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Tubular senescence and proliferative capacity of the aging kidney

衰老肾脏的肾小管衰老和增殖能力

基本信息

批准号：
10613914
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
项目类别：
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/10613914
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Advisory Committees Aging Alzheimer&apos s Disease American Apoptosis Atrophic Attention Biology of Aging CDKN2A gene Cell Aging Cell Cycle Arrest Cell Proliferation Cells Censuses Chronic Kidney Failure Clinical Communities Data Defect Development Disease Elderly Epithelial Cell Proliferation Epithelial Cells Epithelium 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 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 cell dedifferentiation 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

项目摘要

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.

项目概要/摘要急性肾损伤 (AKI) 和慢性肾病 (CKD) 在以下人群中更为常见老年人口增多，美国的老龄化人口正在迅速上升。根据美国人口普查数据统计局称，到 2030 年，65 岁及以上人口将达到约 7200 万，约五分之一的美国人，这是是 2000 年人数的两倍多。医学界已经看到了急性发作的高发病率。老年人群中肾损伤的发生率预计将随着老年人群的增加而继续上升年龄组。这令人担忧的趋势；然而，尽管存在有害和潜在的影响，却很少受到关注与 AKI 发作相关的致命结果，尤其是在这个年龄段。本研究的目的是探索衰老肾脏损伤后修复反应下降的机制特别关注肾小管衰老和上皮细胞增殖。该提案的具体目标包括： 1) 通过去分化的克隆分析来定义年轻与年老的近端小管细胞的增殖能力细胞，2) 评估和表征受伤后年轻肾脏与年老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度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，以指导寻找预防、改善或治愈急性肾病的疗法老年人受伤或其进展为慢性肾脏病。该提案概述了一个为期 5 年的培训计划，为申请人提供支持和指导成为一名独立的医师科学家，研究分子机制的长期职业目标损害衰老过程中急性肾损伤后的再生反应。该计划包括课程作业、培训新的实验室技术和来自 Benjamin Humphreys 博士（肾脏病科主任）的指导华盛顿大学以及拥有丰富专业知识和经验的顾问委员会成员辅导经验。拟议的研究试图解决高度相关的临床问题，例如 AKI 老年人，同时为申请人的职业发展提供资源。