Richard J McGregor
The Role of WT1 in Adult Angiogenesis
Angiogenesis is a highly organised sequence of cellular events comprising vascular initiation, formation, maturation, remodelling and regression, all of which are tightly controlled to meet the tissue’s requirements. The process crucially involves vessel penetration into a vascular regions which, in turn, is dependent on endothelial cells (vessel lining), pericytes (which interact externally with the endothelium), stromal cells (e.g. fibroblasts) and their association with the extracellular matrix. Angiogenesis in the adult maintains physiological homeostasis and tissue integrity during wound healing, inflammation, endometrial growth during the menstrual cycle and following ischaemia.
Aberrant angiogenesis (e.g. within tumours) is associated with excessive growth-promoting signals and a lack of sufficient cues to spatially and temporally control vessel growth, remodelling, maturation and stabilisation.
The Wilms' Tumour Gene (WT1) was originally discovered as a tumour suppressor gene (TSG) owing to loss of function mutations in a subset of childhood neoplasias. However, emerging data indicate that it does not always conform to its TSG label, and some studies suggest it functions as an oncogene, enhancing cell survival and proliferation.
A number of elegant studies have recently depicted a crucial role for WT1 in epicardial epithelial-mesenchymal transition. Interestingly, epicardium-specific knockout of WT1 leads not only to the failure of the formation of the coronary vasculature, but also to a reduction in cardiac progenitor cells. In addition, WT1 is a downstream target of hypoxia inducible factors (HIFs) and WT1 was recently detected in the vasculature (mainly the endothelium) of diverse tumours arising in the skin, breast, endometrium and gut.
My work will address the hypothesis that WT1 is essential for de novo angiogenesis. Its aim will be to exploit a number of complementary experimental tools to determine the expression pattern of WT1 in endothelial cells (as monolayers or during tube formation), demonstrate how expression of this gene influences endothelial cell function and assess the influence of WT1 expression on ischaemia-induced angiogenesis in vivo. This research will make use of unique endothelium specific-WT1-conditional knockout mice generated by Prof Hastie's group. Attaining a greater understanding of the influence of WT1 on angiogenesis in health and disease, will aid the development of therapeutic tools to manipulate this pathway to promote (e.g. post myocardial infarction) or halt/reverse (e.g. tumourgenesis) angiogenesis.
Professor Nick Hastie CBE Director of the Institute of Genetics and Molecular Medicine MRC Human Genetics Unit Western General Hospital Crewe Road Edinburgh EH4 2XU
Dr Paddy Hadoke Senior Academic Fellow in Pharmacology Centre for Cardiovascular Science The Queen's Medical Research Institute 47 Little France Crescent Edinburgh EH16 4TJ
Wellcome Trust Clinical PhD Programme as part of the Edinburgh Clinical Academic Track (ECAT) scheme directed by Professors' John Iredale and Brian Walker.
- PhD (2015), Doctor of Philosophy
- MFSTEd (July 2014), Member ofl the Faculty of Surgical Trainers RCSEd
- MRCSEd (2010), Diploma of Membership of the Royal College of Surgeons of Edinburgh
- MBChB (2007), Bachelor of Medicine, Bachelor of Surgery, Edinburgh University
- BSc Hons (1st Class), Bachelor of Science (2003), University of Edinburgh