MENZIES CENTRE FOR POPULATION HEALTH RESEARCH



PhD Project Opportunities at the Menzies Research Institute Tasmania, University of Tasmania

Research at the Menzies Research Institute Tasmania (Menzies) is organised around five themes that focus on the major diseases affecting the Tasmanian community. A number of PhD project opportunities are available in each theme, as summarised below. More detail for each project is provided on subsequent pages.

More information on Menzies and the five research Themes is available on-line at menzies.utas.edu.au

Public Health & Primary Care

Our public health and primary care research team seeks to better prevent and manage important population health problems. Projects address a broad range of conditions including cardiovascular disease, type-2 diabetes, cancer, multiple sclerosis and depression. Several projects are investigating how lifestyle factors (e.g. smoking, physical activity, diet, alcohol consumption and sun exposure), obesity and hormones in childhood and early adulthood affect the risk of developing disease later in life. Research in the public health area includes epidemiology, behavioural science, environmental health, biostatistics and health economics.

Established partnerships with the Tasmanian State Government and management of the Tasmanian Cancer Registry and Tasmanian Data Linkage Unit ensure a focus on applied research.

Current projects available in this theme include:

• ADVENT (Anxiety Depression & heart rate Variability in cardiac patients: Evaluating the impact of Negative emotions on functioning after Twenty four-months) (Dr Kristy Sanderson)

• Alcohol consumption from childhood to adulthood and its associations with health status (Professor Alison Venn and others)

• Assessment of goodness-of-fit of binary and multinomial regression models (Associate Professor Leigh Blizzard)

• Australia-wide analysis of the risks and costs of bicycle accidents (Professor Andrew Palmer)

• Childhood origins of depressive and anxiety disorders (Professor Alison Venn and others)

• Chronic disease benchmarking in Tasmania (Associate Professor Leigh Blizzard)

• Clinical and genetic factors that influence the onset and progression of MS (Professor Bruce Taylor)

• Depression in the workplace (Dr Kristy Sanderson)

• Development of a digitised screening tool for the prediction of cardiovascular disease risk (Dr Costan Magnussen and Dr Russell Thomson)

• Diet quality, metabolomics and cardio-metabolic risk (Professor Alison Venn and others)

• Epidemiology of Multiple Sclerosis. Several projects available, including identifying modifiable factors of the conversion to MS and MS progression (Dr Ingrid van der Mei and Professor Bruce Taylor)

• Genetics of vitamin D (Dr Ingrid van der Mei)

• Long-term reproductive health outcomes in tall girls treated with high-dose estrogen to reduce their adult height (Professor Alison Venn)

• Modifiers of cardio-metabolic risk in the overweight and obese (Professor Alison Venn and others)

• Patterns of sedentary behaviour and cardio-metabolic risk (Professor Alison Venn and others)

• Predictors and consequences of pre-hypertension and pre-diabetes in young adults (Professor Alison Venn and others)

• The genetic and environmental factors that affect conversion to and progression in MS (Professor Bruce Taylor)

• The impact of job losses on the physical and mental health of Tasmanians (Dr Kristy Sanderson)

• Vitamin D research that builds the evidence-base for new sun exposure recommendations in Australia (Dr Ingrid van der Mei)

Neurodegenerative Disease/Brain Injury

Using cutting-edge tools, our neuroscientists aim to understand the mechanisms underlying the brain's response to trauma (e.g. road accidents and falls) and diseases such as dementia including Alzheimer's disease, multiple sclerosis, Parkinson's disease and motor neuron disease. This research will assist in the development of new ways to diagnose, prevent or treat these devastating disorders that affect hundreds of thousands of Australians each year.

Current projects available in this theme include:

• Can the brain’s endogenous progenitor/stem cells make new cells for brain repair? (Dr Kaylene Young)

• Do primary cilia play a central role in regulating neural progenitor cell behaviour and function in the adult brain? (Dr Kaylene Young)

• How do oligodendroglial cells replenish their ER calcium stores? (Dr Kaylene Young)

• New oligodendrocytes are added to the adult central nervous system – what is their function? (Dr Kaylene Young)

Cardio-metabolic Health & Diseases

The primary aim of the cardiometabolic group is to reduce the burden of cardiovascular and metabolic disease on our community.

The group uses interventions targeted at identifying and preventing the development of obesity, insulin resistance, type-2 diabetes, hypertension and heart disease. Particular areas of interest include blood pressure assessment, assessment of large and small blood vessels functioning and cardiac imaging in heart disease.

The team use a broad set of research techniques from laboratory models, clinical and population health studies and clinical interventions to discover new ways to prevent the progression of cardio-metabolic disease.

Current projects available in this theme include:

• Development and application of a prediction model for readmission to hospital with heart failure (Professor Tom Marwick)

• Impaired adipose tissue blood flow in obesity and the development of hypoxia (Dr Steve Richards, Dr Michelle Keske and Professor Stephen Rattigan)

• Incorporation of right ventricular evaluation in decision-making regarding pulmonary hypertension (Professor Tom Marwick)

• Microvascular blood flow and metabolic regulation in skeletal muscle (Professor Stephen Rattigan)

• Prevention of heart failure based on screening and treatment of subclinical LV dysfunction (Professor Tom Marwick)

• Quality control in cardiovascular imaging interpretation (Professor Tom Marwick)

• Strategies for prevention of cardiotoxicity from cancer therapies (Professor Tom Marwick)

Musculoskeletal Health & Diseases

Research in the musculoskeletal theme optimises Tasmania's unique population characteristics to investigate musculoskeletal disease, with a particular emphasis on osteoarthritis, osteoporosis and ankylosing spondylitis. Epidemiological research into musculoskeletal disease helps us understand the impact of arthritis and other musculoskeletal conditions on both the individual and the community, so the best medical care can be developed and delivered where it is needed. Volunteer participant-based clinical trials are a key feature of this area.

Current projects available in this theme include:

• Vitamin D effects on osteoarthritis (VIDEO) study (Associate Professor Changhai Ding)

Cancer, Genetics & Immunology

Research conducted within this Theme aims to elucidate the underlying genetic and epigenetic changes that underpin complex diseases such as cancer; and secondly to understand the immune response during manifestation of these diseases. At present the group is studying genetic susceptibility to prostate cancer and blood cancers, such as leukaemia. In addition, the team is looking at the immune response in the context of cancer including the Tasmanian devil facial tumour disease, infectious diseases and autoimmune diseases with a particular interest in lupus and multiple sclerosis.

Currently available projects in this theme include:

Immunology

• Comprehensive analysis of Vitamin D receptor expression in immune cells and of its role in autoimmunity (Collaboration with Professor Bruce Taylor and Associate Professor Helmut Butzkoeven) (Professor Heinrich Korner)

• Role of TNF in the regulation of the adaptive T cell response in Leishmaniasis (Professor Heinrich Korner)

• The chemokine CCL20 and its cognate receptor CCR6 in T-B cell collaboration and germinal centre response: Relevance for human autoimmunity? (Professor Heinrich Korner)

Genetic and Epigenetic drivers of complex disease (includes statistical genetics)

There are current projects available in this area. Please contact Associate Professor Jo Dickinson, Theme Leader, to discuss any future opportunities – jo.dickinson@utas.edu.au

Devil Facial Tumour Disease (DFTD)

• Identification and characterisation of DFTD tumour-associated antigens using proteomics (Professor Greg Woods)

Supervisor: Associate Professor Leigh Blizzard (2 projects)

Research Theme: Public Health & Primary Care

Research Area: Biostatistics and Biostatistics/Epidemiology

Email: Leigh.Blizzard@utas.edu.au Phone: +61 (0)3 6226 7719

The primary role of the biostatisticians is to provide statistical advice and support to other researchers at the Institute. In consequence they are involved in a wide range of research collaborations that span each of the five Research Themes.

Research Interests:

In statistical research, Associate Professor Blizzard has contributed to developments in log-link modelling of binary, multinomial and ordinal outcomes of follow-up and cross-sectional studies. Recently he has established a statistical research program in assessment of goodness-of-fit of log-link models in collaboration with Professor David Hosmer, a noted international authority. The significance of this research has been recognised with a NHMRC Project Grant, a Population Health Career Development Award and a Population Health Career Development Fellowship. Associate Professor Blizzard also has expertise in population survey methodology with multiple tested statistical software developments and applications for analysis of population surveys.

Student Background:

The student would be mostly suitable for this project if she/he has a background of clinical medicine.

Projects:

There are projects currently available in this area. Some of them include:

• Assessment of goodness-of-fit of binary and multinomial regression models. The proposed research builds on an established research program in a continuing collaboration with a noted international authority in the field to extend summary measures of goodness-of-fit developed for logistic regression models to binary and multinomial log-link models. Future work is to develop summary measures for models with other links and/or error distributions, and to develop statistical approaches and testing strategies to detect lack of fit at the level of individual observations.

• Chronic disease benchmarking in Tasmania. The first phase of the proposed work involves the use of hospital separation and clinical costing data to estimate, and monitor trends in, the prevalence of hospital-treated chronic disease (HTCD) in Tasmania. The second phase involves estimation of within-hospital resource use by HTCD patients with an eventual goal of determining levels and costs of avoidable hospitalisations and complications and developing methodology to monitor trends and evaluate interventions.

Supervisor: Associate Professor Changhai Ding

Research Theme: Musculoskeletal Health & Diseases

Research Area: Musculoskeletal Epidemiology

Email: Changhai.ding@utas.edu.au Phone: +61 (0)3 6226 7730

Associate Professor Ding has published over 100 manuscripts in international peer-reviewed journals with an h index of 26. He has received > 10 awards including "Future Fellowship" by Australian Research Council (ARC) and "Career Development Award" by National Health & Medical Research Council (NHMRC).

Research Interests:

Associate Professor Ding's research interests centre around the epidemiological and clinical investigation of osteoarthritis using modern techniques such as magnetic resonance imaging. He is looking at the metabolic and inflammatory mechanisms of osteoarthritis and osteoporosis, and is interested in evaluating new therapies on osteoarthritis and other inflammatory diseases. Currently, he is undertaking a clinical trial to determine if vitamin D supplementation can slow disease progression of knee osteoarthritis.

Student Background:

The student would be mostly suitable for this project if she/he has a background of clinical medicine.

Project 1: Vitamin D Effects on Osteoarthritis (VIDEO) study

VIDEO study is a randomised, placebo-controlled double-blind clinical trial investigating whether correcting vitamin D deficiency using vitamin D supplements will slow loss of cartilage and thus worsening of knee osteoarthritis. 400 patients have been, or will be, randomly allocated to vitamin D supplementation (50,000 IU monthly) or placebo for 2 years, with the major outcome being cartilage loss between these two groups. Other knee structural changes including tibial bone area, bone marrow lesions and meniscal pathology (assessed by MRI), and lower limb muscle strength at baseline and 2 years later will also be determined as outcome measures. This study has been supported by the National Health and Medical Research Council (NHMRC).

Supervisor: Professor Heinrich Korner

Research Theme: Cancer, Genetics & Immunology

Research Area: Immunology

Email: heinrich.korner@utas.edu.au Phone: +61 (0)3 6226 4698

Research Interests:

Professor Korner is a New Star Professor at the Menzies Research Institute Tasmania. His researched is focused on Cellular Immunology and Infection Immunology.

Student Background:

These research projects are most likely to be successfully completed by candidates with a life sciences background.

Project 1: Role of TNF in the regulation of the adaptive T cell response in Leishmaniasis

Leishmaniasis is a significant tropical and subtropical disease caused by protozoan parasites of the genus Leishmania. The clinical spectrum of leishmaniasis ranges from relatively benign skin lesions to terribly disfiguring mucosal lesions and, finally, to systemic visceral disease, which is fatal if left untreated In experimental cutaneous leishmaniasis, the infection of C57BL/6 (B6.WT) mice with Leishmania (L.) major causes a cutaneous lesion while an infection of the BALB/c strain causes progressive systemic disease. Due to this genetic dichotomy experimental leishmaniasis is a classic model used to explore the adaptive immune response to pathogens. While much has been learned using this model of adaptive immune responses there is still no vaccine for any major parasitic disease in general and leishmaniasis in particular. We have an immune system that seems to respond to a parasitic infection with a limited protective response and accepts a low level presence of parasitic pathogens due to an array of immune evasive mechanisms, which allows the pathogens, for example, to survive inside a phagolysosome. However, it is also in the interest of the host to curtail the immune response to these challenges, because a strong immune response that would extinguish the pathogens could lead to immunopathology and extensive damage to the host. As a consequence, there is no sterile cure in parasitic infections such as leishmaniasis, but instead we see relatively benign infections and long-lasting persistence, which is controlled by the immune system but harbours the possibility of reactivation. A cytokine that is involved in this immune control is TNF. In TNF-negative mice, which succumb rapidly to leishmaniasis, we find the scenario that at a crucial point in the immune response T cell activation increases and effector T cell populations start to enlarge. Interestingly, the population of regulatory T cells (Treg) is overrepresented at the late stage of disease. We propose to use these highly susceptible mice to further investigate the T cell response in the absence of TNF, investigate the potential to initiate protection and analyse the impact of the enlarged Treg population on the protective immune response.

Hypothesis

TNF influences the adaptive immune response by controlling numbers of Tregs and effector T cells and facilitating a protective but not overreaching anti-parasitic immune response.

Aims

1: To analyze the role of TNF in a) T cell activation, b) the generation of effector T cells and Tregs and c) the maintenance of the suppressive function of Tregs during infection with high- and low-virulent L. major strains using TNF, TNFR1 and 2-deficient mice.

2: To follow the individual fate of single antigen-specific T cells and Tregs in L. major infected mice using transgenic L. major variants for infection.

3: To analyze the potential of low-virulent L. major strains to induce a protective response.

4: To analyze the role of Tregs cells in L. major-infected B6.TNF-/- mice using a genetic model of Treg depletion and IL-10 blockade.

Project 2: The chemokine CCL20 and its cognate receptor CCR6 in T-B cell collaboration and germinal centre response: Relevance for human autoimmunity?

Background: The CC-chemokine receptor 6 (CCR6) is expressed constitutively on naïve B cells at an intermediate level and is strongly upregulated on pre-germinal centre (GC) B cells after activation. The CIAs laboratory investigated the potential role of CCR6 in B cell differentiation in vivo. We showed that B cells of CCR6-deficient mice displayed a significant acceleration in the GC response after immunization accompanied by an increase in the number of GC and, subsequently, in IgG antibodies with low-affinity to NP-KLH. The phenotype was associated with an up-regulation in the number of follicular T helper cells (TFH) and could also be observed using other immunogens such as sheep red blood cells. This phenotype as consequence of a chemokine receptor deficiency represents intriguing correlations to described autoimmune phenotypes as an increase of GC numbers and increased numbers of TFH have been described in the murine B cell associated autoimmune disease models for Systemic Lupus Erythematosus (SLE), sanroque (Roquinsan/san) and generalized lympho-proliferative disease (gld). In humans, increased numbers of GC and increased TFH in the blood are characteristic for SLE patients.

Hypotheses

A) CCR6 and its ligand CCL20 facilitate an exclusion of potential GC B cells from entering follicles. B) Failure of this CCR6-mediated selection results in abundant but low quality GC response.

Aims

1: To establish an adoptive transfer mouse model to dissect the kinetics of intracellular and surface expression of CCR6 and CCL20 on mouse B and TFH cells and analyse the location of CCR6+ and CCL20+ B and TFH cells.

2: To investigate the function of CCR6 and CCL20 in the formation of cognate T -B conjugates and analyse gene expression in those cells and cell conjugates

3: To dissect the contribution of CCR6 and CCL20 to antibody class switch and somatic hypermutation.

4: To analyse the balance of cell death and proliferation in the GC in the absence of CCR6.

Project 3: Comprehensive analysis of Vitamin D receptor expression in immune cells and of its role in autoimmunity (Collaboration with Professor Bruce Taylor and Associate Professor Helmut Butzkoeven)

Vitamin D receptor (VDR) is a cytoplasmic receptor for its ligand 1,25-dihydroxyvitamin D (1,2,5(OH)2D3), which is metabolized from a precursor, 25-hydroxyvitamin D (2,5(OH)D3). VDR has been shown to be involved in the modulation of the gene expression of hundreds of genes including immunologically relevant genes. While the precursor can be supplemented by the appropriate diet the major source of biologically active vitamin D is still the synthesis in the skin driven by sunlight. In higher latitudes of the planet a seasonal deficiency of vitamin D is therefore not unusual. This deficiency has been associated with the occurrence and the relapse frequency of Multiples Sclerosis (MS) and with general seasonal immunodeficiency. Despite the important role of VDR a comprehensive analysis of its expression level and its immunological role in human blood leukocytes is missing.

Hypothesis

The hypothesis to be tested in this project is that the level of VDR expression and its interaction with bioactive vitamin D in leukocytes is correlated with the occurrence of MS.

Aims

1. Analysis of VDR expression and immune-modulatory activity in blood leukocytes of controls and MS patients using flow cytometry and bioassays.

2. Generation of mixed bone marrow mouse chimeras using different precursor cells from VDR deficient mice and wildtype mice and analysis of these chimeras in the mouse model of MS, Experimental Autoimmune Encephalomyelitis.

Supervisors: Dr Costan Magnussen and Dr Russell Thomson

Research Theme: Public Health & Primary Care

Research Area: Cardiovascular epidemiology

Email: cmagnuss@utas.edu.au Phone: +61 (0)3 6226 7762

Email: russell.thomson@utas.edu.au Phone: +61 (0)3 6226 4611

Dr Magnussen is a NHMRC Early Career Research Fellow at the Menzies Research Institute Tasmania (MRIT) and Adjunct Professor of cardiovascular epidemiology at the University of Turku, Finland. He has published in excess of 45 papers in the last five years, many in leading international journals including 11 publications in journals with impact factors >10.

Dr Thomson is a Postdoctoral Research Fellow at the MRIT and the Institute for Marine and Antarctic Studies at the University of Tasmania. He has published in excess of 41 papers, many in leading international journals including 7 publications in journals with impact factors >10.

Research Interests:

Dr Magnussen’s key research interests have focused on the paediatric origin of adult cardiometabolic disease.

Dr Thomson key research interests include the implementation of classification and regression trees for the purposes of risk prediction.

Student Background:

Outstanding candidates would normally be able to demonstrate a background in statistics, programming and health sciences.

Project: Development of a digitised screening tool for the prediction of cardiovascular disease risk.

Although the consequences of cardiovascular disease such as heart attack and stroke do not usually occur before middle age, the processes underlying these complications begin early in life. It has been thought that to achieve greater reduction in cardiovascular disease events, primordial and primary prevention of the risk factors that predispose to the disease need to be implemented much earlier in life, even in childhood. Therefore, the challenge is to develop innovative tools that allow screening of children to identify those at risk of developing the disease in the future who would benefit most from primordial or primary prevention.

The successful candidate will have the opportunity to use data from a major international collaboration, the International Childhood Cardiovascular Cohort (i3C) Consortium (), to: 1) use regression trees to build models that examine the effects of multiple childhood risk factors on cardio-metabolic outcomes in adulthood; 2) predict the risk of cardio-metabolic outcomes for any child, given their risk factors; and 3) develop a digitised screening tool (app) that can be applied in the preventive health care setting.

Data from the i3C consortium have been published in many high-ranking international journals, including the New England Journal of Medicine and the top ranked cardiovascular journals worldwide, Circulation and the Journal of the American College of Cardiology. Therefore, the successful candidate will have the opportunity to use a unique dataset and examine clinically relevant questions with supervision from researchers with a strong track record of publishing in high-impact journals.

References:

Dwyer T, Sun C, Magnussen CG, Raitakari OT, Schork NJ, Venn A, Burns TL, Juonala M, Steinberger J, Sinaiko AR, Prineas RJ, Davis PH, Woo JG, Morrison JA, Daniels SR, Chen W, Srinivasan SR, Viikari JS, Berenson GS. (2012) Cohort Profile: The International Childhood Cardiovascular Cohort (i3C) Consortium. International Journal of Epidemiology. [Epub ahead of print]

Juonala M, Magnussen CG, Venn A, Dwyer T, Burns TL, Davis PH, Chen W, Srinivasan SR, Daniels SR, Kähönen M, Laitinen T, Taittonen L, Berenson GS, Viikari JSA, Raitakari OT.
 (2010) The influence of age on associations between childhood risk factors and carotid intima-media thickness in adulthood. The Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium. Circulation.

Touw, W.G., Bayjanov, J.R., Overmars, L., Backus, L., Boekhorst, J., Wels, M. & van Hijum, S.A.F.T. (2012) Data mining in the Life Sciences with Random Forest: a walk in the park or lost in the jungle? Briefings in Bioinformatics.

Supervisor: Professor Thomas H Marwick MBBS (Hons), PhD, MPH

Research Theme: Cardio-metabolic Health & Diseases

Research Area: Cardiovascular imaging, clinical effectiveness

Email: Tom.Marwick@utas.edu.au Phone: +61 (0)3 6226 7703

Professor Marwick is Director of Menzies Research Institute Tasmania and also works as a Cardiologist at Royal Hobart Hospital. Over the last 25 years, he has published extensively and supervised over 20 postgraduate research students and many clinical trainees in cardiology and cardiovascular imaging.

Research Interests:

Professor Marwick's research interests involve the use of cardiovascular imaging (mainly echocardiography but also magnetic resonance and CT) to better understand the pathogenesis of disease and especially to inform clinical decision-making. Although based strongly in clinical physiology, his current studies are linked with population health and include components of outcomes research and cost-effectiveness. He collaborates widely across specialties and geographically across Australia, North America, Europe and Asia.

Student Background:

These research projects are most likely to be successfully completed by candidates with a clinical background (eg. medicine, health services research, sonography/radiography, nursing, psychology).

Project 1: Development and application of a prediction model for readmission to hospital with heart failure

Acute heart failure (HF) is related to ~100,000 admissions/y and $1 billion spending in Australia. It accounts for ~1% of all hospital separations in Australia, and ~10% of those due to circulatory disease, a frequency of 1.6-2.0 per 1000 population. Readmissions to hospital after HF are frequent. In Tasmania, preliminary data from the Clinical Informatics & Business Intelligence Unit of the Dept of Health and Human Services (DHHS) show 1945 admissions since FY 2008, i.e. about 500 index admissions per year with HF as the primary diagnosis. The 30 day readmission rate for repeat HF (or related) is 25% but ranges geographically and is 36% at Royal Hobart Hospital (RHH, likely related to complexity). There are similar numbers of non-HF admissions. These findings are analogous to readmission rates of 30% within 2 months in the USA and UK. Based on yearly readmission costs of US$17.4 billion in the US, the Center for Medicare and Medicaid Services (CMS) has advocated using 30 day mortality and readmission as one method of measuring overall quality of hospital based care for heart failure.

This work seeks to reduce heart failure (HF) admissions and costs by;

i) Evaluating current performance in HF readmission, and use data linkage to identify sites where community-based service delivery would offer most benefit to reduce HF readmission

ii) Developing a risk algorithm for HF readmission, including psychosocial determinants.

iii) Combining the knowledge derived from data linkage and the risk algorithm to devise a new means of providing a HF disease-management program (DMP), calibrated to risk assessment, and performing a clinical trial to define the merits of this approach.

iv) An evaluation of cost-effectiveness of this intervention.

v) Presentation of educational activities to community-based providers.

Project 2: Strategies for prevention of cardiotoxicity from cancer therapies

As cancer therapies and survival have improved, millions of patients treated with cardiotoxic therapy are now cancer survivors. Prolongation of survival resulting from cancer treatment allows patients to live long enough for cardiac toxicity to become the main determinant of quality of life, and in some cases premature mortality – in fact, for early stage breast cancer, a patient is more likely to die from heart disease than cancer. Preliminary (unpublished) work from the SEER-Medicare database in the USA showed a cancer cohort treated from 2002-7 to have a 5 year incidence of heart failure of 18%.

This study seeks to show that information from cardiac imaging surveillance leads to the use of adjunctive cardioprotective therapy that will limit the development of reduced ejection fraction (EF) at 1 year post chemotherapy (primary outcome), and interruptions to planned chemotherapy and the development of heart failure in follow-up (secondary outcomes). The primary hypothesis is that the use of cardioprotective agents, administered in response to subclinical left ventricular (LV) dysfunction detected on surveillance imaging, prevents the progression to reduction of LVEF or overt heart failure.

Project 3: Prevention of heart failure based on screening and treatment of subclinical LV dysfunction

Despite major advances, the outlook for advanced heart failure (HF) remains dire. In the hope that early recognition and treatment may prevent the progression of disease, two early stages have been defined. Stage A heart failure is characterized by patients having risk factors for HF including hypertension, type 2 diabetes mellitus (T2DM), the metabolic syndrome (MS), family history of HF or atherosclerotic disease, whereas stage B heart failure is identified when patients have evidence of actual heart disease. The distinction of stages A and B is very significant, because their therapeutic implications are quite different. The management of stage A relates mainly to the control of hypertension and underlying risk factors, with specific therapy (angiotensin converting enzyme inhibitors [ACEi] or angiotensin receptor blockers [ARB]) limited to patients in whom these agents are indicated on the basis of T2DM or vascular disease. Based on evidence gathered in patients with asymptomatic LV dysfunction, ACEi or ARB and beta blockers are indicated in all stage B patients, in the belief that HF risk will be decreased by 20-30%. The goal of this study is to define the benefit of a surveillance program to identify stage B HF in “at risk” patients with stage A HF, by showing that medical therapy for Stage B patients found in this way reduces their subsequent presentations with HF.

The primary objective of this work is to show that information from a screening program for LV dysfunction in at-risk patients combined with cardioprotective therapy based on screening will limit the development of heart failure (HF) after a minimum of 2 years. The secondary objectives are to document a treatment benefit with respect to exercise capacity, symptom status and resource utilization. We will seek to achieve this by a randomised controlled trial in at-risk patients. Realisation of this objective would provide evidence for changes in clinical guidelines to include both a screening program as well as justify pharmacological intervention in patients with abnormal screening tests.

Project 4: Quality control in cardiovascular imaging interpretation

Continuous quality assessment and implementation of methods to improve interpretation of imaging studies is an important responsibility of all imaging laboratories. However, the literature on methods to assess and/or improve IOV and accuracy of visual EF quantification is limited. Using topics such as aortic regurgitation, RV and LV function, we have previously developed a process of quality exercises, based on group-based case reviews along with cross-modality comparisons. To date, this has been done mainly on a single-centre basis.

However, there remain several problems. Provision of a lengthy structured educational session may be organizationally challenging at many institutions, and providing an intervention uniformly to all members of a laboratory can be difficult. We are therefore seeking methods to deliver this process over the internet. We also week to identify a subgroup of individuals who may benefit the most from the intervention.

Supervisor: Professor Andrew Palmer

Research Theme: Pubic Health & Primary Care

Research Area: Health Economics, Epidemiology

Email: andrew.palmer@utas.edu.au Phone: +61 (0)3 6226 7729

Professor Palmer is the Head of Health Economics at the Menzies Research Institute Tasmania. Professor Palmer has extensive experience in the area of health economics and outcomes research, and is a widely published, well-known and respected health economist.

Research Interests:

Professor Palmer has conducted research and published extensively in the area of health economics and the modeling of diseases including diabetes, nephropathy, osteoporosis, alcoholism, growth hormone deficiency, rheumatoid arthritis, cardiovascular disease, end-stage renal failure and oncology.

Student Background:

This project will be most suited to a candidate with health economics and /or epidemiological background.

Project 1: Australia-wide analysis of the risks and costs of bicycle accidents

Tasmanians are exposed to dangerous and potentially fatal cycling conditions on a daily basis as they commute by bicycle or cycle for health. There is frequent public debate on the hazards of cycling on Tasmanian roads, as evidenced by a recent Australian Associated Motor Insurers Limited (AAMI) survey and the wave of responses published in the Mercury newspaper in February 2010. Dangerous traffic was cited as a major deterrent to cycling. Furthermore, the large majority of vehicle drivers reported seeing cyclists as a nuisance. This is a potentially fatal cocktail of attitudes that deter the use of bicycles as a form of commuting or exercise for health improvement.

Local and state governments are under increasing pressure to provide adequate and safe infrastructure to improve the safety and acceptability of cycling in Australia.  Public health and environmental research encourages cycling as both a health-giving activity and a means of reducing the state’s dependence on the car as a means of transport, in an era dominated by concerns about carbon emissions, global warming and peak oil.

This study will lend support to creating the necessary infrastructure that is required to provide health benefits to the community.

Professor Andrew Palmer has over 18 years’ experience in the area of health economics and outcomes research, and is a widely published, well-known and respected health economist. He recently published an analysis of the costs of all cycling accident (and other) claims under the Motor Accident Insurance Board (MAIB) scheme from 1991 until 2010 in an international peer-reviewed journal. Andrew is currently supervising a pilot study to measure the risk and associated economic burden of bicycle accidents in Tasmania. An accurate assessment of accident rates and associated costs is needed to inform discussions with local and state government in order to improve cycling infrastructure and the safety of both cyclists and motorists. Current cycling infrastructure in Tasmania is far behind that of other cities in states. Tasmania currently has 2.2km of cycling network for every 100km of road network. This is just over a third of the second lowest-ranked area Perth (6.6km).

The ultimate outcome of this research will be improved safety conditions for cyclists and a reduced economic burden in Australia.

As a pilot study, the information gained has formed the basis for further state and national studies to advance and promote the body of knowledge of cycling risks and benefits.

Moreover, an understanding of the scope of the healthcare burden to Australia, represented by cycling accidents, is vital in order to identify potential cost-offsets that may occur through reduced costs of cycling accident injuries from improvement in safety measures and infrastructure. The proposed research project builds on a pilot Tasmanian-based project initiated by Professor Palmer. It will provide the first insights into Australian cycling habits, accident rates and costs of cycling accidents Australia-wide, will allow comparisons between states and territories, and will shed light on the balance between the health benefits of cycling versus risk of accidents and their associated costs.

Supervisor: Professor Stephen Rattigan

Research Theme: Cardio-metabolic Health & Diseases

Research Area: Muscle Metabolism

Email: Stephen.Rattigan@utas.edu.au Phone: +61 (0)3 6226 2671

Professor Rattigan is Deputy Director of Menzies Research Institute Tasmania. Over the last 25 years, he has published extensively and supervised over 25 postgraduate research students.

Research Interests:

Obesity, hypertension and type 2 diabetes are major health problems for Australia and are likely to increase in the 21st century. One of the common features of these conditions is insulin resistance in skeletal muscle. Professor Rattigan's research has focussed on the factors that regulate glucose metabolism in skeletal muscle and have led to the important finding that blood flow regulation within muscle is critical to the normal responses to insulin. Impairment of normal blood flow distribution within muscle can lead to insulin resistance and it is his current hypothesis that such defects are the early events associated with obesity and hypertension that contribute to type 2 diabetes.

Student Background:

This research project is most likely to be successfully completed by candidates with a biomedical, clinical or bioengineering background with a mathematical interest (eg. physiology, biochemistry, or biophysics).

Project: Microvascular blood flow and metabolic regulation in skeletal muscle

Vasomotion and the resultant flowmotion of blood flow in tissues is a fundamental physiological phenomenon that has been poorly understood. This project combines the use of two innovative techniques of laser Doppler flowmetry and real-time contrast-enhanced ultrasound that enables determination of flowmotion, with methodology that provides information on tissue metabolism in skeletal muscle in vivo. A major aim of this project will be to gain new knowledge about how flowmotion regulates the microvascular blood flow and nutrient delivery to muscle and the control of muscle metabolism. As flowmotion is a fundamental physiological process, the outcomes will be important in a number of medical conditions, such as sarcopenia, vascular derived dementia, athletic performance, injury recovery, sepsis and critical care where blood flow and nutrient delivery are critical determinants of these pathological conditions. In particular this project will have a focus on understanding the development of insulin resistance, the underlying condition associated with obesity, hypertension and type 2 diabetes. The PhD candidate will be expected to have a strong background in physiology and mathematics and be expected to undertake studies in experimental animal models and human clinical research.

Supervisors: Dr Steve Richards, Dr Michelle Keske, Professor Stephen Rattigan

Research Theme: Cardio-metabolic Health & Diseases

Research Area: Diabetes and obesity

Email: stephen.richards@utas.edu.au Phone: +61 (0)3 6226 2673

In healthy subjects, in addition to its well-known metabolic effects in liver and muscle, insulin stimulates increased blood flow in muscle and adipose tissue, enhancing delivery of substrates and hormones to the underlying cells. Our research has established that impaired microvascular responses to insulin contribute significantly to muscle insulin resistance in type 2 diabetes. Our group has expertise in measuring metabolic responses to insulin in rats and humans and has also developed a number of techniques for simultaneous quantification of microvascular blood flow responses, including contrast-enhanced ultrasound (CEU) and 1-methylxanthine metabolism [pic](1,2). Although the relationship between microvascular blood flow and the metabolic responses to insulin in health and obesity or insulin resistance was established by the group for skeletal muscle the same may hold true for adipose tissue. This project involves application of these techniques to study adipose tissue changes in obese and insulin resistant rat models.

Research Interests:

The Muscle Diabetes Research Group has developed techniques for measuring microvascular blood flow within muscle in humans and animals. Importantly, the group (including Professor Stephen Rattigan and Dr Michelle Keske) has shown muscle blood flow to be an important determinant of the sensitivity of muscle to insulin, and that reduced blood flow responses to insulin contribute to insulin resistance, and possibly the development of type 2 diabetes. Dr Richards' research aims to determine why the microvascular actions of insulin are impaired in insulin resistant animal models, and aims to find ways of enhancing muscle blood flow responses to insulin. Two current methods for achieving this focus on (i) the role of the adipocyte-derived hormone adiponectin, and (ii) augmenting the biochemical signalling used by insulin to increase muscle microvascular blood flow, namely the nitric oxide-cyclic GMP pathway, with a view to the development of novel therapeutics.

Student Background:

This research project is most likely to be successfully completed by candidates with a biomedical, clinical or bioengineering background with a mathematical interest (eg. physiology, biochemistry, or biophysics).

Project: Impaired adipose tissue blood flow in obesity and the development of hypoxia

It is now widely recognised that the insulin resistance that precedes type 2 diabetes results from two main factors that block insulin signal transduction: (i) accumulation of fatty acid metabolites in insulin-sensitive tissues other than adipose tissue (eg liver, muscle) (3) and (ii) increased levels of circulating cytokines due to chronic, low grade inflammation, particularly in adipose tissue (4). Inflammation in adipose tissue in obesity is due to macrophage activation and recruitment, and it has recently been recognised that activation of a transcription factor, Hypoxia Inducible Factor 1αa (HIF1α) is the critical event precipitating this process [pic](5). Why hypoxia develops in adipose tissue in obesity is not altogether clear, but we hypothesise that impaired blood flow responses to insulin result in intermittent hypoxia, as a result of increased energy demands from triglyceride synthesis not being matched by a compensatory increase in oxygen supply. A corollary of the inadequate blood flow during insulin is that triglyceride synthesis may also be impaired, reducing lipid storage in adipocytes and promoting lipid accumulation in tissues such as liver and muscle. We further hypothesise that these changes (inflammatory, lipid storage) are more severe in visceral than subcutaneous adipose tissue, explaining the stronger association between insulin resistance and visceral obesity.

This project aims to:

1. Determine the effect of blood flow on metabolism and expression of proinflammatory cytokines in adipose tissue.

2. Compare the vascular actions of insulin in adipose tissue, and compare development of vascular and metabolic dysfunction, hypoxia, inflammation, adipocyte hypertrophy, and vascular rarefaction during the onset of obesity.

3. Determine whether impairment of the vascular actions of insulin contributes to increased susceptibility of visceral adipose tissue to metabolic and proinflammatory changes in obesity.

Techniques

Adipose tissue blood flow in rats will be measured by CEU and the effects of restricting blood flow by injection of microspheres on expression of HIF1a and cytokines will be assessed by semi-quantitive (real time) RT-PCR of mRNA expression and Western blotting for protein levels. The metabolic effects of impaired blood flow on insulin action will be assessed in normal and obese adipose tissue from [3H]2-deoxyglucose and [14C]triolein uptake, and from high energy phosphate levels by HPLC. Adipocyte hypertrophy and capillary rarefaction will be assessed by standard immunohistochemical techniques. All measurements will be performed simultaneously in both subcutaneous (inguinal) and visceral (epididymal) adipose tissue depots at different time points flowing introduction of animals placed to high fat diets.

References

1. Clark, M. G., Wallis, M. G., Barrett, E. J., Vincent, M. A., Richards, S. M., Clerk, L. H., and Rattigan, S. (2003) Am J Physiol Endocrinol Metab 284, E241-258

2. Rattigan, S., Bussey, C. T., Ross, R. M., and Richards, S. M. (2007) Microcirculation 14, 299-309

3. Boden, G., and Shulman, G. I. (2002) Eur J Clin Invest 32 Suppl 3, 14-23

4. Hotamisligil, G. S. (2003) Int J Obes Relat Metab Disord 27 Suppl 3, S53-55

5. Halberg, N., Khan, T., Trujillo, M. E., Wernstedt-Asterholm, I., Attie, A. D., Sherwani, S., Wang, Z. V., Landskroner-Eiger, S., Dineen, S., Magalang, U. J., Brekken, R. A., and Scherer, P. E. (2009) Mol Cell Biol 29, 4467-4483

Supervisor: Dr Kristy Sanderson

Research Themes: Public Health & Primary Care

Research Area: Psychiatric Epidemiology

Email: Kristy.Sanderson@utas.edu.au Phone: +61 (0)3 6226 4724

Research Interests:

Dr Sanderson's research focuses on quantifying and reducing the individual and economic burden of mental disorders and related chronic diseases. Her work has been recognized through selection for the National Health and Medical Research Council “Ten of the Best Research Projects 2011” and from support by an Australian Research Council Future Fellowship.

Student Background:

As outlined for each project.

Project 1: Depression in the workplace

Depression is the leading cause of disease-burden in high-income countries like Australia and is predicted to become the second cause of global burden by 2030. While there are many effective treatments available for depression, the majority of sufferers remain undetected and/or untreated. At least half of the people who experience depression and related disorders are able to continue working, thus workplaces are an important avenue to explore opportunities for reducing the high burden of these disorders.  Using a number of data sources including some funded by NHMRC our group is addressing questions such as:

• What is the current prevalence of depressive and anxiety disorders in the Australian workforce and has it changed over the past decade?

• How much productivity loss (work disability) is associated with these disorders and what does it cost? How much of this cost is borne by the employee?

• How do managers perceive the impact of these disorders on workplace performance?

• Why do these disorders seem to have such a strong association with “presenteeism” (continuing to work when sick)?

• Can continuing to work when sick actually worsen health?

• How can we better manage presenteeism and what is the role of different health and other professionals in this?

• Do these issues have a greater impact in certain occupations or industries?

This research area is growing rapidly and there are substantial opportunities to make a contribution from students with an interest/background in public health, health promotion, epidemiology, or allied health.

Project 2: ADVENT

The ADVENT (Anxiety Depression & heart rate Variability in cardiac patients: Evaluating the impact of Negative emotions on functioning after Twenty four-months) study is a prospective cohort study investigating the interplay between psychosocial and biological factors relevant to symptoms of depression and anxiety in post-MI patients at 12- and 24-months. Depression and anxiety commonly occur in patients with heart disease, particularly those who have had a heart attack. Together they represent a large burden on the healthcare system as well as individual patient’s lives. This study will help us to further understand the complex biological and psychological relationships between depression/anxiety and heart disease.

ADVENT is a NHMRC-funded project led by Monash University in collaboration with Menzies Research Institute Tasmania, University of Melbourne, and Stanford University. This project provides an opportunity to work with leading researchers in cardiology, psychiatry, public health, and epidemiology.

The PhD opportunity at Menzies focuses on the following areas:

1) Methods for screening and diagnosis of mental health disorders in post-MI populations

2) Patterns of mental health symptoms in post-MI populations

3) Association of particular patterns of mental health symptoms with employment outcomes and quality of life.

This project will be suitable for students with an interest/background in public health, epidemiology, or allied health.

Project 3: The impact of job losses on the physical and mental health of Tasmanians

This project aims to investigate in Tasmania among working age adults: i) the temporal association of job loss with hospital use and mortality; ii) the association of hospital use with job loss; iii) whether these associations differ for urban versus rural/remote areas and by prevailing economic climate. This study will use an ecological time series analysis using existing employment and health statistics for Tasmania.

In Tasmania suicide is the leading cause of death in adults up to the age of 44 years, with ischaemic heart disease the second leading cause of death from age 45 onwards. Tasmania has had significant periods of job market contraction with rural and remote areas especially hard-hit. The association between job loss and health may be because job loss contributes to illness, illness contributes to job loss, or both. How soon any health affects appear from job losses, and whether this varies by health outcome, is unknown. It is also unknown whether any health outcomes differ between rural/remote and urban communities, or whether the prevailing economic climate affects different health outcomes in different ways.

This project will be suitable for students with an interest/background in epidemiology, statistics, or allied health.

Supervisor: Professor Bruce Taylor

Research Theme: Public Health & Primary Care

Research Area: Multiple Sclerosis & Statistical Genetics

Email: bruce.taylor@utas.edu.au Phone: +61 (0)3 6226 7704

Professor Taylor's research interests centre on the environmental and genetic factors that influence the development and progression of multiple sclerosis. His previous students include Dr Ingrid van der Mei, now a highly respected researcher investigating MS and Vitamin D deficiencies in the population. Dr van der Mei advises the government on sun exposure policy. Prof Taylor’s team is composed of a strong group of postdoctoral fellows and research students. He works closely with Dr Jac Charlesworth a genetic bio informatician and is a member of the governance committee of the Australian and New Zealand MS Genetics consortium and the steering committee of the International MS genetics Consortium. Consequently we have access to a unique highly curated data set of 5,000 MS GWAS samples, and over 2,000 exome arrays. We also through collaborations as outlined have access to cutting edge international MS genetic programmes.

Research Interests:

Professor Taylor’s research interests include:

• Gene environment interactions in the onset and progression of MS.

• The search for genetic rare variants that contribute to the onset and progression of MS.

• The role of epigenetic changes in the onset and progression of MS.

• The role of non coding variants in the onset and progression of MS.

• The effect of environmental and personal factors on the progression of MS.

Student Background:

Students should have an interest in computational genetics, and some background in genetics of complex disorders. They should have an interest in statistics and a background in epidemiology public health for the non genetic projects. The student will learn how to analyse complex databases using epidemiological processes and novel statistical methods and will be involved in the development of analysis techniques for assessing causation in longitudinal studies.

Project 1: The genetic and environmental factors that affect conversion to and progression in MS

We host the largest longitudinal MS CIS study in the world, The Ausimmune/AUSLONG study that has followed around 250 people with their first episode of MS for at least 5 years and have just received funding to extend this study to 10 years. We have collected a wealth of data on environmental and personal factors that may affect progression to definite MS and modulate the rate of disability progression. As part of this project we will use the bespoke MS chip to acquire exome array data and 200,000 additional SNPs from the immunochip project to assess how genetic variance affects MS progression.

Project 2: Clinical and genetic factors that influence the onset and progression of MS

Utilising the large amount of environmental and genetic data in the AUSLONG study we are looking for students to drive the analysis of this internationally highly regarded data set. This will involve selecting factors that may putatively modulate the progression of MS and using cutting edge genetic analyses determine the contribution of these factors to MS progression. This study is unique in its design and outcome measures and will contribute significantly to the world’s knowledge of MS progression.

Supervisor: Dr Ingrid van der Mei

Research Theme: Public Health & Primary Care

Research Area: Epidemiology

Email: Ingrid.vandermei@utas.edu.au Phone: +61 (0)3 6226 7710

Research Interests:

Dr van der Mei is an epidemiologist who focuses her research on vitamin D deficiency in the general population and risk factors of the onset and progression of Multiple Sclerosis.

Student Background:

Project 1: The student needs to have a background in Epidemiology or Public Health and needs to have an aptitude for statistics.

Project 2: The student needs to have a background in Genetics and a strong aptitude in Genetic Statistics. The student also needs to understand, or be willing to learn, the field of Epidemiology.

Title: Vitamin D deficiency in the general population

Vitamin D is a steroid hormone that is predominantly produced in the body when the skin is exposed to the ultraviolet (UV) rays in sunlight. Vitamin D is required for optimal bone health. While it was previously thought that vitamin D deficiency was uncommon in sunny Australia, there is now evidence that it is more common than expected, even in healthy individuals. In Tasmania, 67% of healthy Tasmanian adolescents and adults are vitamin D deficient ( ................
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