Tubular senescence and proliferative capacity of the aging kidney

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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.