Investigating the role of DNA repair mechanisms in the development of age-related podocyte malfunction and its consequence on key organs

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For decades, clinicians have recognised that the kidney loses function with age. The elderly exhibit progressive decreases in renal blood flow and glomerular filtration rate. As ageing is a systemic event, affecting all organs, it is difficult to resolve between intrinsic age-related (whose that originate within the kidney) and extrinsic events which are responsible for the loss of renal function. Being able to resolve this issue is key to firstly developing a fully mechanistic understanding of the ageing process in the kidney and secondly developing therapies aimed at improving the quality of patient life.Accumulation of DNA damage is one of the key drivers underpinning age-related organ function decline. We have shown that loss-of-function mutations in key regulator of DNA repair (Excision repair cross-complementation 1, Ercc1) lead to progeria (accelerated ageing) which manifests in loss of kidney function. Recently, we have made the striking finding that attenuation of Activin receptor signalling (using the soluble ligand trap protein sActRIIB) prevented many of the key signs of ageing including preventing proteinuria, maintenance of normal podocyte food processes and glomerular basement membrane morphology. Our findings embody an extraordinary prospect to not only identify the signalling pathway the underpin that age-related decline in kidney function but more notably establish a means of discovering pathways and ultimately the molecules that can prevent renal pathology. In this ground-breaking project, we hypothesise that: The accumulation of DNA mutations in podocytes leads to aberrant Activin signalling that attenuates kidney function and initiates a cascade of inter-organ signalling that leads to systemic perturbations. The aims will be reached using a multidisciplinary approach encompassing tissue, cellular and molecular approaches guided by cutting-edge bio-informatic tools. It is our goal that by the end of the project we will not only develop mechanistic insight into the processes that lead to age-related kidney malfunction but also to identify therapeutic targets as a treatment option.