Benign prostatic hyperplasia is a progressive condition in the aging men characterized by the enlargement of the periurethral regions of prostate gland due to nonmalignant proliferations in both the prostate epithelial and stromal compartments. An estimated 50% of men have histologic evidence of BPH by age 50 years and 75% by age 80 years. BPH is often accompanied by lower urinary tract symptoms (LUTS). BPH is rarely fatal, but may cause serious life-threatening complications such as acute urinary retention if left untreated. Androgen targeted therapies such as finasteride are clinically employed for the treatment of BPH. However, the MTOPS study shows that even combination therapy using finasteride and doxazosin only leads to a 66% reduction of risk for clinical progression of LUTS/BPH, suggesting the existence of unrecognized mechanisms that promote disease progression. The goal of this application is to investigate novel molecular mechanisms that contribute to BPH initiation and progression. This application is based on our novel preliminary observation that attenuating the androgen receptor signaling in prostate epithelial cells induces an inflammatory microenvironment. We hypothesize that this prostatic inflammatory microenvironment contributes to progression of BPH. Through the three Aims in this application, we seek to generate novel mouse models for human BPH, use mouse models to determine the contribution of immune cells to prostate epithelial cell proliferation, and identiy novel key signaling mediated by the inflammatory prostatic microenvironment that is capable of promoting epithelial cell proliferation.

Public Health Relevance

Molecular mechanisms of BPH initiation and progression remain incompletely understood. The lack of understanding of these mechanisms is a barrier to improved treatment. Our study will address this knowledge gap by identifying mechanisms and pathways that may evolve as therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK107436-03
Application #
9697205
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rankin, Tracy L
Project Start
2018-09-01
Project End
2020-06-30
Budget Start
2018-09-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Zhang, Boyu; Kwon, Oh-Joon; Henry, Gervaise et al. (2016) Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor. Mol Cell 63:976-89