The overarching goal of my proposal is to acquire technical and professional skills to become an independent investigator at a leading academic institution and develop a research program deciphering the molecular mechanism of inflammation induced prostatic tissue remodeling and fibrosis. This will be pursued through a scientific project that will determine whether osteopontin, a pro-fibrotic secreted phosphoprotein, stimulates prostatic inflammation, fibrosis, and lower urinary tract dysfunction. My training is focused on four key areas: 1) functional testing of mouse urinary function, 2) developing biomedical engineering technologies to study prostatic fibrosis in vitro, 3) testing and further developing animal models to study inflammation-induced prostatic fibrosis and its consequences on urinary function and, 4) gaining essential training in immune-regulated tissue remodeling. UW-Madison and the UW O`Brien Center for Benign Urology Research presents a unique environment for the proposed research and career development activities. This includes seminars presented by local and national leaders of the field, career development activities of several institutes across campus, clinical training of the Department of Urology, and specific training in immunopathology and tissue engineering. Lower urinary tract symptoms (LUTS) secondary to benign prostatic diseases deteriorate the quality of life as men age. The treatment of male LUTS costs $4 billion annually and presents an economic burden on our healthcare system. It has been recently identified that prostatic inflammation and fibrosis are associated with LUTS, but the exact contribution of these mechanism to urinary dysfunction is unknown. Medical therapies targeting inflammation and fibrosis could enhance drug development and provide novel molecular targets for LUTS. Based on my preliminary studies, I hypothesize that inflammation-induced osteopontin levels stimulate prostatic fibrosis and lower urinary tract dysfunction (LUTD). The hypothesis will be tested by the following aims: 1) Test the hypothesis that OPN is required for inflammation-induced prostatic collagen accumulation and LUTD, 2) Test the hypothesis that OPN induces prostatic fibrosis. The proposal will provide novel detection of collagen deposition, 3D in vitro and in vivo models of prostatic fibrosis. It will also decipher the specific role of inflammation-induced prostatic fibrosis in lower urinary tract dysfunction. This will be achieved by capitalizing on recently established prostatic inflammation models and state-of-the-art urinary physiological tests uniquely available at the UW-Madison.
This project will investigate the impact of osteopontin-induced prostatic fibrosis on lower urinary tract dysfunction. Defining the molecular players contributing to prostatic fibrosis and how it relates to urinary dysfunction will provide new diagnostic and therapeutic targets to enhance the treatment of lower urinary tract symptoms in men.