Translational Medicine
University Homepage
University Contact
University Search
The University of EdinburghSkip Navigation

Potential Projects for Successful Candidates

Below are a selection of potential projects that may be available to successful candidates in each of our four centres.

Aberdeen

Sample Project No. 1:

Investigating joint stem cell niches to treat or prevent osteoarthritis

Osteoarthritis (OA) is the commonest joint disease but current therapy is merely symptomatic.  The development of disease modifying OA drugs is hindered by the limited knowledge of OA pathogenesis.
We recently reported that joint surface injury heals in young adult DBA/1 mice but not in C57BL/6, which instead develop OA features.  Our preliminary data suggest contribution of endogenous joint stem cells to cartilage regeneration.  In this study we will investigate the molecular mechanisms of stem cell migration and differentiation to form the cartilage repair tissue.  An understanding of the mechanisms underlying joint surface regeneration will help develop novel measures for treatment or prevention of OA.

Supervisor: Professor Cosimo De Bari

Dundee

Sample Project No. 1:

Cardiovascular disease begins early in life, well before development of clinical symptoms. Endothelial dysfunction and arterial stiffness are central to early development of cardiovascular disease and atherosclerosis. Preventive measures are of key importance and we need to understand the fundamental underlying mechanisms mediating these disorders. Our research programme takes a multi-disciplinary approach and uses established biomarkers, as well as developing new ones, to better understand the pathophysiology of cardiovascular diseases, and to establish the utility of different biomarkers in disease stratification. In particular, we use a combination of biomarkers relating to the microcirculation and macrocirculation and blood borne biomarkers to provide a global assessment of vascular function. The aim is to help increase our understanding of the development and progression of large and small blood vessel disease, and for determining cardiovascular risk and outcome. These tests are being applied within Vascular and Inflammatory Diseases Research Unit to a programme of research that investigates the possible factors involved in early endothelial dysfunction and its modification in normal children and adults, and in asymptomatic disease, as well as in established vascular disease states. A number of projects related to work in these areas are available for prospective PhD students.

Supervisor: Faisel Khan

Sample Project No. 2:

CNS mechanisms that regulate glucose homeostasis in health and disease.
The primary focus of our Laboratory is to examine the CNS mechanisms involved in the maintenance of glucose homeostasis and how they are impacted on, or contribute to the development of disease states such as diabetes. A major research area for our laboratory is in those mechanisms underlying the detection of hypoglycaemia in diabetes and why they fail over time.  Our laboratory uses a number of techniques in order to examine the mechanisms and neural circuitry of hypoglycaemia. These include; (i) the study of hypothalamic glucose-sensing cell lines (ii) in vivo metabolic phenotyping and study of transgenic mice (iii) in vivo study of rats using pharmacological or viral vector-driven manipulation of discrete brain regions and neural tracing studies, (iv) Clinical intervention studies in human subjects with type 1 diabetes designed to restore hypoglycaemia awareness. Potential projects that focus on the impact of environmental stress on the brain, or that examine the examine the potential for novel approaches to the treatment of hypoglycaemia awareness and type 2 diabetes in humans subjects are available and can be discussed with interested applicants.

Supervisor: Dr Rory McCrimmon

Sample Project No. 3:

Analysis of the molecular basis of individuality in RTK pathway expression in human ovarian tumours – identification of patient selection biomarkers for personalised cancer medicine

Project Description: Growth factors (e.g. EGF, FGF, PDGF, VEGF) and associated receptor tyrosine kinases (RTKs) regulate key signal transduction pathways, which are frequently dysregulated in human solid tumours. RTK pathways are common targets in chemotherapy drug development, but optimal patient selection and drug efficacy is often limited by lack of target specificity and/or individuality in target gene expression and activity. We have used qRT-PCR and immunohistochemical analysis to compare growth factor and RTK expression in human ovarian tumours, have described marked inter-individual differences in gene expression, and significant associations comparing gene expression with tumour histology, patient survival and chemotherapy response, highlighting the importance of individuality in RTK pathway expression in both disease pathogenesis and treatment response. We have also analysed growth factor and RTK expression in ovarian tumour cell lines, identified cell lines which mimic expression in human ovarian tumours and developed siRNA-based methods to create stable daughter lines with variable levels of RTK pathway knockdown. We therefore have access to both clinical samples and unique experimental models with which to further explore the functional and clinical consequences of variation in RTK expression in ovarian cancer. This project will use a variety of experimental approaches to perform a detailed quantitative analysis of individuality in mRNA and protein expression, mutation burden and copy number in genes encoding growth factors and RTK signaling pathways in human tumours to investigate (i) the extent of individuality in gene expression and (ii) the molecular mechanisms responsible. In complementary experiments in tumour cell lines, we will manipulate RTK pathway expression in vitro to create novel experimental models to assess pathway specificity of existing and novel RTK-targeted drugs, and to investigate the extent of cross-talk between individual signaling pathways.

Supervisors: Gillian Smith, Michelle Ferguson, Simon Herrington

Sample Project No. 4:

Current research interests are beta-adrenoceptor regulation and associated pharmacogenetics in asthma and COPD, airway inflammation in asthma, therapeutics of allergic rhinosinusitis.

Supervisor: Brian J Lipworth

Sample Project No. 5:

Our work focuses on the biochemical properties of pluripotent cells such as embryonic stem cells (mouse and human) and cells of the early embryo. We are currently examining the signaling pathways controlling self-renewal and differentiation of mouse and human embryonic stem cell lines. In collaboration with the assisted conception unit in Ninewells Hospital we aim to study the same processes in human embryos donated for research. We envisage that a better understanding of early embryo development will lead to better conditions for IVF treatment and higher success rates. Additionally, elucidation of the precise mechanisms of pluripotent cell differentiation is a prerequisite for any potential use of such cells (ES or iPS) for therapeutic purposes.

Supervisor: Marios P Stavridis

Sample Project No. 6:

The major interest in the Dillon laboratory is in non-alcoholic fatty liver disease (NAFLD).
Non-alcoholic fatty liver disease (often associated with obesity or diabetes), hepatitis C and Alcoholic liver disease affect more than 12% of the Scottish population and have a common underlying mechanism of pathogenesis-a failure to adapt to oxidative stress. Currently we are focused around NAFLD as the paradigm, a classic polygenetic and environmental interaction, using proteomic and genomic technologies to generate biomakers for diagnosis and staging, but also to give insights into relevant pathways, this in collaboration with Profs Mike Ferguson and Roland Wolf.
This feeds into our pathway based research in collaboration with Profs John Hayes and Mike Ashford looking at the master regulator of the initial cellular oxidative stress response Nrf-2, mouse knocks of this gene being very susceptible to developing the NASH phenotype. The combination of these approaches harnessing the different skills and talents of the researchers is key to bringing about the translation of our discoveries into the therapeutic arena. In the short term the outputs will include diagnostic tests for disease aetiology and stage; this will also highlight pathways that may be therapeutic targets for drug research. These outputs ink to other themes in the university: personalised medicines research in predicting adverse drug reactions, diabetes, inflammatory atheroma and carcinogenesis, all of  these being a consequence of chronic adaptation failure to oxidative stress.

Supervisor: John Dillon

Sample Project No. 7:

The Pearson laboratory has a major research interest in genetic and phenotypic determinants of response to diabetes treatments. Current research areas are the pharmacogenetics of metformin, sulphonylureas and thiazolidinediones; clinical predictors of response to these agents; and Pharmacovigilance. The Pearson group established that patients with MODY due to HNF1A mutations are sulphonylurea sensitive; and that patients with ‘insulin –dependent’ neonatal diabetes due to potassium channel mutations can be treated with high dose sulphonylureas. Both findings have led to patients successfully transferring off insulin treatment.

Supervisor: Ewan Pearson

Sample Project No. 8:

Investigation of familial cardiac arrhythmias with induced pluripotent stem cells

Familial arrhythmias (FA) are a class of inherited heart conditions which can lead to sudden death of otherwise healthy young people. The root cause(s) for this condition is unknown and the first symptom experienced may be sudden death from a life-threatening arrhythmia. This project is a collaboration between Dr. Anna Maria Choy, chair of Familial Arrhythmia Network of Scotland, and Dr Marios Stavridis, a pluripotent stem cell expert. The aim of this project is to study the physiology of FA cardiac muscle cells, derived via reprogramming of patient skin cells, in order to elucidate the root cause of the condition. The work will involve deriving induced pluripotent (iPS) cells from patients, differentiating them into cardiomyocytes and then studying these using standard biochemical and electrophysiological techniques. Success in this project may reveal the identity of the genetic defect or provide the basis for the development of new drugs for the treatment of this currently untreatable condition.

Supervisors: Marios P Stavridis, Ana. Anna Maria Choy

Sample Project No. 9:

Genomics Of Chronic Heart Failure. Go-CHF.  A study of the genetic determinants of the risk of developing and dying from heart failure

Twenty eight per cent of the risk of heart failure (HF) can be attributed to genetic factors.   Targeted candidate gene studies have led to inconsistent findings which is not unexpected given the complexity of HF.  A more comprehensive genome approach is needed such as through GWAS which has identified new disease-associated loci even in polygenic disorders.   The, CHARGE consortium recently identified loci associated HF risk as well as loci associated with the risk of death among those with HF.  There were also ‘high signal’ SNPs that failed to reach statistical significance.  This single analysis clearly needs further investigation.  In this project, we will exploit the extensive bio-resource and well-phenotyped population in Tayside to investigate and determine the location of the important genomic drivers that underlie the heritable risk of developing and of dying from HF.  Importantly, we will be collaborating with the CHARGE consortium in this effort. This study will help develop genomics as a clinical tool to assist in risk and prognostic assessment in HF.
This project is particularly attractive to academically-orientated clinicians with a real in interest in the application of biomedical science in clinical practice. The candidate will benefit from the excellent bioinformtics and translational research platforms available in Dundee. Specific skills will be attained in the analysis of large datasets and population genetics.

Supervisor: Chim C Lang, Colin Pamer


Edinburgh

Sample Project No. 1:

In vivo cardiovascular effects of urocortin in patients with heart failure

Heart failure remains widely prevalent and has a terrible prognosis. ‘Urocortin’ peptides are emerging with prominent roles in cardiovascular physiology. Urocortins 2 and 3 are potent inotropes and vasodilators, especially in the context of heart failure. To date, no clinical study has separated the regional effects from systemic effects of urocortin 2 and the effects of urocortin 3 have not previously been examined in man. It remains unclear whether urocortins are involved in the maintenance of basal cardiovascular function and peripheral vascular tone.

We will make the first detailed characterisation of urocortins in local venomotor, arterial vasomotor and cardiac inotropic effects in healthy humans and patients with heart failure. We will examine the mechanism of these effects and assess their interaction with the endothelium. These studies will further the understanding of urocortins in vascular physiology and heart failure, and will inform the development of urocortins as novel targets in cardiovascular therapeutics.

Sample Project No. 2:

First-in-man optical molecular evaluation of drug target engagement and efficacy

This project will couple the direct intrapulmonary delivery of experimental drugs with an optical molecular readout of drug target engagement.

Using a combination of clinical grade optical molecular imaging (OMI) reagents sensing both human neutrophil elastase and MMP-9, two key enzymatic targets implicated in inflammatory lung disease, the project will validate in ex vivo human lungs obtained at transplant retrieval, the efficacy of drug delivery via direct intrapulmonary route or via perfusate.

Subsequently a phase 0/1 first-in-man study with the direct intrapulmonary microdosing of the OMI reagents and drugs will be conducted. We aim to show for the first time, drug target engagement deep in the human lung.

The PhD will provide multidisciplinary training in chemistry, tissue assays, molecular imaging, clinical pharmacology, human ex vivo lung models and human clinical trials. It will form part of an ongoing programme of work funded by the WT and MRC.

Supervisors: Kev Dhaliwal, Mark Bradley, Chris Haslett, Dave Singh

Sample Project No. 3:

Treatments for Lacunar Stroke and Cerebral Small Vessel Disease
 
Summary; A quarter of all ischaemic strokes are lacunar in type. These small strokes have been neglected in research to date but cause substantial long term disability. They are assumed to be of similar pathogenesis to large artery atherothromboembolic stroke and treated as such. However increasing evidence indicates that lacunar stroke is due to an intrinsic disease of the brain’s perforating arterioles that is unrelated to atherothromboembolism. Limited trial data indicate that antiplatelet drugs are hazardous and blood pressure lowering, while important, has limited effectiveness in preventing disease progression. Drugs which modify endothelial function and increase nitric oxide bioavailability may be beneficial but require pilot testing for feasibility and to design large clinical trials. The purpose of this project is to develop and perform initial testing of promising treatments for small vessel disease, including the use of imaging and clinical outcome measures of disease progression.

Supervisors: Joanna Wardlaw, David Webb and Martin Dennis

Sample Project No. 4:

Exosomal microRNA as a renal signaling mechanism and injury biomarker

MicroRNA are short, non-protein coding RNA species that repress a set of specific target mRNAs and thereby regulate specific cellular proteins and the phenotype of the cell. These actions are intra-cellular, however, miRNA are present in extra-cellular fluids where they represent a new class of disease biomarker as organ-specific species are released from cells following injury, being very stable in a range of biofluids including blood and urine. Certain of these extra-cellular miRNA are contained in cell-derived vesicles (termed exosomes) that can enter cells. This can change the proteome, and therefore function, of the ‘recipient’ cell by miRNA interference of target protein synthesis. Therefore, extra-cellular miRNA represents a novel mechanism for cell to cell signaling in health and disease.

MiRNA containing exosomes are released into the urine by cells of the kidney’s glomerulus and each region of the renal tubule. Exosomes can potentially transport miRNA along the nephron and so represent a mechanism for inter-cellular signaling within the kidney. Consistent with this hypothesis being correct, we have recently demonstrated that exosomes signal between kidney cells in vitro.

In this project the student will use a kidney cell model to dissect the mechanism of exosome signalling to determine if exosomes transfer active miRNA between cells. In rodent models the student will determine if exosome number, cellular origin and miRNA cargo changes with acute kidney injury using a range of state of the art techniques based in a BHF Centre of Research Excellence.

Supervisors: James Dear, Matthew Bailey & David J Webb

Sample Project No. 5:

Cardiovascular disease remains a leading cause of death world-wide. Our research interest is in the developmental origins of health and disease i.e. that the developing fetus makes adaptations to events in utero, which are initially advantageous for survival, but in later life pre-dispose to increased risk of disease. Our work has dissected one of the key mechanisms thought to underlie fetal programming, namely glucocorticoid over-exposure. We have translated observations made in animal models into human studies, showing that low birthweight is associated with activation of the hypothalamic-pituitary –adrenal axis and this is associated with increased cardiometabolic risk. We are currently investigating maternal obesity as a programming factor. Currently one in five women in the UK is obese at the time of antenatal booking which is a major concern.  We have established a longitudinal study of obesity in pregnancy and this is a valuable resource of participants, blood and tissue samples for dissecting mechanisms linking maternal obesity to offspring disease. These projects included detailed physiological studies, molecular biology techniques, fetal imaging in utero and birth record-data linkage.

Supervisor: Dr Rebecca Reynolds

Sample Project No. 6:

Novel approaches to identifying and treating cerebral amyloid angiopathy, a
common age-related small vessel disease of the brain

Cerebral amyloid angiopathy (CAA) is common: it affects 20-40% of the
elderly population, 50-60% of those with dementia, and may be responsible
for up to a third of spontaneous intracerebral haemorrhages. Intracerebral
haemorrhage is a devastating disease, affecting around 10,000 patients per
year in the UK: 40% of those affected die within one month and there is no
specific acute or preventative treatment. Demographic, clinical, and
radiographic features are currently used to implicate CAA as an underlying
cause of intracerebral haemorrhage, but the performance of the diagnostic
criteria is modest. Outcome could be improved by a translational, stratified
medicine approach involving: [a] better identification of CAA as an
underlying cause of intracerebral haemorrhage by an 18F-labelled PET
radioligand (Flutemetamol, provided by our partner GE Healthcare), [b] an
early phase treatment trial of one of the two anti-amyloid monoclonal
antibodies (Gantenerumab or Solanezumab) being trialled by the Dominantly
Inherited Alzheimer's Network (in collaboration with an industrial partner),
and [c] embedding this evaluation within an ongoing MRC-funded intracerebral
haemorrhage biobank in NHS Lothian identifying all incident intracerebral
haemorrhages and obtaining DNA, MRI, and brain tissue at autopsy from those
who consent.

Supervisors: Dr Rustam Al-Shahi Salman (MRC senior clinical fellow & honorary consultant
neurologist), Prof Edwin van Beek (SINAPSE Chair of Clinical Radiology), and
Dr Colin Smith (Reader in neuropathology)


Glasgow

Sample Project No. 1:

Targeting the immune system to treat bone disease

Bone erosion is one of the most debilitating clinical features of many diseases, including rheumatoid arthritis, osteoporosis and multiple myeloma. We have recently discovered a novel therapeutic approach that harnesses an Fc receptor-mediated feedback mechanism to inhibit the maturation of osteoclasts and the subsequent bone destruction. Current data suggests that this works via alteration of microRNA and MAP kinase-signaling pathways. The aim of this project is to validate the approach and dissect the mechanism of action of our new therapeutic modality. To achieve this a combination of pre-clinical and clinical studies will be performed. This project will provide data to justify this new therapeutic strategy.

Supervisors: Carl Goodyear, Iain McInnes

Sample Project No. 2:

Roles for chemokines and their receptors in the pathogenesis of viral encephalitis.

Encephalitis following viral infections can be significant and, in the context of rabies virus, is inevitably fatal. Currently viral encephalitis is hard to treat and novel therapeutic targets are needed. Leukocytes are likely to traffic to encephalitic foci under the control of chemokines and their receptors and we are interested in using molecular, cellular and imaging technologies to determine the key chemokines and receptors involved in these processes. By doing so, we will highlight chemokine receptors that may be appropriate for therapeutic blocking leading to novel anti-encephalitic therapies which may transform our ability to treat otherwise fatal viral infections. This project will develop model systems together with state of the art molecular biology based approaches to develop new therapeutic strategies in this disease group.

Supervisor: Gerry Graham

Sample Project No. 3:

Imaging Infection and Inflammation in Real Time In Vivo

The recruitment, retention and removal of the cells of the immune system from sites of infection and inflammation are likely key to disease development and outcome yet remain poorly understood. We will employ state of the art developments in real time in vivo imaging together with optical highlighting and fate mapping approaches to investigate the molecular basis of these phenomena in either immune mediated or infectious disease states and models depending on the specific area of interest of the fellow. This project will define at the cellular level the key determinants of the establishment of a chronic inflammatory lesion in the context of pathology and will offer training in molecular and cellular biology and in sophisticated imaging modalities.

Supervisor: Paul Garside & Jim Brewer

Sample Project No. 4:

Diabetes and heart failure: a deadly intersection

Diabetes and heart failure are two modern epidemics recognised as major and increasing causes of mortality and morbidity. Both are related in complex and not fully understood ways. What is clear is that diabetes is much more common in people with heart failure than in those without. The converse is also true, as individuals with diabetes have a much greater risk of heart failure than non-diabetic subjects. These inter-relationships are further complicated by the effects of treatment for one condition on the other e.g. certain drugs for diabetes may lead to worsening of heart failure and certain cardiovascular drugs may exacerbate dysglycaemia and insulin resistance. This project offers the opportunity to explore these issues and other metabolic aspects of heart failure further, exploiting databases from completed clinical trials in patients with heart failure (with and without diabetes/impaired glucose tolerance) and other epidemiological studies. The successful applicant will work on these large datasets under the joint supervision of experts in heart failure and metabolic medicine.

Supervisors: Professor McMurray, Sattar N, Preiss D

Sample Project No. 5:

Organ-specific effects of obesity in type 1 diabetes: heart, blood vessels, muscle and liver

Emerging cardiovascular risk factors in T1D include obesity, markers of insulin resistance, HDL-cholesterol, and fatty liver. The benefits of glucose-lowering via intensive insulin therapy may be outweighed by weight gain and associated aggravation of cardiovascular risk factors. While there are a number of published studies on metabolic, hepatic and skeletal muscle physiological phenotypes in lean patients with T1D, little is known on the potential pathophysiological effects of T1D complicated by obesity in particular effects on vascular function.   The proposed intensive phenotyping studies will be embedded within Prof Petrie’s ongoing REMOVAL trial (http://clinicaltrials.gov/ct2/show/NCT01483560NCT).

Supervisors: Petrie J, Cleland S

Sample Project No. 6:

Evaluation of novel strategies for prevention of in-stent restenosis

Pathologically, this project is focused on neointima formation leading to in-stent restenosis. The proposal brings together plans to develop novel gene delivery strategies with state-of-the-art interventions in order to investigate the potential of modulation of small non-coding RNA (specifically miRNA) in the coronary vessel wall for prevention of in-stent restenosis. In recent years we have developed a strong and unique focus on understanding the basic mechanisms that govern adenovirus-mediated gene transfer in vivo. We have at our disposal a broad range of highly efficient viruses that have the capacity to deliver novel interventions to the vessel wall in vivo. We will engineer these viruses so they are capable of delivering systems to manipulate the levels of key miRNAs in the vessel wall. This will be in conjunction with stent deployment in a porcine model of in-stent restenosis. In vivo studies will be complemented by in vitro studies that will fully assess the effect of miRNA manipulation in smooth muscle cells.

Supervisors: Baker A, Oldroyd K

Sample Project No. 7:

A comprehensive approach to assess cardiovascular risk

Cardiovascular risk management is currently based on traditional risk factors. While such strategies have contributed to improved detection and management of individuals at risk, there is still an urgent need for better approaches because cardiovascular disease remains the major cause of morbidity and mortality worldwide. The Glasgow Blood Pressure Clinic is one of the largest of its kind in the world with detailed follow-up of over 16,000 patients. The discovery of novel and orthogonal risk predictors in this cohort will revolutionise risk assessment and personalised treatment. We aim to comprehensively assess traditional and emerging risk factors and emerging technologies in the management of hypertension and cardiovasular risk using epidemiology, genomics, randomised trials, non-invasive phenotyping, 'omics' and biomarker studies This work is tightly linked to ongoing large-scale collaborative studies on systems medicine in cardiovascular disease and will provide opportunities for interactions locally and internationally.

Supervisors: C Delles, J Dawson, A Dominiczak, E Freel, AJ Jardine, P Mark, M Walters, S Padmanabhan, R Touyz

Sample Project No. 8:

Mechanisms involved in Leukaemic transformation

Understanding the molecular aberrations that occur during cellular transformation is key to the advance of new targeted therapies. We propose to fully investigate the role of the Trib2 oncogene in drug resistance of clinical samples and identify the clinical significance of these findings in both acute myeloid and lymphoid human leukaemia (AML and ALL). TRIB2 is a recently identified oncogene and associates with mixed myeloid/lymphoid human AML phenotypes, and high TRIB2 mRNA expression distinquishes normal karyotype T-ALL and associated with NOTCH1 mutations in paediatric/adult T-ALL. NOTCH1 activating mutations are found in 50% of T-ALL and we have previously shown that TRIB2 is a NOTCH1 target gene. Our previous work has shown that HoxA9, dysregulated C/EBPalpha and NOTCH1 mutations cooperate and/or correlate with elevated TRIB2 mRNA expression in AML and ALL. The prognostic implication of TRIB2 positive leukaemia is currently unknown, nor is it known whether elevated TRIB2 mRNA and protein expression confers a drug resistant or drug sensitive phenotype to a cell. We propose to investigate the chemotherapeutic responses in both AML and ALL cells, using primary human leukaemic cells, established cell lines, and primary murine leukemic cells from our bone marrow transplant model. Taking this approach we aim to identify similar and/or different cell specific response in TRIB2 expressing cells depending on the cell phenotype/lineage. We will use complementary overexpression and knockout systems to address this question to gain an in depth understanding of TRIB2 functions. Recent advances in cell culture technology have greatly improved human leukemic cell survival in vitro. These technologies will be utilized in this study to address the chemotherapeutic response of TRIB2-modulated primary leukemic cells in vitro.

Supervisors: Karen Keeshan, Helen Wheadon, Tessa Holyoake

The University of EdinburghCollege Home

Last modified: 28 January 2014   2007 The University of Edinburgh