Lower Urinary Tract Symptoms (LUTS) comprises a costly and potentially critical medical problem for millions of aging American men. If ineffectively treated, LUTS can progress to Lower Urinary Tract Dysfunction (LUTD) manifest as urinary retention, recurrent urinary tract infections, bladder calculi, and renal impairment. Data recently published from our laboratory and new data presented in this application show that aging- and inflammation-associated changes in the prostate tissue microenvironment are permissive for extracellular matrix [ECM] deposition and fibrotic changes in tissue architecture. These fibrotic changes increase peri-urethral tissue stiffness, compromise urethral flexibility and compliance, and produce urinary obstructive symptoms and LUTD. Though clearly associated with the development and progression of LUTD, fibrosis is not currently monitored or therapeutically targeted in affected men, even though it is clear that current approaches for treating LUTD, e.g., TURP, 5-?RIs and ?-1-ARAs, are not effective for all men. Therefore, therapeutically targeting tissue fibrosis in addition to current approaches could improve LUTD treatment efficacy. In previous studies we have shown that CXC-type chemokines, including CXCL5 (ENA-78), CXCL8 (IL-8) and, most robustly, CXCL12, secreted by aging prostate stroma and inflammatory infiltrate, promote myofibroblast phenoconversion and ECM deposition, which are essential components of the cellular mechanisms causing tissue fibrosis. Moreover, new data presented here suggests that CXCL12/CXCR4-mediated myofibroblast phenoconversion proceeds through novel signaling pathways that do not require TGF-? or Smad-signaling. Based on these findings, we hypothesize that activation of the CXCL12/CXCR4 axis in the prostate promotes myofibroblast phenoconversion and tissue fibrosis through non-canonical mechanisms coupled to EGFR transactivation and MEK/ERK signaling. To test this, we will determine whether CXCL12/CXCR4 axis activation: 1) Promotes myofibroblast phenoconversion through non-canonical signaling mechanisms;2) Is evident in fibrotic human peri-urethral prostate tissues from men experiencing LUTS drawn from 2 separate studies, and 3) is evident in obese SAMP6 mice in association with fibrosis and urinary voiding dysfunction. The results of these studies will assess the extent to which CXCL12/CXCR4 axis activation contributes to lower urinary tract fibrosis and LUTD, and will determine whether inhibition of the CXCL12/CXCR4 axis provides an anti-fibrotic therapeutic strategy for the treatment of LUTD.

Public Health Relevance

LUTS is a costly and critically progressive medical problem for millions of aging American men. Increasing evidence suggests that fibrosis is a previously unrecognized pathobiology contributing to LUTS. The studies proposed here will assess the extent to which CXCL12/CXCR4 axis activation contributes to lower urinary tract fibrosis and LUTD, and will determine whether inhibition of the CXCL12/CXCR4 axis provides an antifibrotic therapeutic strategy for the treatment of LUTD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54DK104310-01
Application #
8838001
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O2))
Project Start
2014-09-24
Project End
2019-07-31
Budget Start
2014-09-24
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$184,093
Indirect Cost
$13,125
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715