Health and Life Sciences

Important Information

The MbyRes projects available below are self-funded, therefore applicants will need to pay their own fees and living costs or have access to suitable third party funding such as a Doctoral loan or other sponsor. In addition to the University’s standard tuitions fees, bench fees (research costs) may also be applied, details of which will be shown if appropriate to the project.

You are encouraged to contact the named supervisor to discuss the project opportunity prior to submitting an application.

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Project Title: The SPOtting Cancer among Comorbidities (SPOCC) programme. Supporting clinical decision making in patients with symptoms of cancer and pre-existing conditions.

Project Description: The SPOCC programme is a 5 year programme of research funded by the NIHR Programme Grants for Applied Research. The student will have the opportunity to contribute to scoping and to conduct a project as embedded in the programme of work. Current recommendations for investigating possible cancer do not take into account the presence of other long term conditions. There are multiple reasons that may make it harder to spot possible cancer in these patients and lead to delays in diagnosis and worse survival rates. We want to improve existing recommendations for investigating possible cancers that take into account other health conditions. As part of a broader programme of research we are using existing data from general practice and The National Cancer Registration and Analysis Service, we will identify which health conditions are associated with delayed cancer diagnosis. Prospective students are encouraged to approach the team to scope/refine ideas for a project.

Additional Project costs: N/A

Supervisors: Assoc. Prof. Gary Abel, Prof. Jose M Valderas, Prof. Willie Hamilton, Dr. Luke Mounce, Dr. Sarah Bailey, Dr. Sarah Price, Dr. Liz Sheppard.

Contact email: G.A.Abel@exeter.ac.uk

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Project Title: Plant-based diets in older age

Project Description: There is increasing interest in plant-based and vegan diets. The vegan market is expanding, aligned with environmental, health and animal welfare concerns. Whilst veganism is often associated with younger people,  populations are ageing globally, therefore it it important to consider provision in later life. Currently there are only 2 exclusively vegetarian and vegan care homes in the UK. This project will carry out a narrative review of literature to identify key issues related to plant-based and vegan diets in older age, including provision in clinical and social care settings.

Additional Project costs: N/A

Supervisors: Professor Victoria Tischler
Contact email: v.tischler@exeter.ac.uk

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Project Title: Exploring the impact of the menopause on co-existent chronic disease, women’s  and healthcare professionals’ views and experiences using qualitative methodology

Project Description: Some chronic diseases such as diabetes and inflammatory bowel disease appear to have a hormonal component and so disease activity and treatment may fluctuate between different weeks of the menstrual cycle, and in pregnancy. The same reproductive hormones are also changing at the time of the menopause, yet little is known about the impact of these changes on disease activity, treatment, and women’s experience. Understanding the views and experiences of healthcare women and healthcare professionals will be important informing future research agendas and service provision.  As such this project aims to explore these aspects using qualitative methodology.

The research project will include:

1) A systematic review of the existing literature on  experiences of menopause and co-existent chronic disease from the perspective of women and healthcare professionals. 

2) Guided by the findings of the review, an exploratory qualitative research project involving semi-structured interviews to understand the views and experiences of women and healthcare professionals will be conducted. Stages will include recruitment of participants (patients and health professionals), semi-structured interviews, transcription of interviews and thematic analysis. 

3) It is expected that findings from both components published in a leading journals and inform research questions for future research.

Additional Project costs: N/A

Supervisors: Dr Emma Pitchforth, Dr Lauren Rodgers, Dr Julia Prague
Contact email: E.Pitchforth@exeter.ac.uk

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Project Title: Genetic insights in autoimmune diabetes

Project Description: This project will leverage whole genome sequencing and clinical information from >100 individuals with early onset diabetes to identify novel genetic causes of autoimmune diabetes, identifying new molecular mechanisms and targets for therapy.

Additional Project costs: N/A

Supervisors: Prof Sarah Flanagan, Dr Matt Johnson, Dr Rebecca Wyatt
Contact email: m.johnson@exeter.ac.uk

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Project Title: Autoimmune genetics in population data

Project Description: Using existing exome sequencing and extensive phenotypic data from >200,000 individuals from UK BioBank, this project will look at associations between rare variants in known disease causing genes and clinical phenotypes.

Additional Project costs: N/A

Supervisors: Prof Sarah Flanagan, Dr Matt Johnson, Dr Kashyap Patel
Contact email: m.johnson@exeter.ac.uk

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Project Title: Understanding the factors that influence glycated haemoglobin

Project Description: Glycated Haemoglobin (HbA1c) is a measure of glucose concentration in the blood. It is used to diagnose diabetes, identify people at high risk of diabetes, and to assess blood glucose control in people who have diabetes. HbA1c is a measure of glucose bound to haemoglobin, the oxygen carrying protein in red blood cells. The level of HbA1c is affected by a person’s average blood glucose, and how long their red blood cells live before they are replaced by the body. As a result, factors that influence the life of a red blood cell also influence HbA1c.  These factors mean that sometimes HbA1c is no longer an accurate reflection of blood glucose concentration.

In this project we want to understand what factors influence HbA1c in healthy individuals, in those with pre-diabetes, and in those with diabetes. The factors we will investigate will include other blood measurements such as haemoglobin itself, as well as genetic factors.  Finding out which factors influence HbA1c may help us improve the way in which it can be used both to diagnose, and to monitor response to diabetes treatment.

Additional Project costs: to be discussed

Supervisors: Prof Inês Barroso,  Prof Mike Weedon

Contact email: ines.barroso@exeter.ac.uk

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Project Title: Novel targets in depression: investigating non-neuronal mechanisms of antidepressants

Project Description: Depression is the most common mental health illness affecting 1 in 4 people in the UK, yet about two thirds of patients do not respond to currently available pharmacological treatments.

During this project, you will investigate novel antidepressant mechanisms acting through the most common glial cell type in the brain, astrocytes. Our preliminary data suggest that the selective serotonin reuptake inhibitor (SSRI) fluoxetine triggers astrocytic release of lactate, a metabolite and messenger molecule with recently described antidepressant properties.

As part of this project, you will test the ability of antidepressants to trigger lactate release in primary astrocytes and brain slice cultures of prefrontal cortex, a key brain area associated with depression. You will further characterise cellular and molecular mechanisms underlying antidepressants action on astrocytes by monitoring intracellular and extracellular levels of metabolites in combination with pharmacological approaches.

Altogether, this project will identify non-neuronal molecular mechanisms of depression, potential novel targets for the development of antidepressant treatments and lay the foundation to further studies elucidating the role of lactate signalling in depression in vivo.

 Additional Project costs: N/A

Supervisors: Dr Valentina Mosienko
Contact email: v.mosienko@exeter.ac.uk

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Project Title: Glia mechanisms in depression: discovering serotonin-independent changes to astrocyte phenotype following stress and antidepressant treatment

Project Description: Depression is the most prevalent mental health disorders affecting more than 300 million people worldwide. It is the second most common cause of disability and together with other mental health disorders costs the UK economy an estimated £105 billion per year. The therapeutic effects of most prescribed antidepressants are ascribed to their ability to elevate brain serotonin. However, there is growing evidence suggesting that the therapeutic effect of antidepressants cannot solely be explained by an increase in serotonin.

Research into depression has primarily focused on studying neuronal functions. However, recent studies suggest an essential role of non-neuronal brain cells called astrocytes in regulating emotional behaviour and the etiology of depression. Previous studies revealed a reduced number of astrocytes in amygdala, hippocampus and prefrontal cortex in brain samples from both depressed patients and animal models of depression – astrocyte phenotype that can be reversed by antidepressant treatment. However, whether antidepressants regulate astrocyte function directly or through elevating serotonin is currently not known.

During this project you will investigate direct effects of serotonin on astrocyte cell number and morphology. You will quantify effects of serotonin loss on astrocyte cell number and morphology in brain areas involved in the regulation of emotional behaviour. You will also investigate whether changes to astrocyte cell number and morphology as a result stress or antidepressant treatment are dependent on serotonin. During the project the student will use immunohistrochemistry, confocal Imaging, Image J and MatLab in combination with animal models of stress and serotonin deficiency, and primary astrocyte culture.

The student will receive training in all the technique required to complete the project. The student will have an opportunity to attend weekly lab meetings and journal clubs, and IBCS and Neuroscience seminars. At the end of the project the student will be encouraged to present the data at the annual Research Showcase at the University of Exeter. Given the excellent quality of the data the student will have a chance to present the data at a conference, for example, at the meeting of the British Neuroscience Association or the Federation of European Neuroscience Societies, and contribute to a research publication.

Additional Project costs: N/A

Supervisors: Dr Valentina Mosienko
Contact email: v.mosienko@exeter.ac.uk

 

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Project Title: Mitochondrial dysfunction: a link between dysregulation of alternative splicing and cellular ageing

 

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Project Title: Use of AI (Deep Reinforcement Learning) in optimisation of healthcare services

Project Description: Deep Reinforcement Learning (Deep RL) is a rapidly developing field in AI, whereby a neural network learns to predict both short term and long term rewards for any given action. It is best known for game-playing AI like Alpha-Go. We are developing simulations of common health service problems (like where to locate free ambulances), and developing and testing Deep RL agents at optimising performance of those systems (such as minimising time taken for an ambulance to get to a patient in a simulated world).

As, an example see: Allen M, Pearn K, Monks T. (2021) Developing an OpenAI Gym-compatible framework and simulation environment for testing Deep Reinforcement Learning agents solving the Ambulance Location Problem. arXiv:210104434 http://arxiv.org/abs/2101.04434

Additional Project costs: Allow £150 per year. The student will use Google Colab Cloud computing. At the moment this is free, but it may start to be charged at about £10 per month.

Supervisors: Dr Michael Allen and Professor Tom Monks
Contact email: m.allen@exeter.ac.uk

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Project Title: Transition from children's to adults' services for children with long term conditions - a review of reviews

Project Description: Children with long-term conditions (such as diabetes, cerebral palsy, or autism) will need to transition from children’s to adults’ services in health and/or social care as they reach adulthood. Transition can involve multiple changes at once for the young person, including changes in medical teams and specialists, changes in living situation, changes in education plan, changes in family involvement in care, and changes in financial and social care support. Existing evidence suggests that young people’s experiences of transition would be improved if transition is planned, they are prepared, and their plan is individualised. Some specific types and components of transition interventions have been found to be associated with patient satisfaction, attendance rates, disease-specific outcomes, patient activation, and other outcomes in individual studies, although the systematic review results are mixed in terms of the effects of specific components on outcomes. This review would assess whether there is evidence of effectiveness for components of transition that are common across conditions and services (health and social care), what gaps exist in this evidence, and what the implications are for practice.

Additional Project costs: n/a

Supervisors: Dr Gretchen Bjornstad, Helen Eke and Professor Stuart Logan
Contact email: g.j.bjornstad@exeter.ac.uk

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Project Title: A prospective, randomised, controlled study of the outcomes and cost effectiveness of the MAKO Partial Knee Replacement (PKR) system:   Mechanical versus alternative alignment philosophy.

Project Description: The orthopaedic department at the RD & E and the medical science department at Exeter University are going to run an RCT that compares two ways of implanting a partial knee replacement using robotic surgery (mechanical alignment methods versus using the alternative alignment technique).  We will assess the results of this study in various ways including looking at gait analysis, patient satisfaction questionnaires, measuring flexibility of the new knee and assessments of the alignment of the new knee on X-rays and CT scans. We will look at short term results for satisfaction and function of the knee, and in the long term look at wear and survivorship. The MbyRes student will be responsible for the gait analysis of the patients in the study.

Additional Project costs: n/a

Supervisors: Professor Sarah Dean, Mr Ben Waterson and Dr Vicky Stiles
Contact email: benwaterson@nhs.net

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Project Title: Using genetics to understand pregnancy outcomes

Additional Project costs: £300 contribution to potential data access fees / high performance computing

Supervisors: Professor Rachel Freathy
Contact email: r.freathy@exeter.ac.uk

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Project Title: Modulation of alternative splicing regulators during epithelial-mesenchymal transitions in tumour progression

Project Description: In spite of a complex arsenal of therapeutic approaches in prostate cancer there is still a high number of cancers that progress to metastatic, incurable disease. We therefore need novel approaches and molecular targets to improve treatments. Faulty alternative splicing is one area of cancer biology that has not been targeted before therapeutically. In previous work we have identified molecules that modify splicing and are able to reverse epithelial-mesenchymal transitions, a process that help prostate cancer progress and spread. In this proposal we will investigate both in vitro and in vivo how these compounds affect cancer cells properties and the potential to grow tumours. We will also understand how they work mechanistically. We expect by the end of this project to obtain strong candidates for novel drug development.

Additional Project costs: £7,000 per annum

Supervisors: Professor Seb Oltean
Contact email: s.oltean@exeter.ac.uk

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Project Title: Modulation of alternative splicing as a novel therapeutic approach in diabetic nephropathy

Project Description: Multiple molecular mechanisms of diabetic nephropathy (DN) progression have been described in recent years, however, mechanism-derived treatments for DN are still lacking. This is partly due to poor understanding of the detailed molecular mechanisms underlying diabetic complications. The standard of care is to control glycaemia but most of the time this does not stop the occurrence of the nephropathy.

There is therefore an increasing need to better understand molecular mechanisms of progression in DN as well as to develop novel treatments that target specifically these mechanisms and are able to slow progression of the underlying chronic kidney disease in DN. This project will be investigating novel mechanisms of progression in DN at the level of alternative splicing.

Additional Project costs: £7,000 per annum

Supervisors: Professor Seb Oltean
Contact email: s.oltean@exeter.ac.uk

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Project Title: Splicing control in tumour angiogenesis

Project Description: Abnormal angiogenesis is one of the hallmarks of cancer; tumours need to grow new vessels to be able to survive and spread in the organism. There is therefore an important need to understand the mechanisms of regulation of angiogenesis and try to manipulate it for therapeutic advantage. While several levels of regulation have been quite well studied – eg transcription factors, signalling molecules, miRNAs - it has become clear in the last few years that alternative splicing also plays a major role in this regulation

Alternative splicing of pre-mRNA allows the generation of multiple splice isoforms from a given gene, which can have distinct functions. In fact, splice isoforms can have opposing functions and there are many instances whereby a splice isoform acts as an inhibitor of the canonical isoform function, thereby adding an additional layer of regulation to important processes.

Our lab has studied extensively the regulation of pro- and anti-angiogenic VEGF-A splice isoforms. However, there are many key molecules involved in angiogenesis that have splice isoforms e.g. VEGFR1, VEGFR2, NRP-1, FGFRs, Vasohibin-1, Vasohibin-2, HIF-1α, Angiopoietin-1 and Angiopoietin-2.

This project will explore how these isoforms are de-regulated in tumour angiogenesis, what are their control mechanisms (eg splice factors involved) and how can they be manipulated therapeutically.

Additional Project costs: £7,000 per annum

Supervisors: Professor Seb Oltean
Contact email: s.oltean@exeter.ac.uk

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Project Title: Tissue-specific splicing: Why spliceosomal mutations do not affect all genes in every type of cell?

Project Description: The spliceosome is a complex macromolecular structure that performs splicing of the pre-mRNA. Because of its ubiquitous function, defects in the spliceosome are expected to have massive detrimental effects in the cell, across the whole organism. However, many mutations of spliceosomal components are not lethal and translate into the phenotype in a tissue-specific fashion. We will explore this specificity by using as a model spliceosomal defects syndromes that present with congenital anomalies.

Additional Project costs: £7,000 per annum

Supervisors: Professor Seb Oltean
Contact email: s.oltean@exeter.ac.uk

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Project Title: Using genetics to understand the links between metabolic and mental health

Project Description: This project will use genetics to improve our understanding of the links between metabolic and mental health in diverse populations. The student will use state of the art genetic methods and data from some of the largest studies in both the UK and China.

Additional Project costs: n/a

Supervisors: Dr Jess Tyrrell
Contact email: j.tyrrell@exeter.ac.uk

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Project Title: Redefining Type 1 diabetes: teasing apart the T1D Endotype Hypothesis in the Pancreas.

Project Description: Type 1 diabetes develops when a person experiences a cataclysmic decline in their ability to produce sufficient insulin to protect against the lethal effects of prolonged hyperglycaemia. This decline occurs due to extensive beta cell loss, mediated by an autoimmune attack with an unknown trigger. However, this process is not the same in everyone and this has been made clear from studies in histology, genetics and clinical outcomes for patients.

Histological evidence derived from post-mortem pancreatic specimens has highlighted this variation. Distinct histological patterns become evident when the extent of beta-cell destruction is measured and variations are also revealed by analysis of the composition of the immune cell infiltrates surrounding the islets of different people. Careful study has shown that these traits can be grouped together, suggesting discrete disease endotypes. This new understanding is revolutionising our view of T1D, paving the way to more personalised approaches to disease prevention and therapy. 

This project will aim to discover additional variations in the immunology and protein expression that occur in those with T1D, focussing particularly on disease endotypes. State-of-the-art digital pathology and analysis techniques will be applied, providing the student with experience of histology, digital imaging, complex data analysis and statistics. Skills of scientific writing and oral presentation will also be honed in small group and conference settings, and also by contributing to publications in the scientific literature.

 Additional Project costs: n/a

Supervisors: Professor Noel Morgan and Dr. Pia Leete
Contact email: p.leete@exeter.ac.uk

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Project Title: Exploring the role of the vasculature and nerves in clinical complications in individuals with type 2 diabetes.

Project Description: Type 2 diabetes is associated with damage to the eyes (retinopathy) and kidneys (nephropathy), which can ultimately result in sight loss and kidney failure. Traditionally, it is believed that these complications result from progressive damage to the small blood vessels, the microcirculation.  However, there is increasing interest whether diabetes related damage to nerves is a major contributor to the development of these complications.

The Diabetes and Vascular Research Team have a longstanding research interest in this area. From ongoing studies this project will investigate the relationship between microvascular function, nerve structure and function with the clinical complications of diabetes (e.g. retinopathy and nephropathy). Examination of this data will (1) provide further insight into the development/progression of these complications and 2) examine whether these novel vascular and nerve assessments have a clinical role in identifying individuals at risk of these complications. The MbyRes student will work as part of the dynamic research team involved in this work and participate in performing the vascular and nerve assessments.  For their MbyRes thesis the student will be able to use the collected data to examine the relationship of microvascular function, nerve structure and function with the clinical complications of diabetes in a well characterised cohort of individuals with and without type 2 diabetes.

 Additional Project costs: n/a

Supervisors: Professor Angela Shore and Dr Kim Gooding
Contact email: K.M.Gooding@exeter.ac.uk

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Project Title: Does exercise alter vascular permeability in humans, in vivo?

Project Description: Previous research from our unit has demonstrated that strenuous exercise increases the amount of protein in the urine, potentially due to an exercise induced increase in blood pressure or an exercise induced increase in the permeability. The aim of this MbyRes project is to extend this early work and examine whether other fluid filtration and permeability measures, as well as urinary albumin, alter with strenuous exercise, and whether this is associated with changes in blood pressure and the glycocalyx, in humans, in vivo. The glycocalyx is a gel-like layer that lines our blood vessels that is critical for vascular health, for example, it is involved in regulating vascular tone and permeability.

For this study, participants would have two study visits: during one visit they would undergo a strenuous exercise test and on the other they would be sedentary for a similar duration. Blood pressure would be regularly monitored during the study visit. Retinal thickness and the integrity of the glycocalyx would be non-invasively assessed before the exercise test / sedentary period, and regularly repeated for 2 hours afterwards. We would also ask participants to collect spot urine tests before and after the exercise test.

 Additional Project costs: n/a

Supervisors: Dr Kim Gooding and Professor Angela Shore
Contact email: K.M.Gooding@exeter.ac.uk

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Project Title: Exploring the mitochondrial epigenome in dementia

Project Description: Mitochondrial dysfunction occurs with age and is reported in many diseases, including various dementias. Mitochondria generate ~90% of a cells’ energy requirements and have their own genome (mtDNA), encoding for key proteins that are vital for energy production. In the nuclear genome it is known that epigenetic processes, such as DNA modifications, regulate gene expression and in recent years there has been a growing appreciation for the role these mechanisms play in health and disease. Indeed, we have published several studies showing nuclear DNA methylation changes in dementia brain samples. However, there is considerable debate as to whether epigenetic mechanisms exist in the mitochondria; although several recent articles have demonstrated detectable levels of DNA modifications on mtDNA, other studies have reported evidence to dispute this. This project will use cutting-edge genomic profiling methods to explore mitochondrial epigenetic mechanisms in dementia.

Additional Project costs: £1,000

Supervisors: Prof Katie Lunnon, Dr Adam Smith
Contact email: k.lunnon@exeter.ac.uk (please cc in wendy.cowell@exeter.ac.uk)

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Project Title: Electrophysiology without electrodes: developing a new tool to study the electrical activity of neuroendocrine cells

Project Description: Cells of the anterior pituitary gland release hormones that control growth, metabolism, reproduction and our response to stress. Amazingly, these cells generate electrical activity, like neurons. This electrical activity is an integral component of how hormones are released, and how this release is tightly regulated to maintain hormone balance. Understanding how pituitary hormones are regulated and how environmental pollutants could affect hormone balance is a key problem. For this, we must understand how the electrical activity of pituitary cells changes in response to chemical messages.

Electrical activity greatly varies from cell to cell, and to grasp this heterogeneity we must record from hundreds of cells. Current electrical recordings using patch-clamp electrodes are extremely informative but painfully slow, one-cell-at-a-time affairs. In this project, we will use a technique called “Voltage Imaging.” The idea is to introduce into the cells a fluorescent molecule that changes the light it emits when the cell voltage changes. In this way, we can image the electrical activity of many cells at a time.

This will reveal how electrical activity varies across populations of pituitary cells, in normal physiological states and in pathological states. It will also enable us to develop high-throughput screens of environmental pollutants.

Additional Project costs: N/A

Supervisors: Dr Joel Tabak
Contact email: j.tabak@exeter.ac.uk

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Project Title: Precision medicine in type 2 diabetes

Project Description: Response to glucose lowering treatment in Type 2 diabetes, and the development of treatment side effects is highly variable. If we could identify predictors of response to treatment or side effects we could target therapies towards those most likely to benefit, an approach called stratified or precision medicine. In this project we will use data from existing clinical studies to investigate how we can best identify what treatments will be most effective for a person with diabetes, or least likely to cause side effects, and build clinical tools (prediction models) to assist treatment selection. A number of different projects are available within this topic area depending on the experience and interest of the applicant.

Students will work in a highly successful clinical research group with previous department Masters by Research students publishing papers and winning conference prizes. They will develop skills that will be valuable in both clinical and science careers, including an understanding of research methods and the potential to develop advanced skills in data analysis.

Additional Project costs: n/a

Supervisors: Dr. Angus Jones, Dr. John  Dennis
Contact email: angus.jones@exeter.ac.uk

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Project Title: Penetrance and expressivity of monogenic endocrine disorders

Project Description: Penetrance and expressivity of rare endocrine monogenic disorders is often unknown or substantially overestimated due because genetic testing is mainly performed in people with the disease (phenotype-first approach). We are now doing more genetic testing even before the development of the disease (genotype-first approach). Accurate assessment of penetrance is therefore crucial for accurate clinical management of these individuals. We now have access to large population cohorts with whole exome data (>700k individuals). This provides a unique opportunity to truly assess the penetrance and expressivity of endocrine monogenic disorders. The student will analyse already available the genetic data of these large cohorts and compare them to the wide range of clinical and biochemical features of these individuals for a given monogenic disorder. This will provide the first time with the prevalence of the monogenic endocrine disorder in the population, expand the clinical phenotype and provide the substantially improved penetrance estimate to use in routine clinical care. The student will be heavily supported with plenty of opportunities to present the data in national and international meetings.

Additional Project costs: n/a

Supervisors: Dr Kash Patel and Professor Michael Weedon
Contact email: k.a.patel@exeter.ac.uk and m.n.weedon@exeter.ac.uk

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Project Title: Finding new subtype of diabetes

Project Description: Maturity-Onset Diabetes of the Young (MODY) is a rare genetic form of diabetes. Identifying MODY is important for the correct treatment. We are now doing more genetic testing than ever before. This has led to two new problems: 1) We are now finding people with defective MODY genes but without diabetes and 2) We are finding people who are ‘MODY-like’ but without defective MODY genes. In this project, we will aim to study these two problems in detail. We will develop ways to accurately predict if and when people with defective MODY genes will get diabetes. We will also aim to identify a reason for this MODY-like diabetes and whether it can be treated differently from common forms of diabetes. This work is therefore has important implications for individuals with MODY, for the wider diabetes community and is relevant to other genetic disorders. The student will be heavily supported and will work with already available data with plenty of opportunities to present the data in national and international meetings.

Additional Project costs: n/a

Supervisors: Dr Kash Patel & Professor Michael Weedon
Contact email: k.a.patel@exeter.ac.uk & M.N.Weedon@exeter.ac.uk

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Project Title: Improving the diagnosis of type 1 diabetes in adults

Project Description: Type 1 and 2 diabetes have very different treatment, however the diagnosis of type 1 diabetes in older people is  is challenging as the vast majority of people will have type 2 diabetes. This means that many people (over 40% of those with adult onset type 1 diabetes)  initially receive the incorrect diagnosis and treatment. In this project we will use information from a recent large prospective study of adult onset diabetes to improve classification. A number of  projects are available depending on the interests and experience of the applicant. This includes determining whether the presentation of type 1 diabetes changes with age, what clinical features are most helpful in identifying late onset type 1 diabetes, developing and updating clinical prediction models (clinical calculators) to help diagnosis, and investigating the performance of new diagnostic tests.

Students will work in a highly successful clinical research group, with previous department Masters by Research students publishing papers and winning conference prizes. They will develop strong skills in research methods and data analysis, with supervision and projects  tailored to their interests. While these projects use existing clinical research data students will be offered experience of all aspects of clinical research in the NIHR Exeter Clinical Research Facility.

Additional Project costs: n/a

Supervisors: Dr. Angus Jones, Dr. Beverley Shields
Contact email: angus.jones@exeter.ac.uk

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Project Title: Do incretin based medications reduce the production and action of circulating microparticles in type 2 diabetes?

Project Description: Type 2 diabetes is associated with vascular complications, including an increased risk of heart attack and stroke.  There is increasing evidence that incretin-based therapies, currently prescribed to individuals with type 2 diabetes, may reduce the risk of these events. However, the way in which this protection occurs is not known.

This studentship will investigate whether incretin-based therapies improve vascular health by reducing the production, and action, of pro-inflammatory microparticles derived from endothelial cells, platelets and leukocytes. The project will use a range of in vitro techniques and ex-vivo patient samples to examine: (a) the effect of the diabetic environment on microparticle production from these cell types; (b) the effect of these derived microparticles on vascular inflammation and (c) the ability of the incretin therapies to mitigate these responses.

This will lead to new insights into the mechanisms by which incretin-based therapies influence the vasculature of individuals suffering from diabetes, potentially highlighting which patients may receive the most benefit from their administration, in addition to their known effects on insulin.

 Additional Project costs: £9,000 per annum

Supervisors: Dr Jacqueline Whatmore and Dr Kim Gooding
Contact email: J.L.Whatmore@exeter.ac.uk or K.M.Gooding@exeter.ac.uk

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Project Title: Identification of novel genetic causes of congenital hyperinsulinemic hypoglycemia

Project Description: Hyperinsulinemic hypoglycemia is a serious disorder of insulin secretion that presents in the neonatal period. In 55% of patients screening of the known disease-causing genes does not identify a pathogenic mutation. Our laboratory provides genetic testing for hundreds of patients a year. In patients where a genetic diagnosis remains to be discovered we use genome sequencing to look for novel genetic causes. The aim of this project will be to analyse clinical information and sequencing data to identify novel genetic causes of hyperinsulinism.

Additional Project costs: n/a

Supervisors: Prof Sarah Flanagan, Dr Thomas Laver
Contact email: S.Flanagan@exeter.ac.uk

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Project Title: Targeting the ‘cytokine storm’ in human coronavirus infection (SARS-CoV, SARS-CoV2, MERS-CoV) – up to 3 projects

Project Description: SARS-CoV, MERS-CoV, SARS-CoV-2 (COVID-19) viruses to gain entry into human cells using ACE2 and hTMPRSS2 proteins resulting in rapid viral replication, subsequent infection of neighbouring cells and an acute, and sometimes massive, lethal, pro-inflammatory response  resulting in excessive IL-6, IL-1, TNFalpha and IFN production by host tissue macrophages, mast cells, endothelial and epithelial cells. These cytokines then activate more immune cells, resulting in extensive hyper inflammation, organ failure and often death. Currently there is no wholly effective treatment strategies to prevent or control the “cytokine storm” and approaches to target individual cytokines using monoclonal antibodies for example to IL-6 (e.g. Tocilizumab), alone or with high dose corticosteroids, have met with limited results (and massive cost). Therefore alternative small molecule therapeutics are sought. In this project you will expose human cells containing ACE2 and/or hTMPRSS2 to pseudo-virus, virus particles/lysates and/or specific spike proteins to illicit a pro-inflammatory effect and characterise that response. You will then use novel UoE chemical entities designed to ‘hit’ a key upstream component required for “cytokine storm” induction to limit and/or reverse pro-inflammatory cytokine synthesis and release, and determine/confirm compound MoA. This project is part of a larger programme of work and will support ongoing anti-virus / cytokine storm work conducted in susceptible animals off-site.

Additional Project costs: £15,000 per year

Supervisors: Professor Matt Whiteman, Dr. Chris Scotton
Contact email: m.whiteman@exeter.ac.uk

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Project Title: Reversal of aberrant immunometabolism with novel mitochondrioptroic agents

Project Description: Macrophages play a critical role in the initiation, maintenance, and resolution of inflammation in several debilitating chronic human diseases of considerable economic burden (e.g. atherosclerosis, rheumatoid arthritis, ulcerative colitis, chronic obstructive pulmonary disease and neurological degeneration). They are activated by cytokines (e.g. IFN-γ, GM-CSF, TNF-α), bacterial lipopolysaccharide (LPS) and other chemical mediators including the gas, nitric oxide (NO). During inflammation, macrophages are auto-regulatory and are inactivated by macrophage-derived anti-inflammatory cytokines (e.g. IL-10, TGF-β) and cytokine antagonists (e.g. IL-1ra and sTNF-R) leading to inhibition of pro-inflammatory cell signalling and repair of damaged tissues. Macrophages therefore produce a wide range of biologically active molecules and participate in both beneficial and detrimental outcomes in inflammation. As such, there is great interest in developing therapeutic agents and experimental tools to control macrophage activity. We have identified a novel approach to metabolically reprogramme immune cells such as macrophages and restore an anti-inflammatory phenotype by using new chemical entities (NCEs) developed and patented at UoE. This work is underpinned by several published, and ongoing rodent and porcine studies. In this project you will examine the effects of the NCEs on pro- and anti-inflammatory signalling in mouse and then human macrophages. This work will support ongoing animal studies on chronic respiratory diseases funded by the MRC (UK) and NHMRC (Australia). Pacitti et al., Anitox. Redox Signl. 2021; doi: 10.1089/ars.2021.0039).

Additional Project costs: £12,000 per year

Supervisors: Professor Matt Whiteman, Dr. Chris Scotton
Contact email: m.whiteman@exeter.ac.uk

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Project Title: In vitro characterisation of novel acetylcholinesterase inhibitors

Project Description: Acetycholinesterase is an economically important druggable target for a number of human disease conditions such as dementia, Alzheimer’s and Parkinson’s disease, myasthenia gravis and glaucoma, and are being explored for use in certain cancers; collectively affecting tens of millions of people worldwide. The estimated global market for treating Alzheimer’s disease alone that this class of drug represents is estimated to be worth in excess of US$11 billion / year. These molecules  are also used as antidotes for anti-cholinergic poisoning (e.g. belladona / atropine, tubocurarine etc) and are drugs of choice as insecticides (e.g. malathion, parathion) and form a class of nerve agents ( e.g. sarin, VX, some novichok constituents etc). However, many of the drugs in this class are reversible inhibitors (other than nerve agents) and result in short duration of action, dose-limiting toxicity, inadequate efficacy etc. As such, there is an urgent need for ‘better’ acetycholinestersase inhibitor molecules. In this project you will characterise novel acetylcholinesterase inhibitors synthesised at UoE. You will first use cell-free assays to determine binding kinetics and inhibition nature, and determine basic pharmacological parameters (IC50, Emax, Kd etc). You will then use a novel cell permeabile fluorophore to determine acetylcholinesterase inhibition in using human neuroblastma cells.

Additional Project costs: £12,000 per year

Supervisors: Professor Matt Whiteman
Contact email: m.whiteman@exeter.ac.uk

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Project Title: Metabolic reprogramming in Friedreich’s Ataxia

Project Description: Friedreich’s Ataxia (FRDA) is a rare autosomal inherited disease and leads to progressive degeneration of the nervous system. It is caused by a mutation in the FXN gene and results in lower cellular levels of the mitochondrial protein frataxin, impaired mitochondrial function, manifesting in patients as gait disturbance, scoliosis, heart disease and diabetes. Although FRDA has no known cure or effective treatment, recent studies have suggested metabolic reprogramming of defective mitochondria may offer an attractive novel therapeutic strategy. We have therefore developed a series of novel (patent protected) molecules to target mitochondria by several distinct processes. Clear therapeutic efficacy has been determined in multiple rodent models with the molecules administered through several standard drug routes, but the compounds have not yet been evaluated in FRDA. In this project you will use C. elegans models of FRDA (life/health span, mitochondrial and muscle function in situ etc) and identify the molecules mechanism(s) of action. Where appropriate, this work will be supported by cell culture using cells from FDRA patients and unaffected controls.

Additional Project costs: £12,500 per year

Supervisors: Professor Matt Whiteman, Associate Professor Tim Etheridge
Contact email: m.whiteman@exeter.ac.uk

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Project Title: Metabolic reprogramming in Spinocerebellar ataxia-3

Project Description: Spinocerebellar ataxia type 3 (SCA3) is a rare progressive and irreversible degenerative neurological genetic disease resulting from defective ataxin-3 protein and extensive deficit in mitochondrial activity. This leads to atrophy of the cerebellum/hindbrain, upper neuron deficits and loss of muscle coordination. There is no effective treatment or cure representing an area of unmet therapeutic need. One possible approach for disease treatment is to metabolically programme defective mitochondria and correct aberrant metabolism, and our team has successfully developed and patented several new chemical entities (NCEs) to investigate this. In this project you will use C. elegans models of SCA3 and identify the molecules mechanism(s) of action ((life/health span, mitochondrial and muscle function in situ etc). Where appropriate, this work will be supported by cell culture using cells from SCA3 patients and unaffected controls.

Additional Project costs: £12,500 per year

Supervisors: Professor Matt Whiteman, Associate Professor Tim Etheridge
Contact email: m.whiteman@exeter.ac.uk

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Project Title: Metabolic reprogramming in Muscular Dystrophies - 2 projects

Project Description: Muscular dystrophy (MD) is a group rare inherited of muscle diseases, typified by Duchenne’s MD (DMD) and Becker’s MD (BMD); each result increased weakening and breakdown of skeletal, cardiac and respiratory muscle and life expectancy of < 30 years. There is no effective treatment but current approaches involve corticosteroids, physiotherapy and palliative care. Recent studies by our group have shown metabolic reprogramming of defective mitochondria may offer an attractive novel therapeutic strategy. To do this, we have recently developed a series of novel (patent protected) mitochondria-targeted new chemical entities (NCEs). These compounds correct aberrant cellular bioenergetics respiration and ATP synthesis by targeting specific mitochondrial ETC components. Recent studies in mice, rats and pigs have shown reversal of mitochondrial, and myocardial, respiratory and skeletal muscle damage after heart, brain, burn injury, kidney ischaemia-reperfusion injury etc at very low doses, delivered by a variety of pharmacological routes (i.n.,s.c., i.v., i.p., i.o. etc ). They also prevented age-induced respiratory and skeletal cachexia indicating potent effects on muscle cells in vivo. Based on these observations, we propose that metabolic reprogramming in with these compounds will be similarly protective in MD. In this project you will culture muscle cells from DMD and / or BMD patients (and unaffected controls) and expose them to biologically relevant insults and perform standard viability and mechanistic cell rescue assays. You will then perform supporting studies using a C. elegans model of DMD and / or BMD. Proof of principle of this approach using “older compounds” has recently been illustrated by our team (Elwood et al., PNAS 2021; 118: e2018342118).

Additional Project costs: £12,500

Supervisors: Professor Matt Whiteman, Associate Professor Tim Etheridge
Contact email: m.whiteman@exeter.ac.uk

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Project Title: Metabolic reprogramming in Leber’s Hereditary Optic Neuropathy (LHON)

Project Description: Leber’s hereditary optic neuropathy (LHON) is a rare mitochondrially transmitted degeneration of retinal ganglion cells that leads to an acute or sub-acute loss of central vision in predominantly young adult males. LHON is usually due to one of three pathogenic mtDNA point mutations in complex I of the mitochondrial respiratory chain complex and results in mitochondrial uncoupling, electron leakage and oxidant production (oxidative stress) and cell loss. There is no effective current therapy but recent studies have suggested metabolic reprogramming of defective mitochondria may offer an attractive novel therapeutic strategy. To do this, we have recently developed a series of novel (patent protected) mitochondria-targeted new chemical entities (NCEs). These compounds correct aberrant cellular bioenergetics respiration and ATP synthesis by targeting specific mitochondrial ETC components. Recent studies in mice, rats and pigs have shown reversal of mitochondrial damage after heart, brain, burn injury, kidney ischaemia-reperfusion injury etc at very low doses, delivered by a variety of pharmacological routes (i.n.,s.c., i.v., i.p., i.o. etc ). Based on these observations, we propose that metabolic reprogramming in with these compounds will be similarly protective in LHON. In this project you will culture cells from LHON patients (and unaffected controls) and expose them to biologically relevant insults and perform standard viability and mechanistic cell rescue assays. You will then perform supporting studies using a C. elegans model of LHON. Proof of principle of this approach using “older compounds” has recently been illustrated by our team (Fox et al., J. Inhert. Metabol. Disease 2020; doi: 10.1002/jimd.12345).

Additional Project costs: £12,500

Supervisors: Professor Matt Whiteman, Associate Professor Tim Etheridge
Contact email: m.whiteman@exeter.ac.uk

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Project Title: Metabolic reprogramming in Leigh Syndrome

Project Description: Leigh Syndrome (LS) is a rare mitochondrially transmitted neurometabolic disorder affecting the CNS caused by incorrect assembly of mitochondrial oxidative phosphorylation components. It is characterised by muscular/neuromuscular debilitation, hypotonia/dystonia, ataxia and eventually respiratory failure and death. There is no effective current therapy but recent studies have suggested metabolic reprogramming of defective mitochondria may offer an attractive novel therapeutic strategy. To do this, we have recently developed a series of novel (patent protected) mitochondria-targeted new chemical entities (NCEs). These compounds either correct aberrant cellular bioenergetics respiration and ATP synthesis by targeting specific mitochondrial ETC components directly (and other mechanism subject to patent restrictions). Recent studies in mice, rats and pigs have shown reversal of mitochondrial damage after heart, brain, burn injury, kidney ischaemia-reperfusion injury etc at very low doses, delivered by a variety of pharmacological routes (i.n.,s.c., i.v., i.p., i.o. etc ). Based on these observations, we propose that metabolic reprogramming in with these compounds will be similarly protective in LS. In this project you will culture cells from LS patients (and unaffected controls) and expose them to biologically relevant insults and perform standard viability and mechanistic cell rescue assays. You will then perform supporting studies using a C. elegans model of LS, and help identify the drugs’ mechanism of action. Proof of principle of this approach using “older compounds” has recently been illustrated by our team (Fox et al., J. Inhert. Metabol. Disease 2020; doi: 10.1002/jimd.12345).

Additional Project costs: £12,500

Supervisors: Professor Matt Whiteman, Associate Professor Tim Etheridge
Contact email: m.whiteman@exeter.ac.uk

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Project Title: Metabolic reprogramming in ageing / sarcopenia – 2 projects

Project Description: Ageing is associated with a progressive decline in skeletal muscle mass and strength, a condition known as sarcopenia. Loss of skeletal muscle mass occurs at a rate of 1-2% per year after the age of 50, with losses in strength occurring more rapidly, such that older muscles become disproportionately weak. Sarcopenia leads to increased frailty, loss of mobility, an increased risk of falls/fractures, a diminished quality of life, and in some cases, premature mortality. In the UK, 18% of the population (~12 million people) are currently over 65 years ol and ~30% of those aged 75-84 suffer from sarcopenia, costing the NHS £2.5 billion / year; hospital care costs are >3 fold higher in patients with muscle weakness those without muscle weakness. As such, there is clear and pressing need to develop targeted therapeutic strategies to alleviate the debilitating effects of sarcopenia. Our team has identified a novel pathway by which skeletal muscle is ‘lost’ during ageing (Zivanovic et al., Cell Metabolism 2019; 30(6):1152-1170). You will characterise this pathway using C. elegans as an in vivo model system and try to (a) prevent and then (b) reverse detrimental age-induced signalling mechanisms using novel mitochondriotropic and other agents developed at UoE.

Additional Project costs: £12,500 per year

Supervisors: Professor Matt Whiteman, Associate Professor Tim Etheridge
Contact email: m.whiteman@exeter.ac.uk

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Project Title: Are mitochondriotropic agents a potential novel therapeutic approach in homocystinuria / cysthathionine-beta-synthase (CBS) deficiency?

Project Description: Homocystinuria is a rare autosomal recessive metabolic condition characterised by excess homocystine in urine. In most cases (“classical homocystinuria”) this is caused by reduced activity of the enzyme cystathionine-beta-synthase (CBS). Infants with this condition show a “failure to thrive” in that they do to grow and gain weight at the expected rate, and often exhibit developmental abnormalities, particularly in the eyes and progressive intellectual abnormalities. CBS depletion (pharmacological inhibition or genetic removal/suppression) causes extensive mitochondrial dysfunction and detrimental cellular bioenergetics changes. Individuals are also at a higher risk of life-threatening thromboembolisms (accounting for nearly a quarter of all deaths by age 30) and life-long vascular complications. Currently the only treatment option is vitamin B6 and a methionine restricted diet but ~50 % do not respond sufficiently to this. As such there’s great interest in therapeutics to treat this condition. To counteract this, we have developed a series of novel compounds to “metabolically re-programme” defective mitochondria (i.e. using novel mitochondriotropic agents). In this project you will culture muscle cells from CBS deficient patients (and unaffected controls) and expose them to biologically relevant insults and perform standard viability and mechanistic cell rescue assays. You will then perform supporting studies using a C. elegans model of DMD focussing on healthspan and muscle specific and metabolic assays in situ physiological readouts of overall mitochondrial ‘health’ and compound efficacy.

Additional Project costs: £12,500 per year

Supervisors: Professor Matt Whiteman, Associate Professor Tim Etheridge
Contact email: m.whiteman@exeter.ac.uk

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Project Title: Nature in Care Homes

Project Description: Gardens and outdoor spaces in residential and nursing care homes are often under-utilised by residents, despite evidence for the many benefits for health and well-being. Care home standards for Scotland and Northern Ireland clearly suggest the need for outdoor access for residents but there appears to be no comparable requirement for England and Wales. Arguably, it is the culture of the care home that influences the extent to which nature and outdoor garden spaces are incorporated into the daily living of care homes. Care home managers are responsible for establishing the organisational culture within a care home which deeply affects the quality of life of those who live and work there. There is a need to understand how organizational culture impacts on resident experience, the extent to which this depends on the care manager, and how this relates to use of outdoor garden spaces.

The student will use systematic review methods to investigate the ways in which organisational culture in care homes is understood to impact on resident experience, and how this may relate to outdoor spaces. The student will undertake primary research in a sample of care homes,to understand how nature is valued, what supports and constrains the use of outdoor spaces and the challenges to integrating nature activities into the daily routines of care homes.

Additional Project costs: Software costs e.g. Endnote

Supervisors: Professor Ruth Garside, Dr Noreen Orr, Professor Jo Tompson-Coon, Ms Rebecca Whear
Contact email: R.Garside@exeter.ac.uk

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Project Title: Understanding how the social practice of eating influences the weight management of patients in Tier 3 obesity programmes: implications for programme optimisation

Project Description: The NHS provides specialised weight management services (called ‘Tier 3’ clinics) for people with severe obesity, but what these clinics do and how effective they are at helping people lose weight is unclear. Many programmes focus on changing individual behaviours of patients without also addressing the social context in which patients eat. Self-management of weight could be considerably more effective if the experiences, social and contextual interactions, and sense making processes of both patients and health professionals were prioritised in intervention design, evaluation, and implementation. Eating is embedded in social relations and as such is a social practice. This project will draw on Social Practice Theory and the Social Identity Approach to health to understand food choice patterns in Tier 3 WM patients and how they relate to family eating practices. Findings will be used to optimise T3WM services by supporting patients to address how the social practice of eating in their family impacts their ability to manage their weight and by providing patients with appropriate tailored strategies to create the necessary family conditions to affect positive behaviour change. This approach to Tier 3 weight management will shed light onto unequal patterns of access and engagement between participants and how best to support those who are lacking opportunities to change eating practices and maintain a healthy weight. This project will involve the collection and analysis of mixed methods data (qualitative and quantitative). The successful applicant will join an established research team currently developing and evaluating a group-based behavioural intervention (https://www.plymouth.ac.uk/research/primarycare/obesity/progroup) for people with severe obesity in Tier 3 settings.

Additional Project costs: n/a

Supervisors: Dr Jenny Lloyd and Dr Ross Watkins
Contact email: j.j.lloyd@exeter.ac.uk

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Project Title: Moving Through Motherhood

Project Description: Moving through Motherhood is a research project looking at the barriers to women doing physical activity, including understanding how the simple guidelines can apply to them and their individual situations. The guidelines for physical activity before, during and after pregnancy are based on clinical research but much of the detail is lost by the time it reaches healthcare providers and patients. This project would involve a scoping review and co-design of resources developed with stakeholders and pregnant women.

Additional Project costs: n/a

Supervisors: Dr Lauren Rodgers, Dr Richard Pulsford, Malika Felton
Contact email: L.R.Rodgers@exeter.ac.uk

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Project Title: Identification of acceptable changes to food choices and practices to increase diet quality and reduce energy intake

Project Description: The project aims at collecting and analyse diet intake and perceptions and attitudes around food choices in a group of people with obesity (or participants from the PROGROUP study). Understanding eating patterns (i.e. specific foods, timing, eating occasions) and practices/perceptions about food that are common across participants, could help identify opportunities for dietary changes that could improve participants' diet and reduce their energy intake. Involving participants in the identification and acceptability of these changes could ensure acceptability and sustainability of behaviour change. Further, this information could be implemented as part of intervention programs targeting dietary behaviour change in people with obesity.

Additional Project costs: n/a

Supervisors: Dr Luciana Torquati, Dr Jenny Lloyd, Dr Mark Tarrant
Contact email: l.torquati@exeter.ac.uk

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Project Title: Impact of fungal infection on immunometabolic responses in glia

Project Description: Fungal infection of the brain leads to meningoencephalitis: The pathogenic fungus Cryptococcus neoformans invades the mammalian brain to cause meningoencephalitis, inflammation of the brain and meninges which is responsible for ~180,000 deaths each year. To tackle this major health burden, we need to better understand how the fungus overcomes tissue-specific barriers and brain immunity. Microglia and astrocytes can kill C. neoformans, but the full spectrum of their response to fungal infection is poorly understood. A deeper understanding of the glial-fungal interactions will inform design of novel therapeutics. This project will test the overarching hypothesis that changes in cellular metabolism are key components in the astrocytic and microglial response to this infection.

Additional Project costs: £6,000-9,000/annum

Supervisors: Dr. Carolina Coelho, Professor Kate Ellacott
Contact email: c.coelho@exeter.ac.uk

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Project Title: Food fight: how a human fungal pathogen feeds inside mammalian hosts

Project Description:  The fungus Cryptococcus neoformans kills approximately 200, 000 people every year. To cause disease, a microbe needs to scavenge food from the host. Conversely blocking of food acquisition is an atractive antifungal targets. We have found several genes that are essential for food scavenging in C.neoformans, and excitingly, their functions are completely novel. In this project the student will decipher the key functions of these enzymes.

Additional Project costs: £6,000-£9,000

Supervisors: Dr. Carolina Coelho
Contact email: c.coelho@exeter.ac.uk

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