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.