Project ID CM-HD2024_66


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, Vascular themeWebsite

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

High blood pressure evolving into hypertension and potentially heart failure occurs excessively in African-Caribbean-(AfC) and directly sub-Saharan-origin (Af) women. Curiously, hypertension is significantly associated with (i.e. coincides more frequently than expected) with uterine fibroids and keloid scars, both also excessive in these populations. The origin or causes of such excess, and their excess coincidence, is unknown. We hypothesize that uterine fibroids and keloid share molecular mechanisms of fibrosis with small vessel, aortic and myocardial fibrosis, underlying their links with hypertension.

To test this hypothesis, this PhD project will study fresh and stored tissues from patients with these conditions using cell culture, advanced microscopy, -omic/bioinfomatic methods as well as help in clinical testing (e.g. cardiac MRI), contributing to an entirely new angle for the origins of heart failure in under-served populations with high disease burdens.

1. Characterise the cellular and molecular commonalities/differences between the three pathological tissue types;
2. Investigate a candidate mechanism mediating the tissue stiffening/extracellular matrix changes common across the three diseases;
3. Help to establish clinical cardiovascular features of high blood pressure in fibroid & keloid patients.

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 three 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; establish necessary tissue/cell collections; help recruiting Af/AfC women with imminent fibroid or keloid surgery +/- hypertension for cardiac/vascular health assessment;
Years 2&3: pursue mechanistic hypotheses generated in rotation/Year1 with lab-based strategies; complete/analyse/disseminate clinical data.

Representative Publications

  • Ung CY, et al, McGrath JA, Shaw TJ*, Dand N*. Keloid and hypertrophic scars in UK Biobank. JAMA Derm 2023. doi: 10.1001/jamadermatol.2022.5607.
  • Bell RE, Shaw TJ. Keloid tissue analysis discredits a role for myofibroblasts. Wound Repair Regeneration 2021. doi: 10.1111/wrr.12923.
  • Barallobre-Barreiro J, et al, Mayr M, Shaw TJ. Cartilage-like composition of keloid scar extracellular matrix suggests fibroblast mis-differentiation. Matrix Biol Plus 2019. DOI: 10.1016/j.mbplus.2019.100016
  • Rahman H, Chiribiri A, Webb AJ, Perera D. Stratifying Patients with Angina due to Coronary Microvascular Dysfunction. J Am Coll Cardiol 2020. doi: 10.1016/j.jacc.2020.03.051.
  • O’Gallagher K, Chowienczyk P, Webb A, Shah AM., 2021, Direct cardiac versus systemic effects of inorganic nitrite on human left ventricular function. Am J Physiol Heart Circ Physiol. 2021 doi: 10.1152/ajpheart.00081.2021.
  • Schutte AE, Kruger R, Gafane-Matemane L et al, Cruickshank JK. Ethnicity and Arterial Stiffness. ATVB. 2020. doi: 10.1161/ATVBAHA.120.313133.