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.

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。