Project title Interplay Between Stem Cells and Inflammation in Benign Prostatic Hyperplasia Project summary The development of therapies that target the causes rather than the symptoms of benign prostatic hyperplasia (BPH) requires a novel approach to understanding its cellular etiology. We are building a clinically annotated fresh tissue repository for interrogating cell-specific fluctuations and molecular signatures. Evidence in mice and humans demonstrate that androgen-independent stem cells are enriched in the basal epithelium, which is also the site of the majority of proliferating cells in BPH tissue. It is unclear whether increases in stem cells or their progeny are causative in BPH. In addition, human prostate volume is directly correlated with chronic inflammation, and prostate epithelial stem cells are activated by inflammation in mouse models. Accordingly, this study will build a fresh tissue human BPH repository that will be used to investigate the hypothesis that inflammation is correlated with stem cell activity in human BPH. Pioneering studies looking for a cell of origin in prostate cancer have recently produced standardized protocols for harvesting and functionally characterizing stem cells from human prostate, creating an opportunity to address the connections between inflammatory cells and epithelial stem activity in BPH. Towards this end, I have leveraged my department's high patient volume to optimize protocols for fresh tissue collection, stem and inflammatory cell identification by multicolor flow cytometry, and serial passaging of stem cells in 3D organoid culture. The preliminary data has been generated solely in my new laboratory and is a natural progression of my K award hypothesis that metabolism regulates prostate epithelial self-renewal and differentiation. This research proposal is significant because it provides a cellular etiology for the clinical observation that patients with a large prostate volume display high inflammation and are resistant to anti-androgen therapy, and it is innovative in its development of a fresh human prostate biorepository for use of the latest technical advances in flow cytometry and 3D organoid culture. The development of a human tissue repository will provide the resources and preliminary data for an R01 application with Early Stage Investigator status in 2 years.
The proposed research is relevant to men's health because it will provide an alternative mechanism for inhibiting human prostatic enlargement where current therapies fail. The research is highly relevant to the NIDDK Prostate Research Strategic Plan for identifying the cellular etiology of BPH.
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