Cellular senescence in the pathogenesis of benign prostatic hyperplasia and associated lower urinary tract dysfunction

PROJECT SUMMARY/ABSTRACT Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) is a prevalent condition among aging men, affecting ninety percent of all men above the age of eighty years. The causes of BPH/LUTS are considered multifactorial although it is known that aging is the number one risk factor for development and progression of disease. Despite initial effectiveness, current medical management strategies that target smooth muscle dysfunction or prostatic proliferations often fail to effectively manage disease progression, leading patients to seek out invasive surgical interventions. A key factor hypothesized to contribute to BPH/LUTS progression is prostatic fibrosis, which current therapies do not address. Age mediated cellular senescence, defined as a stable and irreversible cell-cycle arrest, has been implicated in the dysregulation of prostate tissue homeostasis. I hypothesize that age-mediated cellular senescence within the prostate drives prostatic fibrosis and therefore contributes to the development of lower urinary tract dysfunction (LUTD) and BPH. Our study aims to determine the role of senescent cells in BPH/LUTS pathogenesis and evaluate the therapeutic potential of senescent cell elimination. I aim to evaluate this hypothesis using clinical human prostate tissues and mouse models for BPH/LUTS. Specifically, I will investigate whether the degree of lower urinary tract senescence correlates with dysfunction and if targeting p16-positive senescent cells can decrease prostate fibrosis and improve urinary health. Additionally, I will examine the relationship between senescent cells and prostatic fibrosis in human BPH tissues and assess the impact of pharmacologically eliminating senescent cells using a clinically translatable senolytic dasatinib and quercetin (D+Q) in aged mice. This research will provide insights into the role of cellular senescence in BPH/LUTS and explore novel therapeutic approaches to improve patient outcomes. The extensive resources at the University of Wisconsin School of Medicine and Public Health create an optimal setting for the successful execution of this proposed work. Completing this study will foster the development of crucial experimental, mentorship, communication, and clinical skills, facilitating a smooth transition to a career as an independent researcher and surgeon-scientist.