Connecting Cellular Senescence to Human Disease

这个项目旨在将细胞衰老和衰老疾病之间的不和谐关系联系起来。衰老已被证明在各种年龄肾病中起重要作用，然而它在其他组织中的存在仍然不明确。我们建议通过一项新的研究将衰老和疾病的病理联系起来，该研究将定义一组新的远端疾病变异，我们将根据它们对衰老表型的影响进行评分。然后，我们将利用临床数据库建立这个模型，在肾脏中验证这个模型——衰老与肾脏密切相关——然后将它与新的与年龄相关的疾病类型联系起来。项目目标1：哪些人类疾病与衰老有关？在这里，我们正在计算可以通过衰老特异性启动子/增强子相互作用（PCHi-C）而不是通过控制表型（增殖和静止，已生成数据）来解释的综合遗传风险（即给定疾病表型的易感位点的比例）。该方法已成功应用于组织特异性相互作用（Javierre et al., 2016），并允许筛选大型GWAS目录。因此，我们将能够在所有经过充分研究的人类疾病中对衰老的参与进行评分，并提出可能涉及衰老的新条件。目的2：衰老在肾脏疾病中的作用是什么？在这里，我们(a)旨在确定与衰老和肾脏疾病相关的遗传变异，并(b)在肾脏功能（谢尔实验室）和衰老（钱德拉实验室）的细胞模型中测试这些变异。(a)首先，我们将通过Aim 1中描述的大型GWAS研究将衰老与肾脏疾病联系起来，这将为我们留下一些风险位点和候选基因，通过衰老特异性相互作用来解释。然后，我们将从GTEX数据中提取eqtl（对肾脏和年龄依赖性进行分层），以进一步优先考虑在Aim 1中确定的LD块中的候选遗传变异。因此，出现的变异将涉及调节特定基因的表达（通过GTEX数据），并与肾脏表型相关（通过GWAS目录），以及涉及衰老过程中调节相互作用的改变。(b)其次，我们将使用CRISPR技术在肾输出量（Shiels实验室）和衰老（Chandra实验室）的细胞模型中测试候选变体。这不仅将增加我们对衰老如何参与肾脏疾病的认识，也将为肾脏疾病中衰老的研究提供新的细胞模型。例如，我们将检测个体基因变异对细胞过早衰老的易感性，这是肾脏疾病的潜在成分，当在CKD患者的血清中生长时，对应于临床定义的1-5级肾功能的不同等级。

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.