Tubular senescence and proliferative capacity of the aging kidney

衰老肾脏的肾小管衰老和增殖能力

• 批准号: 10397142
• 负责人: Monica Chang-Panesso
• 金额: $ 15.05万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397142
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Advisory Committees; Aging; Alzheimer' s Disease; American; Apoptosis; Atrophic; Attention; Biology of Aging; CDKN2A gene; Cell Aging; Cell Cycle Arrest; Cell Proliferation; Cells; Censuses; Chronic Kidney Failure; Clinical; Clone Cells; Communities; Data; Defect; Development; Disease; Elderly; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; FOXM1 gene; Fatal Outcome; Fibrosis; Gene Expression Profile; Goals; Impairment; In Vitro; Incidence; Injury; Injury to Kidney; Kidney; Knock-in Mouse; Label; Laboratories; Medical; Mentorship; Molecular; Morphology; Mus; Natural regeneration; Nephrology; Organ; Parkinson Disease; Pathogenesis; Persons; Phenotype; Physicians; Play; Population; Predisposition; Proliferating; Recording of previous events; Recovery; Regenerative response; Reporting; Repression; Resources; Risk; Risk Factors; Role; Scientist; Site; Techniques; Testing; Therapeutic Intervention; Time; Training; Training Programs; Tubular formation; United States; Universities; Washington; World Health Organization; age group; age related; aged; aging population; biomarker panel; career; career development; clinically relevant; experience; human old age (65+); in vivo; injured; insight; interest; member; new therapeutic target; novel; overexpression; prevent; profibrotic cytokine; repaired; reparative capacity; response; senescence; transcription factor; trend

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) and chronic kidney disease (CKD) are much more common among the elderly, and the aging population in the United States is rising rapidly. According to data from US Census Bureau, there will be about 72 million people 65 and older by 2030, about one in every five Americans, this is more than twice their number in 2000. The medical community is already seeing a high incidence of acute kidney injury in the elderly population and it is expected that this will continue to rise with an increase in this age group. This concerning trend; however, has received little attention despite the detrimental and potential fatal outcomes associated with an episode of AKI, especially in this age group. The purpose of this study is to explore the mechanisms that underlie the decrease reparative response in the aging kidney after injury with a special focus on tubular senescence and epithelial cell proliferation. The specific aims of this proposal include: 1) Define the proliferative capacity of young vs. old proximal tubule cells by clonal analysis of dedifferentiated cells, 2) Assess and characterize proximal tubule senescence in young vs. old kidneys after injury, and 3) To determine if augmenting the proliferative response via transient overexpression of the transcription factor Foxm1 leads to enhance renal recovery. Through these aims, our goal is to get an understanding of the biology of the aging kidney in order to guide the quest for therapies to prevent, ameliorate or cure acute kidney injury in the elderly or its progression to chronic kidney disease. This proposal outlines a 5-year training program to provide support and guidance towards the applicant long-term career goal of becoming an independent physician-scientist studying the molecular mechanisms that impair the regenerative response after acute kidney injury in aging. The plan consists of coursework, training in new laboratory techniques and guidance from Dr. Benjamin Humphreys, Chief of Division of Nephrology at Washington University, and members of the advisory committee who have a diverse wealth of expertise and mentorship experience. The proposed studies try to address a highly relevant clinical problem such as AKI in the elderly while providing resources for the applicant's career development.

项目摘要/摘要 急性肾损伤(AKI)和慢性肾脏疾病(CKD)在 老年人，而美国的老龄化人口正在迅速上升。根据美国人口普查的数据 统计局，到2030年将有大约7200万65岁及以上的人，大约每五个美国人中就有一个，这是 数量是2000年的两倍多。医学界已经看到急性肺炎的高发病率 老年人群中的肾脏损伤，预计随着这一比例的增加，这一比例将继续上升 年龄段。这一令人担忧的趋势；然而，尽管有有害的和潜在的 与AKI发作相关的致命后果，特别是在这个年龄段。这项研究的目的是 探讨老年肾脏损伤后修复反应降低的机制 特别关注肾小管衰老和上皮细胞增殖。这项建议的具体目标包括： 1)通过去分化克隆分析确定年轻和老年近端小管细胞的增殖能力 细胞，2)评估和表征损伤后年轻肾脏和老年肾脏近端小管的衰老，以及3) 确定是否通过转录因子的瞬时过表达来增强增殖反应 FOXM1可促进肾功能恢复。通过这些目标，我们的目标是了解 肾脏老化生物学，以指导预防、改善或治愈急性肾脏的治疗方法的探索 老年人的损伤或其进展为慢性肾脏疾病。 该提案概述了一项为期5年的培训计划，为申请者提供支持和指导 长期的职业目标是成为一名独立的内科医生-科学家，研究 损伤老年急性肾损伤后的再生反应。该计划包括课程作业、培训和 新的实验室技术和本杰明·汉弗莱斯博士的指导，他是华盛顿大学肾脏病学部主任 华盛顿大学和咨询委员会成员，他们拥有丰富的专业知识和 指导经验。拟议的研究试图解决一个高度相关的临床问题，如急性肾功能衰竭 在为申请者的职业发展提供资源的同时，为老年人提供服务。