Investigating the Genetic, Cellular, and Metabolic Events Important for Urothelial Homeostasis and Response to Injury

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OVERALL: PROJECT SUMMARY/ABSTRACT The Columbia University George M. O’Brien Urology Cooperative Research Center is made up of Columbia’s leading Urologists, Microbiologists, Geneticists, Developmental and Cell Biologists dedicated to solving the central problems of Benign Urology. Our focus builds on the work conducted in prior cycles and proposes to identify solutions to clinical diseases at the juncture between clinical urology, epithelial biology and microbiology. Our faculty include the leading clinical and scientific minds at Columbia, including Chairs and Professors of Urology, Nephrology, Pathology & Cell Biology, Genetics & Development and Medicine. Together our faculty provide the expertise to identify the root causes of urologic disability in three scientific groups. Dr Gharavi has identified major risk loci for vesiculoureteral reflux and is now correlating developmental phenotypes with both changes in the urinary microbiome and lower urinary tract symptoms. Dr Gharavi’s tools include large datasets such as the Lower Urinary Tract Symptoms Research Network (LURN), the UK Biobank and the eMERGE consortium. This effort establishes the field of personalized genomics in benign urology. Dr Mendelsohn evaluates signaling pathways downstream of Pparg, a nuclear receptor that turns out to be a major regulator of cell type specific differentiation in the urothelium, as well as the inflammatory response to injury and infection. The work identifies an off-the-shelf drug that can be a potential treatment for urothelial repair. Dr Barasch focuses on epithelial metabolism identifying a central mechanism of defense against UTI called “nutritional immunity”. He discovered NGAL a protein that blocks iron capture by bacteria, and now has identified a highly active pathway of heme metabolism that produce CO gas. His tools include novel methods of RNA isolation from small amounts of cells, novel probes and chelators of CO, of heme and iron and reporter bacteria and mice. Dr Uhlemann focuses on the evolutionary basis of drug-resistant microorganisms deciphering their molecular mechanisms of virulence. The Microbial Genomics Biomedical Core not only directs all microbiological studies in the O’Brien but also serves as a national resource for microbiome and metagenomic analyses and as a biorepository for drug- resistant UTI isolates. The excitement of our group is encapsulated in the interactions of each component of research from gene discovery to therapeutic applications including both human and mouse models. In this new cycle, we will continue to contribute to urological sciences by generating new genomics datasets (to be shared on dbGAP and GEO), gene lists, animal models (deposited at JAX), bacterial gene editing plasmids and reagents that can be shared with the urology community. We will continue to collaborate with urology experts in Wisconsin, Missouri, Maryland. We will fund new Opportunity Pool recipients, building on the roster of 6 new investigators already funded; and continue to train the next generation of investigators, building on the success of the nearly 90 students who have trained and who have published, received national awards and who are now Urologists and medical doctors.