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.

项目总结/摘要 急性肾损伤（阿基）和慢性肾病（CKD）在老年人中更为常见。 老年人，美国的老龄化人口正在迅速增加。根据美国人口普查局的数据， 到2030年，大约有7200万65岁及以上的人，大约每五个美国人中就有一个，这是 是2000年的两倍多。医学界已经看到了急性 老年人群中的肾损伤，预计这将继续上升， 年龄段然而，这一令人担忧的趋势几乎没有受到关注，尽管它具有有害和潜在的影响。 与阿基发作相关的致命结局，尤其是在该年龄组中。本研究的目的是 探讨衰老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)通过去分化的细胞克隆分析来确定年轻与老年近曲小管细胞的增殖能力。 细胞，2）评估和表征损伤后年轻肾与老年肾的近端小管衰老，以及3） 确定是否通过转录因子的瞬时过表达增强增殖反应 Foxm 1可促进肾脏恢复。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病的疗法。 老年人的损伤或其进展为慢性肾脏疾病。 本建议书概述了一个为期5年的培训计划，为申请人提供支持和指导 长期的职业目标是成为一名独立的医生科学家，研究分子机制， 损害衰老中急性肾损伤后的再生反应。该计划包括课程作业， 新的实验室技术和来自肾脏科主任Benjamin Humphreys博士的指导， 华盛顿大学，以及咨询委员会成员谁拥有丰富的专业知识和 指导经验。拟议的研究试图解决高度相关的临床问题，如阿基， 同时为申请人的职业发展提供资源。