Uterine fibroids, keloids, and hypertension affect women of African origin disproportionately. Consistent with this, we studied the UK Biobank to investigate co-morbidities of keloid scarring and discovered an ethnicity-dependent (unique to African-Caribbean and African-origin) association with hypertension and a co-vulnerability for uterine fibroids. This leads us to hypothesise that there are common disease mechanisms underlying keloids, uterine fibroids, and cardiovascular fibrosis-related hypertension in this vulnerable and underserved population.
The Shaw Lab has reported details of cartilage-like changes in the extracellular matrix (ECM) composition in keloids. Excitingly, this can be observed histologically in all three tissue types, which display areas of ECM “hyalinisation” (glass-like appearance) reminiscent of cartilage (Figure-A). Such ECM changes have the potential to cause tissue stiffening, thus directly influencing the behaviour of cells residing in the tissues (blood pressure as well as). The next steps (the objectives of this PhD project) are:
Obj.1. Establish in vitro models of cartilage-like tissue changes in cell types representing the three organ systems: We have recently established 2D and 3D culture models of keloid fibroblasts that recreates the cartilage-like phenotype (Figure-B). This project will next use commercially available human aortic adventitial and fibroid fibroblasts to characterise their responses to these pro-chondrogenic conditions, creating models to interrogate common mechanisms across the three tissue types.
Obj.2: Use pharmacological and genetic approaches to investigate the susceptibility and triggers of these pathological cell differentiation events. The literature, considered together with our own multi-omics data of keloid fibroblasts, indicates that epigenetic plasticity pre-disposes to the inappropriate cellular differentiation in disease, and implicates signalling pathways activated by tissue stiffness and molecules that regulate cartilage formation in development. We will scale the culture models to: i) test the minimum components necessary to drive the disease phenotype in healthy versus genetically susceptible cells, and ii) test the ability of drugs or genetic changes targeting the candidate pathways to inhibit the pathological cell changes.
In addition to the translational lab work described, there is opportunity to incorporate Public & Patient Involvement, clinical research, and population data and healthcare record analysis.
Techniques/Skills:
Histology/microscopy, cell/molecular biology, advanced in-vitro modelling, multi-omics/bioinformatics
Yearly objectives:
Rotation (optional): in vitro modelling of the three tissues; preliminary investigation of one candidate mechanism.
Year1: perform pharmacological screen; primary tissue/cell collections
Years 2/3/4: test mechanistic hypotheses; and (based on interests of student) integrate findings with population/healthcare records; clinical research to characterize the cardiovascular health of keloid/fibroid patients. Complete/analyse/disseminate.
