Connecting Cellular Senescence to Human Disease

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This project aims to connect the dissonant relationship between cellular senescence and diseases of ageing. Senescence has been shown to play an important role in varied renal diseases of age, however its presence in other tissues remains poorly defined. We propose to connect the pathologies of ageing and disease via a novel study that shall define a novel set of distal, disease variants that we will score depending on their effects on the senescence phenotype. We will then build this model up using clinical databases to verify the model in the kidney - where senescence is strongly implicated - and then link it to novel age-related disease types. Project AimsAim 1: Which human disease conditions involve senescence? Here we are calculating the combined genetic risk (i.e. the fraction of predisposing loci for a given disease phenotype) that can be explained through senescence specific promoter/enhancer interactions (PCHi-C) and not through interactions of the control phenotypes (proliferating and quiescence, for which data has been generated). This approach has successfully been applied using tissue specific interactions (Javierre et al., 2016) and allows one to screen large GWAS catalogues. As a result, we will be able to score the involvement of senescence across all well studied human diseases and propose new conditions where senescence is likely to be involved. Aim 2: What is the role of senescence in renal disease? Here we (a) aim to identify genetic variants associated with senescence and renal disease and to (b) test these in cellular models of kidney function (Shiels lab) and senescence (Chandra lab). (a) Firstly, we will implicate senescence in renal conditions through large GWAS studies as described in Aim 1, which will leave us with a number of risk loci and candidate genes explained through senescence specific interactions. We will then extract eQTLs from GTEX data (stratified for kidney and age-dependence) to further prioritise candidate genetic variants within the LD blocks identified in Aim 1. The variants that emerge will thus be implicated in modulating the expression of particular genes (via GTEX data), and be associated with kidney phenotypes (via the GWAS catalogue), as well as implicated in altered regulatory interactions during senescence. (b) Secondly, we will test the candidate variants in cellular models of renal output (Shiels lab) and senescence (Chandra lab) using the CRISPR technology. This will not only increase our understanding of how senescence is involved in renal disease, but also provide new cellular models for the study of senescence in renal disease. For example, we will assay individual genetic variants for susceptibility to premature cellular ageing, an underlying component of renal disease, when grown in serum derived from CKD patients, corresponding to distinct grades of clinically defined renal function from 1-5.