Novel Gremlin-1 Mutants as therapeutics in Diabetic Kidney Disease (360G-Wellcome-202395_Z_16_Z)
Diabetic kidney disease affects ≈40% of those with diabetes and is the leading cause of end stage renal disease. Current therapies focusing on regulation of glycaemia, hypertension and RAAS blockade are inadequate, merely slowing progression to eventual organ failure. Given the increased prevalence and devastating consequences of DN there is an urgent need to develop novel therapies. The development of fibrosis, a key pathogenic factor in DN, reflects an imbalance in the activities of endogenous drivers and suppressors of fibrosis typified by the BMP agonist-antagonist system. Prof.Godson’s group previously reported that the BMP antagonist Gremlin-1 is a key driver of DN in experimental models and human disease. Increased Gremlin-1 expression drives fibrotic responses of renal cells antagonizing the activity of BMP agonists. Prof.Godson's group have used in silico tools to design Gremlin-1 molecules which are functional dominant negatives[FDN]. These molecules are expected to bind Gremlin-1 and not agonists, therefore allowing local bioavailability of endogenously generated agonist, thus limiting fibrosis. Prof.Godson's group have expressed these molecules in mammalian cells. We propose to evaluate these novel FDN Gremlin-1 using established in vitro models of DN and renal fibrosis routinely used in Dr.Crean’s laboratory. Such data will identify their utility as therapeutics.
£2,000 01 Apr 2016