Mechanisms of epithelial renewal in normal and diseased urinary bladder

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DESCRIPTION (provided by applicant): As an NIH-funded post-doctoral fellow, I have worked independently to formulate and test new hypotheses to address unanswered questions in the pathogenesis of an important and common infection, and to improve the understanding of urinary tract biology, in general. The training environment within the lab, department, and medical school provide invaluable support and resources to pursue these questions. Blending multi-disciplinary skills in cell biology, genetics, and microbiology, I discovered mechanisms that permit persistence of E. coli within the bladder epithelium and enable re-emergence to cause recurrent infections. I have established new and genetically well-defined in vivo models to delineate the intricate and integrated signaling network underlying bladder epithelial renewal during development and following injury. My preliminary findings suggest that the bladder has both stem cell-dependent and independent cellular/molecular mechanisms to regulate turnover, that the type of turnover may depend on the type of injury, and that stem cell activation is in part regulated by the Bmp4 signaling pathway. Loss of function analysis of Bmp4 pathway activity will be performed using an inducible bladder-specific gene knockout system to determine a role in USC activation in response to injury and evaluated using histological techniques and qRT-PCR, in situ hybridization, immunohistochemical analyses. Mouse models to elucidate the stem-cell dependent and independent mechanisms of urothelial renewal induced by a spectrum of stimuli will be developed and molecular pathways regulating these processes will be identified using cellular and global gene expression analyses. The longterm goal of this proposal is to identify the molecular mechanisms and signaling pathways underlying the rapid, injury-induced renewal of urothelial progenitor cells and to apply what we learn about the normal mechanisms to disease processes with abnormal urothelial turnover (e.g., recurrent urinary tract infections, interstitial cystitis, bladder cancer). Relevance: This proposal will establish systems to study bladder stem cells and how they are activated during diseases such as urinary tract infections. This work should be of tremendous value and interest, given the propensity for bladder differentiation to go awry in human diseases and should help improve techniques to regenerate bladder tissue in vivo or ex vivo for patients whose bladders have been lost or damaged due to disease.