Benign prostatic hyperplasia (BPH) is defined by the expansion of both epithelial and stromal cells within the transition zone of the prostate. Although there is greater expansion of stromal cells in early BPH, epithelial hyperplasia is a significant contributor to larger symptomatic BPH prostates. While numerous studies have linked chronic and recalcitrant inflammation to the development of BPH, the mechanisms by which inflammation leads to cellular proliferation and hyperplasia are unclear. It is known that inflammation produces a microenvironment rich in cytokines, growth factors, and other morphogens that promote proliferation of prostate epithelial cells, including basal prostate stem cells (bPSC). The regulatory mechanisms that control and limit inflammation- induced epithelial cell proliferation under normal homeostatic conditions are not well defined and represent a significant deficit in understanding the potential link between inflammation, uncontrolled cellular growth and prostate enlargement. Data reported herein identify pathways controlling prostate epithelial cell expansion and form the foundation for proposed studies to better define the regulation of inflammation-induced prostate epithelial cell proliferation that leads to hyperplasia. Understanding the pathways involved in inflammation- induced cellular expansion will provide a foundation for the development of novel approaches to block uncontrolled epithelial growth. Adult basal prostate stem cells (bPSC) are specialized cells that maintain and repair the cellular integrity of the prostate; however, studies describing the effect of inflammation on adult bPSC are limited. Previous data from our laboratories show that inflammation stimulates bPSC expansion and generates basal and luminal epithelial hyperplasia in vivo as well as larger organoids compared to non-inflamed (nave) bPSC ex vivo, demonstrating a sustained proliferative effect on these cells. Given that inflammation drives a bPSC to luminal cell transition, which requires androgen receptor (AR) and the data reported herein that inflammation stabilizes AR via phosphorylation and IL-1? and its naturally occurring inhibitor, IL-1ra, where IL-1? inhibits AR expression and IL1ra enhances expression leading to bPSC-driven expansion of epithelial cells. Based on these data, we hypothesize that inflammation drives AR stabilization that drives bPSC expansion and epithelial hyperplasia in BPH. To test the hypothesis we propose to define the molecular basis for inflammation induced AR stabilization, evaluate pathway impact using novel genetically modified mice and define AR-dependent programmatic changes in bPSC linked both to proliferation and epithelial hyperplasia.

Public Health Relevance

The project focuses on determining the impact of inflammation on adult basal prostate stem cells. Preliminary data demonstrate an inflammation induced stabilization of androgen receptor that modulates gene expression in basal prostate stem cells. The project will define the genes/pathways linked to basal stem cell proliferation and its contributions to the development of benign prostate hyperplasia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK126478-01
Application #
10072966
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rankin, Tracy L
Project Start
2020-08-01
Project End
2024-06-30
Budget Start
2020-08-01
Budget End
2021-06-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Purdue University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907