Investigating the Genetic, Cellular, and Metabolic Events Important for Urothelial Homeostasis and Response to Urinary Tract Infection

OVERALL: PROJECT SUMMARY/ABSTRACT The Columbia University George M. O?Brien Urology Cooperative Research Center brings together an experienced group of investigators with a long track record of productive collaboration to address the causes of the most common benign genitourinary disease, urinary tract infection (UTI). UTIs are prevalent in the United States with 13.3% of women, 2.3% of men and 3.4% of children requiring medical intervention due to E. coli infection of the urethra, bladder, ureter, and kidney. Since 2014, the Columbia O?Brien Research Center has investigated the origins of common developmental defects of the pediatric genitourinary system that cause urinary tract obstruction in human and mouse models. For the proposed renewal application, the Center will build upon these efforts and employ a multidisciplinary approach to address the genetic, cellular, and metabolic events that are important in maintaining urothelial homeostasis and that contribute to the body?s response to UTI. The Center consists of three Research Projects, a new Microbial Genomics Biomedical Core (MGBC), and an Administrative Core. Project 1 will determine the influence of the host genome and the urinary microbiome in UTI, as well as genitourinary structural defects in humans. Project 2 will use mouse models to investigate how the transcriptional regulation of urothelial differentiation differs between normal homeostasis and repair during UTI. Project 3 will elucidate how a novel metabolic pathway, the ?heme machine?, regulates UTI in the bladder. The scientific aims for each of these projects are highly interconnected, and will require a dynamic exchange of knowledge, seamless data sharing, and multidisciplinary, collaborative efforts to achieve success. To achieve these aims, the three projects will be supported by the MGBC that will provide high-quality services for biobanking, extended bacterial culture, microbial genomics (microbiome analyses, comparative genomics, RNASeq), microbial genetics, and consultation for study design. Additionally, the Administrative Core will provide the supporting framework for the Projects and MGBC in addition to integrating and overseeing all of the Center?s activities including the Educational Enrichment Program and the Opportunity Pool Program. Over the past five years, the Center has placed a major emphasis on educating the next generation of clinician-scientists in urologic research, with annual retreats, seminar series, a summer student training program, and minority outreach programs. We have also successfully used the Opportunity Pool mechanism to interact with other NIDDK-funded centers and to attract new investigators to study important disorders in benign urology. Building on our experience from the last five years and leveraging the infrastructure of Columbia?s top-tier biomedical research institution, this proposed renewal will continue to foster multi- and interdisciplinary collaborations between basic, translational, and clinical researchers. The Center will also address questions related to the genetic, cellular, and metabolic events that lead to UTI, while providing opportunities for educational enrichment and engaging investigators from within urology and other fields to serve the larger urological research community.