Transcriptional regulation of urothelial differentiation and cell type specification during homeostasis and regeneration

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PROJECT 2: PROJECT SUMMARY/ABSTRACT The mission of the Columbia University George M. O’Brien Urology Cooperative Research Center is to advance the understanding of benign genitourinary diseases/disorders. The Center consists of an Administrative (Admin) Core, a Microbial Genomics Biomedical Research Core, and three Research Projects that include preclinical and clinical studies. Our focus includes: (1) the intersection of the host genome and the urinary microbiome; (2) the transcriptional regulation of urothelial differentiation during homeostasis and repair in response to UTI; and (3) how the regulation of urinary chemistry and urothelial iron metabolism (“iron-heme machine”) is a component of the urothelial response to UTI. We anticipate that the proposed studies will provide new insight into the pathogenesis of disorders of high relevance to benign urology and also facilitate introduction of genetic testing into the practice of Urology and even suggest new treatments. We will examine the interactions between host and invading bacteria, and the role of nutrient iron in shaping the outcome of UT infections; we will undertake a new GWAS analysis to search for mutations that lead to LUTD, including incontinence, obstruction and pelvic floor prolapse, we will analyze the urinary microbiome of patients with lower urinary tract disfunction (LUTD), and we propose to identify pathways that program urothelial cell types that may be used to treat benign urothelial abnormalities associated with disease. The most important goal of this center is to utilize the expertise and experience of the urological community to increase the scope of our studies and to help direct the kinds of questions we will address. We have directly integrated members of the P20/U54 community as well as clinicians and scientists in the benign urological community. Co-investigators on our projects include Indira Mysorekar (P20), an expert in UTI and urothelial biology who will work with Dr. Mendelsohn and Dr. Barasch, Chad Vezina (Wisconsin U54) and collaborating scientists and clinicians from the benign urological community, (Lori Birder, Gerry Apodaca, Doug Strand). In addition, we have invited outside experts to join our work, for example, the heme biologist, Iqbal Hamza (University of Maryland). We are also highly focused on education and outreach: Our summer program has trained 73 students since our center has been established, including undergraduates, fourth year medical students and urology residents. we have provided opportunity pool funds to Dr. Putonti (Loyola University) and Dr. Catherine Brownstein, (Harvard University). We held a Symposium in October of 2019 that was extremely successful "The problem of UTI: The microbiome of the Urogenital Tract and its immune Defense" bringing together a dozen experts with >138 members of the Urological community.