Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY/ABSTRACT Congenital urinary tract obstruction (UTO) is a leading cause of chronic kidney disease and end stage renal disease in children. Current management strategies cannot prevent chronic kidney disease progression. Recently published data from my F32-funded postdoctoral studies identify renal urothelial remodeling as a protective adaptation to UTO. Both congenital and acquired UTO trigger the formation of Uroplakin (Upk) expressing urothelial cells (UC) that synthesize a bladder-like urothelial plaque. Depletion of urothelial plaque in mice with congenital UTO accelerates renal parenchymal loss, functional impairment, and death – attesting to key roles for Upk-UCs in preventing obstructive nephropathy. A greater understanding of renal urothelial development and repair may lead to therapies aimed at attenuating obstructive kidney disease. Fundamental knowledge gaps exist, however, in our understanding of the formation of Upk-UCs during development and UTO. I have recently demonstrated that Keratin 5 (K5)-expressing UCs differentiate into Upk-UCs during development and following UTO. This application takes direct aim at the hypothesis that K5-UCs are progenitors whose fate is governed by an intrinsic molecular program that varies over time and in response to injury. The anticipated outcome of this research is to establish molecular mechanisms that govern K5-UC progenitor activity, and to determine the contributions of K5-UC progenitors during development and following UTO. In Aim 1, I will investigate whether temporally restricted K5-UC progenitor activity is cell-intrinsic using organoid assays; examine the role of Notch signaling in the regulation of K5-UC fate; and define molecular programs that regulate urothelial development and repair. In Aim 2, I will investigate the significance of the K5-UCs by evaluating the impact of depletion and expansion of K5-UCs on urothelial development and repair during UTO. The studies proposed in this application will reveal the cellular and molecular basis of Upk-UC formation – with the hypothesis that K5-UCs form Upk-UCs in a Notch dependent manner. Successful completion of these aims will provide the foundation for the development of therapies that target K5-UCs for differentiation to attenuate obstructive kidney disease in patients with UTO. In fulfilling these Aims, I will develop critical skills in rare cell isolation, organoid development, signaling pathway analysis, bioinformatics, renal physiology and pathophysiology of obstructive nephropathy. Mastery of these skills, in combination with structured career development activities under the guidance of my mentors and research advisory team, will prepare me to successfully compete for R01 funding and launch my career as an independent scientist focused on developing therapies aimed at attenuating chronic kidney disease progression in children with UTO.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
