The urothelium is a water-proof epithelium lining ureters and the bladder, that acts as a critical barrier to protect against infection and prevent the exchange of water and toxic substances between the blood and urinary outflow tract. The urothelium is one of the most quiescent epithelia in the body, but can rapidly regenerate in response to injury from exposure to toxins and drugs such as cyclophosphamide or urinary tract infection (UTI), one of the most common infections in women. The urothelium is composed of several sub- populations of cells that may be distinguished based on morphology and expression of combinatorial markers. These sub-populations are crtical to maintaining homeostasis and responding when the urothelium is injured; however, our understanding of the cellular processes that contribute to urothelium homeostatsis and repair in response to injury remain lacking. Our initial results using loss-of-function and gain-of-function mutants, indicate that Peroxisome proliferator-activated receptor gamma (Pparg), a nuclear receptor family member expressed in the urothelium, may be an important regulator of two sub-populations of cells, S-cells and K14- Basal, in vivo. In this application for Project 2 of the Columbia George M. O?Brien Urology Research Center we will use genetic mouse models to identify Pparg-regulated transcriptional pathways that are normally important for urothelial homeostasis, differentiation, and regeneration. Working closely with the Microbial Genomics Biomedical Core, we will characterize cell-type specific functions of Pparg in urothelial homeostasis and regeneration, using a mouse model of Urinary Tract Infection. Additionally, we will determine whether Pparg is important in K14-Basal cells for suppressing squamous differentiation. We will also assess whether activated Pparg can direct K14-Basal cells to undergo an S-cell differentiation program. With these aims, we will fulfill the larger mission of the Columbia O?Brien Center by investigating the genetic and cellular events that are important in maintaining urothelial homeostasis and that contribute to the body?s response to UTI.
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