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: 10207622
• 负责人: Monica Chang-Panesso
• 金额: $ 14.99万
• 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/10207622
• 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; 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; cytokine; experience; human old age (65+); in vivo; injured; insight; interest; member; new therapeutic target; novel; overexpression; prevent; 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 急性肾脏损伤（AKI）和慢性肾脏病（CKD）在 老年人和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 局，到2030年，大约有7200万人65人及以上，每五个美国人中有一个，这是 在2000年，他们的人数超过两倍。医学界已经看到很高的急性发病率 老年人口的肾脏受伤，预计这将随着这一增加而继续增加 年龄段。这种有关趋势；但是，尽管有不利和潜力，但很少受到关注 致命的结果与AKI发作有关，尤其是在这个年龄段。这项研究的目的是 探索以A的衰老肾脏的降低的机制 特别关注管状衰老和上皮细胞增殖。该提案的具体目的包括： 1）通过克隆分析定义年轻与旧小管细胞的增殖能力 细胞，2）评估和表征年轻与旧肾脏的近端小管衰老，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导致增强肾脏恢复。通过这些目标，我们的目标是了解 衰老肾脏的生物学，以指导寻求预防，改善或治愈急性肾脏的疗法 老年人或其发展为慢性肾脏疾病的伤害。 该提案概述了一项为期5年的培训计划，以向申请人提供支持和指导 长期职业目标是成为研究分子机制的独立医师科学家 衰老急性肾损伤后的再生反应损害。该计划包括课程，培训 Benjamin Humphreys博士的新实验室技术和指导 华盛顿大学和咨询委员会成员，拥有丰富的专业知识， 指导经验。拟议的研究试图解决一个高度相关的临床问题，例如AKI 老年人在为申请人的职业发展提供资源时。