The genetics of human scarring – cross-cutting approaches to the understanding of human wound repair

The MRC Integrative Epidemiology Unit at the University of Bristol is the leading group for the development and application of causal analysis and evidence triangulation in health research to improve lives. This student will be supported by an interdisciplinary team of academic staff who are experts in their fields. For more information about the MRC Integrative Epidemiology Unit and the PhD programme, please visit the website.

Rationale

Repair of adult tissues involves a complex interplay of several key cell lineages and inevitably leads to formation of a fibrotic collagenous scar. We use human phenotypic variation to examine genetic correlates of scarring and to better understand biological contributions to wound healing. As an introduction into using population approaches to identify scar-associated genes, we have already assessed a sample of mothers from the Bristol-based Avon Longitudinal Study of Parents and Children (ALSPAC, www.bris.ac.uk/alspac) for their scarring response to a standard lesion that they all will have received as teenagers. The first natural experiment in this case was that of receiving a BCG vaccination in early life. Genome-wide association analysis of this phenotype revealed a low frequency single nucleotide polymorphism (SNP) in a regulatory intronic region of the GPCR, LGR4, that we find associates with the tendency to scar less.

Aims and objectives

1. Complete current ALSPAC studies of scarring genetics – across human association studies and lab-based model.
2. Combine existing recall by genotype (RbG) and GWAS results, developing bioinformatic analysis of established and possibly new signals for scarring traits.
3. Extend results from the ALSAC to other data sets and other pertinent phenotypes – specifically measured BCG and C-section scars in the Pelotas cohort, Brazil.
4. Work with a collaborator consortium focused on fibrosis traits more generally to widen the analysis of genetic contributions to scarring.

Methods

Extension of existing population health data will be to combine the existing evidence available from GWAS and the RbG undertaken in ASPAC in order to provide best estimates of association between known loci and scarring. Work will expand on the initial GWAS analysis through the incorporation of the Pelotas 1982 birth cohort where we examine BCG scar size at the current whole cohort clinic and expand this to include the study of C-section scars which – in Brazil – are far higher in frequency than in the UK and provides an excellent opportunity to examine both the observational factors and genetic factors associated with differential scarring. Lastly, as part of a broad and exploratory portfolio of approaches to the assessment of genetic contributions to scarring events which may flag loci of interest for mechanistic studies in model organisms (below), we propose to incorporate the systematic followup of new findings for pulmonary fibrosis through a GWAS study that is currently being collaboratively led by colleagues at the University of Leicester.

University of Bristol, Bristol Medical School

Bristol Medical School is the largest and one of the most diverse Schools in the University of Bristol, with approximately 1100 members of staff, 1350 undergraduate, 250 postgraduate taught and 240 postgraduate doctoral research students. The Head of School is Professor Matt Hickman. The Medical School has two departments: Population Health Sciences and Translational Health Sciences. The School is a leading centre for research and teaching across these areas. Research in the School is collaborative and multi-disciplinary, with staff coming from a wide range of academic disciplines and clinical specialties.

The 2021 Research Excellence Framework (REF) confirmed the University of Bristol’s position as a leading centre for health research. Bristol Medical School contributed to three Units of Assessment including UoA1 (Clinical Medicine), UoA2 (Public Health, Health Services and Primary Care) and UoA4 (Psychology, Psychiatry and Neuroscience). The UoA2 submission, comprising predominantly Medical School staff. was ranked 3^rd in the UK with 94% of our submitted research outputs rated as world leading (4*) or internationally excellent (3*). Submissions to UoA1 and UoA4 were shared with varying degrees of representation with the Faculty of Life Sciences. Respectively UoA1 and UoA4 had 94% and 84% of submitted research ranked as 4* or 3*, which represented increases in each category in the proportions of 4* ranked papers as well in growth in GPA rankings above the previous REF2014.

The Medical School has responsibility for the undergraduate medical (MBChB) programme. Undergraduate and postgraduate teaching programmes within the School provide training and career development for undergraduate and intercalating medical students, academic clinical trainees, other clinicians, and research staff. There are taught postgraduate programmes in Epidemiology, Molecular Neuroscience, Orthopaedic Research, , Perfusion Science, Public Health, Reproduction and Development, Stem Cells and Regeneration, and Translational Cardiovascular Medicine. There is an active programme of research seminars in term-time.

Candidate requirements:

We strongly encourage applications from a range of disciplines (e.g., mathematics, statistics, computer science, life or natural sciences, psychology, social sciences or other related quantitative discipline). Applications are sought from high performing individuals who have, or are expected to obtain, a 2.1 or higher degree (or equivalent). Possession of a relevant Master's degree or research experience would be advantageous but is not expected.

How to apply

When applying, candidates must select the Population Health PhD programme and enter supervisor names as listed under the project title for which they are applying. Please state IEU funding in the funding box. Full details on what to include in your application can be found in the Admissions Statement.

Personal statement: Please also provide a personal statement that describes your training and experience so far, your motivation for doing a PhD, your motivations for applying to the University of Bristol, and why you think we should select you. We are keen to support applicants from minority and under-represented backgrounds (based on protected characteristics) and those who have experienced other challenges or disadvantages. We encourage you to use your personal statement to ensure we can take these factors into account.

Closing Date: 5pm, 27^th March 2023