B4368 - Using large cohort studies to identify scar-associated genetic variants for mechanistic testing in mouse and zebrafish models of - 03/07/2023

B number: 
Principal applicant name: 
Nicholas Timpson | University of Bristol/ALSPAC (UK)
Dr Vanessa Tan, Dr Laura Corbin, Andrei Constantinescu, Dr Oscar Pena Cabello
Title of project: 
Using large cohort studies to identify scar-associated genetic variants for mechanistic testing in mouse and zebrafish models of
Proposal summary: 

Repair of adult tissues involves a complex interplay of several key cell lineages and inevitably leads to formation of a fibrotic collagenous scar, whereas embryonic tissues heal perfectly without any resulting scar deposition. This dramatic difference in repair efficiency between embryonic versus neonatal/adult tissues has been instrumental is guiding us towards potential causes of scarring. Indeed, we now believe that one major driver of scarring is the wound inflammatory response which doesn't initiate until a transition period in fetal development which, in turn, coincides with the developmental onset of tissue scarring. This insight has led us towards further mechanistic cell and molecular studies in model organisms, such as mouse and zebrafish, which help us better understand the scarring process and how one might modulate the wound inflammatory response in order to improve or prevent scarring.

Whilst these approaches, motivated by comparing embryonic versus adult healing, have been fruitful, it is clear that scarring is a complex, multifactorial response likely driven by a number of interacting mechanisms. We would like to use a conceptually similar comparative approach to gain further insights into the fundamental cell and molecular mechanisms of scarring by analyzing differences in degree of scarring, not between embryo and adult, but rather across human adult populations since we know there is a range of “scarring phenotypes” from “minimal scarrer” to keloid scarring individuals. This use of human phenotypic variation in a population based, genetic association approach (genomewide association studies – GWAS), has the potential not only to yield gene variant correlates of scarring, but also to point towards specific biological contributions to wound healing. The use of natural human experiments (e.g. Bacillus Calmette–Guérin (BCG) vaccination wound healing, Caesarean section (C-section) wound scarring and examples of human disease related fibroses) has never before been used for identification of scarring genes, even though the approach has proven to be powerful for discovering genes associated elsewhere with a wide variety of complex health outcomes (www.ebi.ac.uk/gwas/). Furthermore, alongside a growing number of catalogues charting the results of human genetic association studies for health outcomes and intermediates there are tools able to consider (in frameworks of causal analysis) the existence of potentially causal and modifiable relationships between exposures of interest (e.g. inflammation, differential wound repair or scar) and health outcomes (e.g. wound healing, recovery, and disease).

Using human genetic data to help explore the potential of biological pathways contributing to health and disease in applied epidemiological designs is an approach that we have refined and developed and is an integrated approach to health research that has yielded important clinically relevant insights, but has also indicated opportunities (e.g. associated signaling pathways for targeting) to unify basic science approaches with human population based health data (see below).

Impact of research: 
Greater understanding of the aetiology of wound repair or internal/non-overt wounding and repair.
Date proposal received: 
Sunday, 25 June, 2023
Date proposal approved: 
Monday, 3 July, 2023
Genetic epidemiology (including association studies and mendelian randomisation), Wound repair and wound healing. , GWAS, Genetics