Identification of mechanisms predisposing to renal fibrosis in Chronic Kidney Disease (CKD)

CKD represents a large healthcare burden worldwide. The causes of CKD are multitude yet the underlying feature irrespective of aetiology, is progressive renal fibrosis resulting in end-stage renal disease (ESRD) and the need for renal replacement therapy. The mechanisms of renal fibrosis remain poorly understood and there are no effective anti-fibrotic drugs. It is currently not possible to predict rate of decline in renal function and wide variation in the course of disease in different individuals subjected to the same insult suggests the presence of modifying or pre-disposing factors. Membranous nephropathy (MN) is an autoimmune disease caused by autoantibodies to two recently identified renal antigens (PLA2R and THSD7A). Approximately one third of MN patients develop severe fibrosis and ESRD, one third develop a milder degree of fibrosis and chronic renal impairment while one third have no scarring/renal impairment thus MN provides a unique model in which to identify genetic factors that predispose to fibrosis. The project will exploit our unique stratified cohort of MN patients to identify genes associated with the degree of fibrosis using state-of-the-art genotyping (GWAS) and transcriptomic profiling (RNASeq). The functional relevance of identified genes will be investigated in vitro using pharmacological and gene manipulation strategies in well-established fibrogenic assays. Elucidating the mechanism of action may identify candidate targets for therapeutic intervention. Further, in longitudinal studies, it will be possible to establish whether the identified gene(s) predict disease outcome.

References:
Stanescu et al: Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med 2011, 364:616-626.
Cattran DC, Brenchley PE: Membranous nephropathy: integrating basic science into improved clinical management. Kidney Int 2017, 91:566-574.
Gewin L, Zent R, Pozzi A: Progression of chronic kidney disease: too much cellular talk causes damage. Kidney Int 2017, 91:552-560.

Further details on how to apply for this project can be found using the Apply Online button below.

Informal enquiry contact details:
Professor Robert Kleta [Email Address Removed] or Dr Jill Norman [Email Address Removed]
How to Apply
Please send your covering letter (detailing why you would like to apply) and CV to [Email Address Removed]. Please indicate the project you would like to apply for. More information on the science underpinning this programme can be found at www.qmul.ac.uk/citi/ and www.ucl.ac.uk/flarre.

Deadline for applications: 1st July 2017.

Interviews will be held in the middle of July 2017.