This project is one of a number that are in competition for funding from the GW4 BioMed2 MRC Doctoral Training Partnership which is offering up to 20 studentships for entry in October 2023.
The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities. More information may be found on the DTP’s website.
SUPERVISORY TEAM:
- Dr David Gurevich (lead), University of Bath, Department of Life Sciences
- Dr Joshua Bell, University of Bristol, Bristol Medical School
- Prof Nicholas Timpson, University of Bristol, Bristol Medical School
- Prof Dylan Thompson, University of Bath, Department for Health
THE PROJECT:
Obesity affects over 1 billion people globally and is causally implicated in numerous diseases and complications. Recent biological evidence indicates that obesity triggers chronic inflammation, decreased capillary density and poor oxygenation throughout the body in general, and aberrant inflammation, impaired angiogenesis, reepithelialisation and fibrosis as well as hypoxia at wound sites in particular. A poor blood supply and excessive inflammation are well accepted clinically as key in establishing chronic wounds. It is therefore plausible that obesity causes impaired wound healing at a population level, but this remains to be established.
Tissue repair is incredibly complex, involving many cell lineages and signalling pathways that are under-investigated, particularly in the context of obesity. Therefore, the precise mechanisms driving deficient wound healing in individual obese patients remain poorly understood. This lack of understanding is driven partly by the inherent heterogeneity of obesity: furthermore, issues of bias in population data make it challenging to infer group-level causality. This project will integrate biology and population health science including genetic epidemiology to unravel the underlying mechanisms of tissue repair that are dysregulated as a result of obesity and examine how these might be ameliorated to rescue wound healing among patients.
Aims & objectives:
Our overall objective is to understand whether and how obesity causes impaired tissue repair and compromised wounds. This project has 3 main aims:
- To establish whether adiposity influences wound repair at a population level.
- To define which obesity-related genes are related to deficient wound healing at an individual level and how these genes affect wound healing by dissecting these targets in vivo using zebrafish.
- To identify potential therapeutic drug targets that might rescue wound healing in obese patients.
Methods:
We will use large-scale human data on adiposity/body scanning and proteomics with techniques of genetic epidemiology, particularly genome-wide association studies (GWAS) and Mendelian Randomisation (MR) analyses, to generate population-level causality estimates (Aim 1). These analyses will also allow us to prioritise adiposity-associated genes and pathways related to inflammation and other specific outcomes related to deficient wound healing, using ICD codes from hospital records. (Aim 2). To dissect how these obesity related genes mechanistically affect wound healing, we will use recent advances in zebrafish CRISPR mutagenesis, in combination with established zebrafish obesity models, wound assays and high resolution fluorescence imaging, to define what effect manipulating these genes has on key aspects of tissue repair such as re-epithelialisation, inflammation, angiogenesis and fibrosis (Aim 2). We will also use proteomic data and MR approaches to identify factors that modulate these key repair processes, which might rescue these obesity-related wound healing defects in patients and represent future therapeutic targets (Aim 3). This will facilitate us performing a small molecule screen on wounded, obese zebrafish, and we will validate the most promising targets using established tissue culture and co-culture assays performed on tissue samples (e.g. immune cells) obtained from overweight/obese patients (Aim 3). Within this broad framework, we will encourage the student to actively steer the project in terms of genetic epidemiology analyses used, repair processes to be focused on, and therapeutic targets to be pursued.
Training experience:
This project spans the disciplines of fundamental discovery biology and population health science, providing the successful PhD student a diverse and integrated set of skills – from in vivo imaging and CRISPR gene editing to genetic epidemiology – that are in high demand in the modern academic and industry job markets. This project will allow the candidate to build a more complete picture of health and disease while becoming part of a growing community within GW4 focused on linking human health and candidate gene identification to mechanistic studies.
REQUIREMENTS:
Applicants must have obtained, or be expected to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an area appropriate to the skills requirements of the project. Academic qualifications are considered alongside significant relevant non-academic experience.
ENQUIRIES AND APPLICATIONS:
Informal enquiries are welcomed and should be directed to Dr David Gurevich on email address [Email Address Removed].
Formal applications must be submitted direct to the GW4 BioMed2 DTP using their online application form.
A list of all available projects and guidance on how to apply may be found on the DTP’s website. You may apply for up to 2 projects.
APPLICATIONS CLOSE AT 17:00 (GMT) ON 2 NOVEMBER 2022.
IMPORTANT: You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application for an offer of study from Bath.
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