Many aging men suffer from lower urinary tract symptoms (LUTS). Although LUTS pathophysiology is almost certainly multi-factorial, it is often caused or exacerbated by bladder outlet obstruction (BOO) associated with benign prostatic hyperplasia (BPH). The etiology of BPH and BOO are unknown. This project is highly significant because it will uncover molecular pathways driving BPH and BOO. Our new preliminary data are consistent with the hypothesis that changing hormone levels in aging men and/or reactivation of a developmental growth-regulatory pathway mediated by beta-catenin (CTNNB1) are underlying causes of BPH and BOO. In our preliminary studies we used an innovative mouse model driven by the hormonal milieu known to be present in aging men. Hormone treatment causes prostate enlargement and urinary dysfunction. Hormone treatment also increases mouse bladder and prostate expression of WNT ligands, canonical WNT pathway target genes, and extracellular matrix constituents. The hypothesis of this project is that hormone-induced CTNNB1 activation in prostate and bladder epithelium mediates cellular and molecular changes that drive benign prostate enlargement, urinary dysfunction, and fibrosis. The hypothesis will be tested in three aims.
In aim 1, we will determine whether CTNNB1 activation in mouse prostate and/or bladder independently causes cellular, molecular, and functional changes in the lower urinary tract.
In aim 2, we will determine whether CTNNB1 deletion protects against hormone-induced mouse urinary dysfunction.
In Aim 3, we will examine associations between expression of WNT/CTNNB1 pathway components and target genes in human symptomatic BPH. It is anticipated that successful completion of this project will identify new mechanisms (and potential new drug targets) for BPH and BOO by demonstrating that WNT signaling via CTNNB1 activates pro-fibrogenic changes in the extracellular matrix of prostate and bladder.

Public Health Relevance

Most aging men will develop symptomatic benign prostate hyperplasia. Factors that impact urinary function and prostate proliferative growth have a clear role in this disease. Our preliminary results support the notion that the hormonal environment of aging men activates CTNNB1 signaling. The proposed studies will test whether CTNNB1 drives cellular and molecular changes that lead to benign prostate enlargement, bladder and prostate fibrosis, and urinary dysfunction.

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 #
8838000
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
$290,609
Indirect Cost
$97,513
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Hill, Warren G; Zeidel, Mark L; Bjorling, Dale E et al. (2018) The void spot assay: Recommendations on the use of a simple micturition assay for mice. Am J Physiol Renal Physiol :
Tomko, Lucas A; Hill, Ryan C; Barrett, Alexander et al. (2018) Targeted matrisome analysis identifies thrombospondin-2 and tenascin-C in aligned collagen stroma from invasive breast carcinoma. Sci Rep 8:12941
Wegner, Kyle A; Abler, Lisa L; Oakes, Steven R et al. (2018) Void spot assay procedural optimization and software for rapid and objective quantification of rodent voiding function, including overlapping urine spots. Am J Physiol Renal Physiol 315:F1067-F1080
Patalano, Susan; Rodríguez-Nieves, José; Colaneri, Cory et al. (2018) CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation. Sci Rep 8:3499
Ruetten, Hannah; Wegner, Kyle A; Romero, Michael F et al. (2018) Prostatic collagen architecture in neutered and intact canines. Prostate 78:839-848
Shea, Michael P; O'Leary, Kathleen A; Wegner, Kyle A et al. (2018) High collagen density augments mTOR-dependent cancer stem cells in ER?+ mammary carcinomas, and increases mTOR-independent lung metastases. Cancer Lett 433:1-9
Joseph, Diya B; Chandrashekar, Anoop S; Abler, Lisa L et al. (2018) In vivo replacement of damaged bladder urothelium by Wolffian duct epithelial cells. Proc Natl Acad Sci U S A 115:8394-8399
Hao, Ling; Wang, Jingxin; Page, David et al. (2018) Comparative Evaluation of MS-based Metabolomics Software and Its Application to Preclinical Alzheimer's Disease. Sci Rep 8:9291
Weaver, Samantha R; Fricke, Hannah P; Xie, Cynthia et al. (2018) Peripartum Fluoxetine Reduces Maternal Trabecular Bone After Weaning and Elevates Mammary Gland Serotonin and PTHrP. Endocrinology 159:2850-2862
Abler, Lisa L; Vezina, Chad M (2018) Links between lower urinary tract symptoms, intermittent hypoxia and diabetes: Causes or cures? Respir Physiol Neurobiol 256:87-96

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