Connecting Cellular Senescence to Human Disease

该项目旨在将细胞衰老与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老年肾脏疾病中起重要作用，但其在其他组织中的存在仍然不清楚。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体，我们将根据其对衰老表型的影响对其进行评分。然后，我们将使用临床数据库建立这个模型，以验证肾脏中的模型-其中衰老是强烈暗示的-然后将其与新的年龄相关疾病类型联系起来。项目目标1：哪些人类疾病与衰老有关？在这里，我们正在计算组合遗传风险（即给定疾病表型的易感基因座的分数），其可以通过衰老特异性启动子/增强子相互作用（PCHi-C）而不是通过对照表型（增殖和静止，已生成数据）的相互作用来解释。这种方法已经成功地应用于组织特异性相互作用（Javierre等人，2016年），并允许一个屏幕大型GWAS目录。因此，我们将能够在所有研究充分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）旨在鉴定与衰老和肾脏疾病相关的遗传变异，并（B）在肾功能（Shiels实验室）和衰老（Chandra实验室）的细胞模型中测试这些变异。(a)首先，我们将通过目标1中所述的大型GWAS研究揭示肾脏疾病中的衰老，这将为我们留下许多通过衰老特异性相互作用解释的风险位点和候选基因。然后，我们将从GTEX数据中提取eQTL（根据肾脏和年龄依赖性分层），以进一步优先考虑目标1中确定的LD块内的候选遗传变异。因此，出现的变体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），以及涉及衰老期间改变的调节相互作用。(b)其次，我们将使用CRISPR技术在肾输出（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理解，而且还为肾脏疾病衰老的研究提供了新的细胞模型。例如，我们将测定个体遗传变异对细胞过早老化的易感性，这是肾脏疾病的潜在组成部分，当在来自CKD患者的血清中生长时，对应于临床定义的肾功能的不同等级1-5。

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.