Project ID CM-HD2023_43

ThemeCM-HD

Co Supervisor 1A School of Immunology & Microbial SciencesWebsite

Co Supervisor 1B Clinical Pharmacology/Cardiovascular & Metabolic//Vascular Risk & SurgeryWebsite

Common mechanisms of fibrosis? Hypertension, Fibroids and Keloid in African-origin women

Hypertension and related aortic/myocardial stiffening leading to heart failure disproportionately affect people of African-Caribbean-(AfC)/directly African origin-(Af). Curiously, hypertension/cardiac-vascular stiffening coincides frequently with uterine fibroids and keloid scars, both also excessive in these groups. Moreover, coronary microvascular dysfunction closely associates with hypertension and fibrosis. From these observations, we hypothesize that uterine fibroids and keloid share molecular mechanisms of fibrosis with small vessel, aortic and myocardial fibrosis, underlying their links with hypertension. This PhD project will use translational and multidisciplinary methods to test this hypothesis, contributing to an entirely new angle for the origins of heart failure in under-served populations with high disease burdens.

Aims:
1. Establish clinical cardiovascular features of hypertension in fibroid & keloid patients.
2. Characterise the commonalities/differences between the three pathological tissue types, in health and disease.
3. Investigate a candidate mechanism mediating the tissue stiffening/ECM changes common across the three diseases.

Techniques and Skills:
Histology/microscopy, cell culture/advanced in-vitro modelling, -omic analyses/bioinformatics, MRI analysis, patient data analysis

Yearly objectives:
• Rotation: use histological and bioinformatic approaches to identify common histological, genetic, transcriptional, and/or proteomic features; in vitro modelling of the extracellular matrix representative of the range of tissues of interest; witness/understand gadolinium-enhanced cardiac MR scans; observe/gain competence in vascular measures in the clinical labs

• Year1: complete hypothesis-generating rotation objectives; initiate clinical arm of study (recruit Af/AfC women with imminent fibroid or keloid surgery +/- hypertension for cardiac/vascular health assessment); establish necessary tissue/cell collections

• Years2&3: complete/analyse/disseminate clinical data; pursue mechanistic hypotheses generated in rotation/Year1 with lab-based strategies.

One representative publication from each co-supervisor:

• Barallobre-Barreiro, J.… and Shaw, T.J. (2019) Cartilage-like composition of keloid scar extracellular matrix suggests fibroblast mis-differentiation in disease. MatrixBiolPlus 4,100016.

• Sinha, A., Rahman, H., Webb, A., Shah, A. M. & Perera, D. (2021) Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction. Eur Heart J. 42(43),4431-4441.