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

Project Summary/Abstract - Shayna T. J. Bradford, Ph.D. Americans of African descent are more than four times at risk for developing end-stage renal disease relative to Americans of European descent (2023 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 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 state-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 serious gaps in renal health. In the R00 phase, she will continue gaining expertise in single-cell biology and computation, in vivo modeling of renal injury and regeneration, molecular mediators of health disparities, and in additional scientific and leadership areas. The R00 phase of this career development proposal will be carried out at Northwestern University Feinberg School of Medicine, a top 20 research oriented medical school with state-of-the art facilities and world class faculty dedicated to improving human health through education and discovery.