The Intersection of Podocyte Disease and Aging

问题的范围是，随着美国人口寿命的延长，肾脏疾病变得更加常见。 特别是，CKD的风险、发病率和患病率随着年龄的增长而增加。因此，疾病的严重程度是 老年患者比例较高，首次接受慢性透析的人数最多。足细胞残骸的损伤 衰老和疾病中肾小球硬化的主要原因。然而，理解 足细胞损伤和衰老及其潜在机制是一个主要的未得到满足的需求。要结束这件事 知识空白，我们的先导研究表明，幼年小鼠足细胞损伤来自两种实验性模型 局灶性节段性肾小球硬化(FSGS)意外地诱导短期复制和应激诱导 早衰。从长远来看，这会导致中年早期小鼠的足细胞过早衰老， 在健康的条件下，通常不会表现出衰老和老化的迹象。这种表型是 伴有肾小球硬化和肾功能减退。最后，同样的相关性也是存在的 在年轻的FSGS患者中观察到。基于这些初步数据，我们提出了一种新的范式， 足细胞损伤和衰老是相交的，由于这些重叠的机制，损伤会放大衰老。 这项提案的总体目标是确定足细胞损伤进展的新机制 年事已高。具体目标#1将证明足细胞损伤会导致足细胞过早衰老 表型。这将通过检验以下假设来实现：(I)对非老化足细胞的损伤原因 依赖p16的复制性衰老和衰老表型；(Ii)年轻足细胞的损伤导致p53- P21轴依赖应激诱导的早衰；(Iii)损伤诱导的长期后果 衰老是一种足细胞过早衰老的表型，导致肾小球瘢痕形成和肾脏萎缩。 功能。具体目标2将证明足细胞损伤和衰老的机制是相交/重叠的 并在彼此叠加时被放大。我们将检验以下假设：(I)截然不同 足细胞亚群负责损伤和衰老之间的交叉；(Ii) 由于衰老而分泌的炎性细胞因子、免疫调节剂和生长因子- 足细胞损伤引发的相关分泌表型促进疾病进展。 使用的创新实验方法包括两种足细胞损伤模型、功能丧失模型 使用四种新的足细胞特异性小鼠突变体来限制足细胞衰老/衰老，获得- 功能途径利用两种新的足细胞特异性转基因小鼠，单核转录损伤 足细胞随时间的变化和全面研究足细胞信号的实验设计方法学 环境。这项提议对整合我们的鼠标数据产生的短期翻译影响意义重大 与来自老年人和患病的人肾脏的大型转录数据集以及它在 开发新的策略来对抗疾病导致的肾功能随年龄增长的衰退。

The scope of the problem is that kidney diseases become more abundant as the US population lives longer. In particular, the risk, incidence, and prevalence of CKD increases with age. As a result, disease severity is higher in elderly patients, the largest group to undergo first-time chronic dialysis. Injury to podocytes remains the primary cause for glomerulosclerosis in both aging and disease. Yet, understanding the intersection of podocyte injury and aging, and the underlying mechanisms responsible are a major unmet need. To close this knowledge gap, our pilot studies showed that podocyte injury in young mice from two models of experimental Focal Segmental Glomerulosclerosis (FSGS) unexpectedly induces short-term replicative- and stress-induced premature senescence. In the long-term this results in premature podocyte aging in early middle-aged mice, which under healthy conditions typically do not exhibit signs of senescence and aging. This phenotype was accompanied by glomerulosclerosis and a reduced kidney function. Finally, the same correlations were also observed in young patients with FSGS. Based on these preliminary data, we propose a novel paradigm that podocyte injury and aging intersect, and because of these overlapping mechanisms, injury amplifies aging. The overall goal of this proposal is to identify novel mechanisms for podocyte injury progression with advancing age. Specific Aim #1 will prove that injury to podocytes causes a premature aging podocyte phenotype. This will be achieved by testing the following hypotheses: (i) Injury to non-aged podocytes causes a p16-dependent replicative senescence and an aged phenotype; (ii) Injury to young podocytes causes a p53- p21 axis-dependent stress-induced premature senescence; (iii) Long-term consequences of injury-induced senescence is a premature podocyte aging phenotype causing glomerular scarring and reduced kidney function. Specific Aim #2 will prove that the mechanisms of podocyte injury and that of aging intersect/overlap and are amplified when superimposed on one another. We will test the following hypotheses: (i) Distinct subpopulations of podocytes are responsible for the intersection between injury and aging; (ii) A combination of inflammatory cytokines, immune modulators and growth factors secreted as a result of the senescent- associated secretory phenotype triggered by podocyte injury promotes disease progression. Innovative experimental approaches used include two models of podocyte injury, loss-of-function approaches using four new podocyte-specific mouse mutants to limit podocyte senescence/ aging, gain-of- function approaches using two new podocyte-specific transgenic mice, single nuclei transcriptomics of injured podocytes over time and the Design-of-Experiment methodology to holistically explore the podocyte signaling environment. The proposal is significant for its short-term translational impact by integrating our mouse data with large transcriptomic data sets from aged and diseased human kidneys and for its long-term impact in developing new strategies to counter the age-dependent demise of kidney function from disease.