Defining The Role of Failed-Repair Proximal Tubule Cells in AdvancedRenal Disease in African Americans

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Project Summary/Abstract - Shayna T. J. Bradford, Ph.D. Americans of African descent are more than four times as likely to reach end-stage renal disease than those of European descent (2021 USRDS report). Acute kidney injury along with diabetes and hypertension are top risk factors for developing end-stage renal disease. Acute kidney injury can be initiated via diabetic and/or hypertensive events causing nephron injury, among other causes. New nephrons cannot regenerate after injury. Following acute kidney injury, epithelial cells lining proximal tubules of the nephron can repopulate damaged tubules to promote repair. However, a portion of cells fail to repair (termed failed-repair proximal tubule cells) and express proinflammatory and profibrotic markers. Failed-repair proximal tubule cells are hypothesized to cause local inflammation and fibrosis which can promote the acute kidney injury to chronic kidney disease transition, which leads to end-stage renal disease. Using single nucleus RNA-seq we identified a Traf2 and Nck interacting kinase (Tnik) to be specifically expressed in failed-repair proximal tubule cells after acute kidney injury in mice. In this MOSAIC K99/R00 career development proposal, Dr. Shayna Bradford aims to define the role of Tnik in failed-repair proximal tubule cells using a novel mouse model with Tnik ablation specifically in renal tubules. Additionally, she aims to use start-of-the-art single cell multiomic technologies to define the role of failed- repair proximal tubule cells in the advanced acute kidney injury to chronic kidney disease transition in African Americans. Dr. Bradford’s career goal is to be at the forefront of unraveling the molecular mechanisms of renal health disparities in order to develop novel therapeutics to lessen gaps in renal health. Her career development plan consists of gaining expertise in single cell biology and computation, in vivo modeling of renal injury and regeneration, molecular determinants of health disparities, and in additional scientific training areas. She will also continue to build professional Diversity, Equity, and Inclusion skills in order to promote safe and inclusive training experiences in biomedical research. The K99 phase of the MOSAIC award will be carried out under the direction of Dr. Benjamin Humphreys, a distinguished physician-scientist in renal disease research and single cell biology at Washington University. The award will also be guided by an exceptional Faculty Advisory Committee with expertise in multiomics, mouse models of renal regeneration, and health disparities. Washington University is well known for excellence in research and has state-of-the art facilities and robust resources to carry out the proposed studies and career development plans.