# Role of E-Cadherin Down-Regulation in Prostatic Inflammation and Lower Urinary Tract Dysfunction

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $511,124

## Abstract

Title: Role of E-cadherin down-regulation in prostatic inflammation and lower urinary tract dysfunction
Summary:
 Benign prostatic hyperplasia (BPH) is one of the most common disease conditions in older men. Its
symptoms significantly impact quality of life and treatment costs over $4 billion annually. The proposed study
will focus on histological glandular BPH and associated LUTS. About half of the men with histological BPH are
asymptomatic, and not all patients with LUTS or clinical BPH have large prostate. Histological BPH can lead to
clinical BPH or LUTS as men age. How histological glandular BPH leads to clinical BPH or LUTS is not clear.
Our preliminary studies showed prostatic secretion is leaked into the stroma of all tested glandular BPH,
reflecting compromised epithelial cell-cell junctions in BPH. This observation is consistent with down-regulation
of E-cadherin, a key protein required for cell-cell junction formation, in glandular BPH specimens. To evaluate
the role of E-cadherin down-regulation, we generated an inducible prostate luminal epithelial cell specific E-
cadherin gene (Cdh1) knockout mouse model. In this model, Cdh1 heterozygosity caused prostatic
inflammation, prostatic proliferation, and bladder overactivity, which are 3 key phenotypes associated with
BPH/LUTS. Importantly, these phenotypes were developed in old but not young mice, making these mice an
ideal model for this age-related disease. To explore the mechanisms of E-cadherin down-regulation in BPH,
our preliminary study revealed altered/elevated androgen signaling in BPH epithelial cells and androgen
suppression of E-cadherin expression in explants derived from BPH but not from normal prostate. The above
preliminary data led to our hypothesis that E-cadherin down-regulation in BPH predisposes prostate to
developing inflammation and subsequent bladder overactivity via afferent nerve sensitization. Based
on this hypothesis, we propose the following 3 specific aims. Aim 1 will determine the molecular and cellular
alterations caused by luminal epithelial E-cadherin loss in the prostate of a mouse model – role of prostatic
inflammation. Aim 2 will determine the prostate-to-bladder afferent cross-sensitization mechanisms inducing
bladder overactivity and the effects of COX-2 inhibition or androgen blockade in Cdh1 KO mice. Aim 3 will
determine the roles of altered androgen signaling and inflammatory cytokines in E-cadherin down-regulation in
BPH epithelial cells. The success of the proposed project will provide insights into the causes and effects of E-
cadherin down-regulation in glandular BPH, which will help guide future studies to develop and optimize
therapeutics that could restore E-cadherin expression and/or suppress prostatic inflammation and related
pathways in BPH/LUTS management.

## Key facts

- **NIH application ID:** 10798158
- **Project number:** 5R01DK134580-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Zhou Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $511,124
- **Award type:** 5
- **Project period:** 2023-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798158

## Citation

> US National Institutes of Health, RePORTER application 10798158, Role of E-Cadherin Down-Regulation in Prostatic Inflammation and Lower Urinary Tract Dysfunction (5R01DK134580-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10798158. Licensed CC0.

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