The Intersection of Podocyte Disease and Aging

足细胞疾病与衰老的交叉点

• 批准号: 10733868
• 负责人: Stuart James Shankland
• 金额: $ 76.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733868
• 关键词: Acceleration; Address; Adriamycin PFS; Adult; Affect; Age; Aging; Antibodies; Cardiovascular system; Cell Aging; Cell Culture Techniques; Cell Nucleus; Cell physiology; Cells; Chronic; Chronic Kidney Failure; Cicatrix; Clinical; Coupled; Data; Data Analyses; Data Set; Deterioration; Dialysis procedure; Disease; Disease Progression; Elderly; End stage renal failure; Environment; Exhibits; Experimental Designs; Experimental Models; Focal and Segmental Glomerulosclerosis; Gene Expression; Glomerular Filtration Rate; Goals; Grant; Growth Factor; Health; Heterogeneity; Human; Immunomodulators; Incidence; Inflammatory; Injury; Injury to Kidney; Kidney; Kidney Diseases; Knowledge; Longevity; Methodology; Modeling; Molecular; Morbidity - disease rate; Mus; Mutant Strains Mice; Nuclear RNA; Outcome; Pathway interactions; Patients; Persons; Phenotype; Pilot Projects; Population; Premature aging syndrome; Prevalence; Public Health; Publishing; Renal function; Renal glomerular disease; Research; Research Personnel; Risk; Role; Severity of illness; Signal Transduction; Stress; TP53 gene; Testing; Time; Transgenic Mice; Work; age related; aged; cytokine; gain of function; gene function; glomerulosclerosis; healthspan; healthy aging; human data; human disease; human old age (65+); injured; innovation; loss of function; mathematical model; middle age; mouse model; novel; older patient; overexpression; podocyte; premature; primary endpoint; secondary endpoint; senescence; transcriptome sequencing; transcriptomics; translational impact

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.

这个问题的范围是，随着美国人口寿命的延长，肾脏疾病变得越来越多。 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 老年患者较高，是首次接受慢性透析的最大群体。足细胞损伤仍然存在 肾小球硬化的主要原因在衰老和疾病。然而，理解 足细胞损伤和老化以及相关的潜在机制是一个主要的未满足的需求。要关闭此 由于缺乏相关知识，我们的初步研究表明，两种实验模型中幼龄小鼠足细胞损伤 局灶节段性肾小球硬化症（FSGS）意外地诱导短期复制和应激诱导的 过早衰老从长远来看，这会导致中年小鼠的足细胞过早老化， 其在健康条件下通常不表现出衰老和老化的迹象。该表型是 伴有肾小球硬化和肾功能下降。最后，同样的相关性也是 在FSGS的年轻患者中观察到。基于这些初步数据，我们提出了一个新的范式， 足细胞损伤和衰老相互交叉，并且由于这些重叠的机制，损伤放大了衰老。 本提案的总体目标是确定足细胞损伤进展的新机制， 年龄增长。具体目标#1将证明足细胞损伤导致足细胞过早老化 表型这将通过检验以下假设来实现：（i）非老化足细胞损伤导致 p16依赖性复制性衰老和衰老表型;（ii）年轻足细胞损伤导致p53- p21轴依赖性应激诱导的早衰;（iii）损伤诱导的 衰老是一种过早的足细胞老化表型，导致肾小球瘢痕形成和肾功能减退 功能具体目标#2将证明足细胞损伤和衰老的机制交叉/重叠 并且当彼此叠加时被放大。我们将测试以下假设：（一）不同的 足细胞的亚群负责损伤和衰老之间的交叉;（ii） 炎症细胞因子、免疫调节剂和生长因子的分泌， 由足细胞损伤触发的相关分泌表型促进疾病进展。 创新的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/老化， 功能的方法，使用两个新的足细胞特异性转基因小鼠，单核转录组学损伤 足细胞随时间的变化和实验设计方法，以全面探索足细胞信号传导 环境通过整合我们的小鼠数据，该提议对于其短期翻译影响具有重要意义 从老年和患病的人类肾脏中获得的大量转录组数据集，以及其对人类肾脏疾病的长期影响， 开发新的策略来对抗疾病导致的肾功能的年龄依赖性死亡。