in
methodological review using systematic methods, quantitative skills for managing and
analysing large databases, applying health econometric principles to policy evaluation, and
using the results of observational data analysis to populate health economic models
informing NHS policy decisions. This studentship will build on econometric, statistical,
epidemiological or computational skills and will be based in the Peninsula Technology
Assessment group (Dr Mujica-Mota) with input from epidemiology (Prof Melzer) and medical
statistics (Prof Henley) research groups. For further information contact Dr Ruben MujicaMota (r.e.mujica-mota@exeter.ac.uk).
Angrist, JD & Pischke JS. 2008. Mostly Harmless Econometrics: An Empiricist's Companion.
2008. Princeton University Press. 392 pp.
23
MURRAY/WEEDON
The genetics of reproductive ageing:
Supervisors:
Anna Murray (UEMS)
Mike Weedon (UEMS)
More women are having children in their 30s than in their 20s for the first time in history, in the UK.
Yet the risk of infertility increases exponentially after 35 years of age, with 50% of women not able
to conceive naturally by the age of 40. Thus there is increasing need to resort to assisted conception
techniques such as IVF to achieve a pregnancy. Natural fertility declines because the pool of eggs
that women are born with are depleted gradually over a woman’s lifespan until they reach
menopause. The end of reproductive life occurs about 10 years before menopause. Our group is
interested in the genetic control of the reproductive ageing process. We have led several
international collaborative projects in this area, which have resulted in publications in the top
biological journals, eg. Nature and Nature Genetics. Our PhD students typically publish 4-5 papers
during their studentship, which form the basis of their thesis.
This project will be involved in discovering new genes involved in reproductive ageing and
determining what biological role those genes play. The project will use the extensive data resources
available to the group, including access to genetic and phenotype information from half a million
individuals in the UKBiobank study (http://www.ukbiobank.ac.uk/). We will also use data from the
Exeter based study EXTEND, which has recruited 10,000 individuals and enables us to re-contact
those carrying a particular genetic variant and investigate how it affects the individual. The project is
a computer-based project and would suit someone with an aptitude for
bioinformatics/computing/mathematics. Full training will be provided however from our
multidisciplinary team of computer scientists, bioinformaticians, medics, molecular biologists and
geneticists. The student will develop skills that will make them extremely employable in this era of
‘Big data’ and genomics.
For more information contact: Anna Murray a.murray@exeter.ac.uk
References:
Perry et al. Parent-of-origin specific allelic associations among 106 genomic loci for age at
menarche. Nature, in press.
Stolk et al., Meta-analysis of genome-wide association studies of age at menopause: novel loci
highlight DNA repair and immune pathways. Nature Genetics, 2012 Jan 22;44(3):260-8.
24
PETERS/COOPER/ANDERSON
Project Title: Identifying evidence to evaluate the cost-effectiveness of health care
technologies: how systematic and transparent can, and should, we be?
Supervisors: Jaime Peters, Chris Cooper, Rob Anderson
Decision analytic models (DAMs) are routinely used in Health Technology Assessments to
aid the decision making process when recommending new treatments or tests to be funded
by healthcare systems, such as the NHS. DAMs are used to predict the costs and health
impacts of different treatments, or test strategies over time, to evaluate their costeffectiveness within a health care system. Results from DAMs are estimated to be
responsible for the approval of 82% of new technologies in the UK between 1999-2013
(Helen Dakin., 2014), so their importance as a decision making tool is well established. A
great deal of evidence is required to populate DAMs. This might include (but is not limited
to): data on the clinical effectiveness of treatments or tests, associated costs, and the quality
of life of individuals. These data might come from a variety of sources, such as: published
randomised controlled trails, systematic reviews, grey or unpublished literature, or
unpublished case study reports. In spite of the range of evidence which might be needed to
populate a DAM, and the wealth of evidence sources to be considered, there is no
methodological guidance on how to systematically and transparently search, identify and
appraise, all of the evidence required for a DAM (Kaltenthaler et al., 2013). Whilst guidelines
for reporting DAMs exist (Husereau et al., 2013), and international working parties are
actively discussing the need for transparency in the evidence gathering process, transparent
models are not common place. The lack of transparency in DAMs creates uncertainty about
the relevance and credibility of the DAMs results, limiting the usefulness of these models for
decision-making.
This PhD seeks to address this weakness. It will aim to identify methods to pragmatically,
systematically and transparently identify evidence for DAMs and seek to develop a method
of documenting the process of building the DAM, with a view to making the process and the
model transparent.
For further information please contact Dr Jaime Peters (j.peters@exeter.ac.uk)
References
HELEN DAKIN., N. D., YAN FENG., NIGEL RICE., PHILL O’NEILL., DAVID PARKIN., 2014.
The Influence of Cost-effectiveness and Other Factors on NICE Decisions: Research
Paper 13/06r Office for Health Economics.
HUSEREAU, D., DRUMMOND, M., PETROU, S., CARSWELL, C., MOHER, D.,
GREENBERG, D., AUGUSTOVSKI, F., BRIGGS, A. H., MAUSKOPF, J. & LODER,
E. 2013. Consolidated Health Economic Evaluation Reporting Standards (CHEERS)
statement. BMJ, 346.
KALTENTHALER, E., TAPPENDEN, P. & PAISLEY, S. 2013. Reviewing the evidence to
inform the population of cost-effectiveness models within health technology
assessments. Value Health, 16, 830-6.
25
PITT/CHALK/BRITTEN
Project Title :Using agent-based simulation to predict individual behavioural changes in
models of health and social care systems
Supervisors: Martin Pitt, Daniel Chalk, Nicky Britten
A focus on patient- or person-centred care is increasingly important in health and social
care, and a growing factor for strategic decision making (e.g. healthcare commissioning).
Traditional simulation modelling approaches such as discrete event simulation have been
used to determine the potential impact of changes to clinical pathways, but necessarily
assume an idealisation of the real world in which patients follow a prescribed protocol.
Agent-Based Simulation offers a means of modelling a system in which patients are
represented explicitly as individuals, with specific behaviours, characteristics and
motivations. By modelling a population of patients as agents, it is possible to observe the
emergent population-level dynamics of a system of individual behaviours, and determine the
impact of both behavioural changes on the system, and system changes on behaviour.
Agent-based simulation therefore offers an important way to model aspects of personcentred care, such as patient choice, one to one interactions, and person-centred outcome
measures, in such a way that the potential reconfigurations of service systems can be
assessed in a patient-centred context. The use of agent based simulation in healthcare is in
its infancy with few studies demonstrating the potential benefits. This project would seek to
explore the use of Agent-Based Simulation and assess its value in healthcare modelling.
Specific case-study areas would be chosen to demonstrate the use of “what if” analysis for
the assessment of alternative health and social care service configurations which more
suitably meet the individual needs of patients, and improve individual patient outcomes.
Reference:
Multi-agent systems for healthcare simulation and modeling; applications for system
improvement (2010). Paranjape R and Sadanand. A. (eds). IGI Global
26
RICHARDSON/MORGAN
Investigation of the relationship between enteroviral infection and the development of
islet cell autoimmunity in type 1 diabetes
Dr Sarah J Richardson & Prof Noel G Morgan
There is a considerable weight of circumstantial (epidemiological) evidence implicating
infection with strains of enterovirus and the development of type 1 diabetes (T1D) in human
populations. It has also been shown by ourselves, and others, that viral antigens can be
detected in the pancreatic islets of T1D patients, suggesting that enteroviral infection may
spread to the islets under some circumstances. However, the progression of such islet
infections appears unusual in that large scale lysis of islet cells does not occur, as might be
expected. Rather, we have evidence that a sustained, more persistent, infection develops in
which viral replication is relatively low and direct cell damage is minimal. This represents a
rather novel aspect of enteroviral biology which is still to be understood but we hypothesise
that the presence of latent enterovirus in islet cells may lead to impaired handling of cellular
proteins and that this leads to the aberrant presentation of antigens to the immune system
leading to islet autoimmunity. In the present project, this hypothesis will be tested directly by
the development of in vitro model systems in which cultured islet cells are infected with
attenuated strains of enterovirus that are capable of developing persistent infections. The
cells will then be monitored to discover whether they mount specific anti-viral responses,
display evidence of increased stress or altered metabolism, aberrantly process islet antigens
and display these on their surface in association with HLA Class 1 molecules and/or have
altered secretory properties. The overall aim is to establish the influence of a persistent
infection on beta –cell function and viability as a means to understand how autoimmunity
might develop in type 1 diabetes.
References:
Richardson, S.J., Willcox, A., Bone, A.J., Foulis, A.K. and Morgan, N.G. 2009. The
prevalence of enteroviral capsid protein, vp1, immunostaining in pancreatic islets in human
type 1 diabetes. Diabetologia. 52, 1143-1151.
Richardson, S.J., Willcox, A., Bone, A.J., Morgan, N.G. and Foulis, A.K. 2011.
Immunopathology of the human pancreas in type 1 diabetes. Seminars Immunol. 33, 9-21.
Richardson, S.J., Morgan, N.G. and Foulis, A.K. 2014. Pancreatic pathology in type 1
diabetes. Endocrine Pathol. 25, 80-92.
27
SCOTTON/GIBBONS/JAYASINGHE
Title: Development of a three-dimensional in vitro lung organoid model for pre-clinical drug
evaluation
Lead supervisor:
Dr Chris Scotton, Senior Lecturer, UEMS
Co-supervisors:
Dr Michael Gibbons, RD&E Consultant and Honorary University
Fellow
Dr Suwan Jayasinghe, University College London
Pulmonary fibrosis (PF) is the end stage of several interstitial lung diseases (ILDs),
characterized by excessive matrix deposition and destruction of the lung architecture. In the
UK, >5000 people die each year from the commonest form, Idiopathic PF (IPF) - and the
incidence is rising. IPF has a five-year survival rate of only 20%; novel therapeutic strategies
are therefore urgently required. A variety of animal models of PF are in common usage, but
their applicability to the human disease is the subject of constant debate (1); no single model
recapitulates all of the pathological features seen in PF, and throughput for pre-clinical
screening is limited. In the human disease, epithelial-mesenchymal crosstalk is thought to be
central to disease progression (2). The development of an in vitro lung organoid model,
incorporating epithelium and fibroblasts in a relevant three-dimensional network, would be of
enormous benefit for translational medicine, providing insight into the underlying biology of
the disease and a high-throughput screening tool for anti-fibrotic agents. This could enable
pre-screening of lead compounds as a viable alternative to testing in vivo, thereby having a
significant impact on the ‘replacement, reduction and refinement’ of animal use in research.
Our preliminary work has established that lung fibroblasts can self-organise into a threedimensional spheroid. Using bio-engineering technology (3, 4), this studentship would
establish the incorporation of airway epithelium into these structures, and investigate
downstream epithelial-mesenchymal crosstalk to test the hypothesis that “Epithelialfibroblast spheroids will provide a unique three-dimensional in vitro model of
pulmonary fibrosis for screening of anti-fibrotic interventions”.
1. Scotton, C. J., Chambers, R. C. (2010). Bleomycin revisited: towards a more
representative model of IPF? American Journal of Physiology - Lung Cellular & Molecular
Physiology 299(4), L439-41.
2. Datta A., Scotton C.J. and Chambers R.C. (2010). Novel therapeutic approaches for
Idiopathic Pulmonary Fibrosis. Br J Pharmacol. 163(1), 141-172.
3. Jayasinghe, S.N., Warnes, G., Scotton, C.J. (2011). Bio-electrosprayed living composite
matrix implanted into mouse models. Macromol Biosci. 11(10), 1364-1369.
4. Peng, Y., et al. (2012). Human fibroblast matrices bio-assembled under macromolecular
crowding support stable propagation of human embryonic stem cells. J Tissue Eng
Regen Med, 6: e74–e86. doi: 10.1002/term.1560
For further information please contact Dr Scotton (c.j.scotton@exeter.ac.uk)
28
THOMPSON COON/GWERNAN JONES/ABBOTT
How can we improve the accessibility, utility and usefulness of systematic reviews?
Supervisory team: Jo Thompson Coon, Ruth Gwernan-Jones and Rebecca Abbott with
support and mentoring advice from Ken Stein
Systematic reviews are recognised as being at the heart of evidence-based practice and the
first port of call for those seeking solutions to their clinical uncertainties. However, the
production of systematic reviews is not sufficient to ensure that their messages will be
incorporated into routine practice; qualitative research suggests that there are many barriers
to the uptake of evidence from systematic reviews (e.g. lack of awareness, lack of access,
lack of usefulness). One approach that has been proposed to ensure that systematic
reviews are accessible, credible and relevant is to involve stakeholders in their production.
However, there are few published evaluations of stakeholder involvement in systematic
reviews and little is known about the impact of this approach on the subsequent uptake of
evidence.
Using a suite of systematic reviews (see below) recently completed by the NIHR CLAHRC
South West Evidence Synthesis Team on topics relevant to the care home setting, this PhD
will seek to i) explore and develop methods to assess the barriers and facilitators to the
uptake of evidence into routine practice in this setting, ii) to use this information to develop
guidelines for the effective involvement of stakeholders to ensure that systematic reviews
are useful and the findings widely incorporated into routine practice, iii) to co-create a
template for a communication strategy that could be used to share the findings of systematic
reviews with a range of different audiences and incorporated into the standard protocols of
future reviews and iv) to develop methods to assess the impact and value of stakeholder
involvement in systematic reviews on subsequent uptake of research findings. The focus of
the work and methods employed will be refined in light of emerging findings but may include
using qualitative interviews, focus groups and surveys. The project will involve the
collaboration of stakeholders at all levels and in all stages (e.g. residents, families, care
home staff and owners, GPs etc.) to enable co-ownership of the findings.
Whear R, Abbott R, Thompson-Coon J, Bethel A, Rogers M, Hemsley A, Stahl-Timmins W,
Stein K. Effectiveness of mealtime interventions on behaviour symptoms of people with
dementia living in care homes: a systematic review. J Am Med Dir Assoc. 2014
Mar;15(3):185-93.
Abbott RA, Whear R, Thompson-Coon J, Ukoumunne OC, Rogers M, Bethel A, Hemsley A,
Stein K. Effectiveness of mealtime interventions on nutritional outcomes for the elderly living
in residential care: A systematic review and meta-analysis. Ageing Res Rev. 2013
Sep;12(4):967-81.
Whear R, Thompson Coon, Bethel A, Abbott R, Stein K, Garside R. What is the impact of
using outdoor spaces such as gardens on the physical and mental well-being of those with
dementia? A systematic review of quantitative and qualitative evidence. J Am Med Dir
Assoc (in press).
Thompson Coon J, Abbott R, Rogers M, Whear R, Pearson S, Lang I, Cartmell N, Stein K.
Interventions to reduce inappropriate prescribing of antipsychotic medications in people with
dementia resident in care homes: A systematic review J Am Med Dir Assoc (under peer
review).
29
VOS/GAZE
Experimental Lateral Gene Transfer in pathogenic bacteria
Supervisors: Michiel Vos and Will Gaze
Unit:
Coastal Pathogens Group, European Centre for Environmental and Human
Health
Location:
Penryn Campus
The genetic diversity harboured by bacteria is enormous. Your own genome is made up of
around 30.000 genes. However, your microbiome (the bacteria that live in and on you)
encodes for millions of unique genes. One reason for this diversity is that bacteria do not
only slowly accumulate point mutations, but that they are able to promiscuously exchange
genes at a high frequency. This process of Lateral Gene Transfer (LGT) is fundamental to
the evolution to bacteria, from the formation of distinct Phyla over hundreds of millions of
years to the rapid evolution of antibiotic resistance over the course of the treatment of an
infection. Much of our knowledge on LGT comes from retrospective sequencing studies. In
this PhD project, we will design controlled experiments to directly quantify distinct modes of
LGT. Using flow cytometry and genome sequencing, we will collect fundamental data on the
rate at which genes are transferred under various relevant conditions, and how this can
impact antibiotic resistance and virulence.
Please feel free to contact Dr Vos for more information (m.vos@exeter.ac.uk).
30
WELTERS/WHATMORE/MORGAN
Title: Investigation of Wnt4 activated signalling pathways that lead to inhibition of
proliferation and insulin secretion in pancreatic beta-cells
Supervisory team: Hannah Welters, Jackie Whatmore and Noel Morgan
Type 2 diabetes is a rapidly growing health problem estimated to become the 7th leading
cause of death worldwide by 2030. The pancreatic beta-cells produce insulin to regulate
levels of blood glucose. Diabetes occurs when insufficient insulin is produced to maintain
normal blood glucose levels; this is often due to a reduction in beta-cell numbers.
The aim of this PhD is to investigate how insulin secreting beta-cells (located in pancreatic
islets) respond to a relatively under-studied signalling molecule, Wnt4. We have preliminary
data revealing that Wnt4 can inhibit beta-cell growth and insulin secretion. Hence, we
propose that Wnt4 may be one of the factors which promotes beta-cell dysfunction in type 2
diabetes. In this PhD we propose to study the actions of Wnt4 in beta-cells including;
investigating whether Wnt4 acts in an autocrine fashion, which of the branches of the noncanonical pathways Wnt4 activates, and how Wnt4 inhibits the canonical Wnt signalling
pathway. In addition to test the potential importance of Wnt4 in diabetes, we will measure the
expression of Wnt4 mRNA in human islet samples from controls and patients with diabetes.
This work will generate unique information about the role of Wnt4 in beta-cells. The data will
give an important insight into the molecular mechanisms by which Wnt4 is able to inhibit
beta-cell growth and insulin secretion. This should uncover new mechanisms important in
regulating beta-cell mass and function, which is an important step towards the development
of new drugs for diabetes treatment.
References:
Welters, H.J., and Kulkarni, R.N. 2008. Wnt signaling: relevance to beta-cell biology and
diabetes. Trends Endocrinol Metab 19:349-355.
Butler, A.E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R.A., and Butler, P.C. 2003.
Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes
52:102-110.
Heller, C., M.C. Kuhn, B. Mulders-Opgenoorth, M. Schott, H.S. Willenberg, W.A.
Scherbaum, and S. Schinner, Exendin-4 upregulates the expression of Wnt-4, a novel
regulator of pancreatic beta-cell proliferation. Am J Physiol Endocrinol Metab, 2011. 301(5):
p. E864-72.
For further information please contact Dr Welters (h.j.welters@exeter.ac.uk)
31
WHATMORE/GUTOWSKI
The role of platelets in lung tumour cell metastasis to the brain
Supervisors: Dr Jacqueline Whatmore and Dr Nicholas Gutowski
Lung tumour metastasis to the brain is a major clinical problem1. Primary lung tumours
frequently metastasise to the brain via the blood stream. This process involves growth of a
local tumour into a mass that invades blood vessels in the lung, dispersal though the
circulation, arrest of circulating tumour cells in the blood vessels in the brain and finally entry
into brain tissue and secondary tumour growth. We are particularly interested in the process
by which lung tumour cells survive in the blood stream and how they arrest in small blood
vessels in the brain. Indeed, circulating tumour cells are subjected to both destructive
haemodynamic forces generated by the blood flow and the defences of the innate immune
system. There is evidence to suggest that circulating tumour cells form aggregates with
blood platelets and white blood cells that not only shield them from these insults, but also
help attachment of the tumour cells to the blood vessels walls of their target organs by acting
as linkers between the tumour cells and the cells lining the blood vessels i.e. endothelial
cells2. This project will build on our existing programme of work and examine how factors
secreted from lung tumour cells influence platelet activation and tumour cell/platelet
interactions with each other and brain endothelial cells.
For further information about this project please contact Dr Jacqueline Whatmore
(J.L.Whatmore@exeter.ac.uk)
1. Gutowski N. (2007) Neurological problems in cancer. Clin Med. 7:159-64
2. Stegner D, Dütting S, Nieswandt B. (2014) Mechanistic explanation for platelet
contribution to cancer metastasis. Thromb Res. 133:S149-57.
32
WHITEMAN/WHATMORE/WOOD
Hydrogen sulfide and diabetic microvascular complications
Supervisors: 1Matt Whiteman, 1Jacqueline L. Whatmore, 2Mark E. Wood
1
University of Exeter Medical School, 2Biosciences, College of Life and Environmental
Sciences
Hydrogen sulfide (H2S) is rapidly emerging as an important mediator in diverse physiological
and pathophysiological settings [1] including the regulation of vascular tone, suggesting H2S
may be a novel endothelium dependent hyperpolarising factor (EDHF) [2]. We (and others)
have previously shown that there are decreased levels of H2S in the vasculature in obesity
and diabetes, and that lower plasma H2S levels were associated with impaired glycaemic
control, insulin sensitivity, adiposity, blood pressure and impaired microvascular function in
vivo [3]. These studies strongly suggest that strategies that increase H2S bioavailability may
be useful pharmacological tools to prevent or treat the vascular complications associated
with obesity and diabetes (e.g. hypertension, retinopathy, nephropathy etc.). This project will
investigate the effects of novel slow release and mitochondria-targeted H2S donor molecules
on vascular signalling using (i) human microvascular endothelial cells and (ii) pressure
myography of human microvessels. The project will also investigate how H2S dilates human
microvessels in health and in the pro-diabetic environment. You will work closely with the
Exeter National Institute for Health Research Clinical Research Facility to consent volunteers
for this study (cells and microvessels). As part of the European Network on Gasotransmitters
(http://www.gasotransmitters.eu), you will be expected to engage in network meetings and
study visits to relevant partner laboratories in Europe. There will also be opportunities to
learn basic synthetic organic chemistry and contribute to the Intellectual Property protection
process associated with novel H2S modulators where appropriate. You will join a rapidly
expanding research group examining H2S and diabetes in Exeter which has recently
attracted major funding and published in this area [4].
1. Whiteman et al., Emerging role of hydrogen sulfide in health and disease: critical appraisal
of biomarkers and pharmacological tools. Clin Sci (Lond). 2011;121(11):459-88.(open
access)
2. Mustafa et al., Hydrogen sulfide as endothelium-derived hyperpolarizing factor
sulfhydrates potassium channels. Circ Res. 2011;109(11)1259-68.
3. Whiteman et al., Adiposity is a major determinant of plasma levels of the novel vasodilator
hydrogen sulphide. Diabetologia. 2010;53(8):1722-6.
4. Sophie Le Trionnaire, Alexis Perry, Bartosz Szczesny, Csaba Szabo, Paul G. Winyard,
Jacqueline L. Whatmore, Mark E. Wood and Matthew Whiteman. The synthesis and
functional evaluation of a mitochondria-targeted hydrogen sulfide donor, (10-oxo-10-(4-(3thioxo-3H-1,2-dithiol-5-yl)phenoxy)decyl)triphenyl phosphonium bromide (AP39). Med
Chem. Commun., 2014;5:728-736
For further information about this project please contact Prof. Matt Whiteman
(m.whiteman@exeter.ac.uk; www.researcherid.com/rid/C-6079-2009
33
WINYARD/SMERDON/CURNOW
Can the efficacy of photodynamic skin cancer therapy be improved by increasing the
oxygen concentration in treated cells?
University of Exeter Medical School, proposal for a match-funded PhD project
Paul Winyard, Gary Smerdon* and Alison Curnow, University of Exeter Medical School,
Exeter and Tremough, UK and *Diving Diseases Research Centre, Plymouth, UK
Protoporphyrin IX (PPIX)-based photodynamic therapy (PDT) is a sophisticated and highly
selective way to ablate tissue, and is clinically used for treating non-melanoma skin cancers.
PPIX-based PDT involves three components: pro-drug(s) aminolaevulinic acid/or
methylaminolaevulinate (ALA/MAL, which are converted intracellularly to the natural
photosensitiser PPIX), light and – importantly – oxygen. The combination of these
components leads to the production of reactive oxygen species (ROS) which kill the targeted
cancer cells. To further improve the efficacy, we propose to combine the use of PDT with
hyperbaric oxygen therapy (HBO) which increases skin tissue O2 concentrations. The
proposed PhD project will test in vitro whether this could be a feasible approach, using
cultured cells (normal human skin keratinocytes and squamous cell carcinoma cells) which
have been exposed to different concentrations of O2 for varying periods of time prior to
photodynamic irradiation. Cell death (apoptosis and necrosis) will be measured by flow
cytometry and confocal microsocopy. PPIX accumulation will be measured by
spectrofluorometry. ROS will be detected using fluorescence-based probes and by electron
paramagnetic resonance spectrometry (EPR) in conjunction with spin trapping. Gene
expression will be determined at the mRNA level (qRT PCR) and the protein level (Western
blotting). The effects of inhibitors of various antioxidant enzymes (e.g. thioredoxin-1, SOD-2,
etc) will be tested. The study will build on on-going and published work from the group, part
of a collaboration with the Diving Diseases Research Centre (DDRC). The DDRC has
agreed to provide 50:50 matched funding of the studentship.
References:
Curnow A, Dogra Y, Winyard PG, Campbell S. Using iron chelating agents to enhance
dermatological PDT. Proceedings of SPIE 7380, 738026. Published online: June 29, 2009.
DOI: 10.1117/12.822239.
Kendall AC, Whatmore JL, Harries LW, Winyard PG, Smerdon GR, Eggleton P. Changes in
inflammatory gene expression induced by hyperbaric oxygen treatment in human endothelial
cells under chronic wound conditions. Experimental Cell Research, 2012; 318: 207-16.
Tyrrell J, Thorn C, Shore AC, Campbell S, Curnow A. Oxygen saturation and perfusion
changes during dermatological methyl-aminolevulinate photodynamic therapy. Br J
Dermatol, 2011; 165: 1323-31.
For further information please contact Professor Winyard (P.G.Winyard@exeter.ac.uk)
34