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.
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.
|Drifka, Cole R; Loeffler, Agnes G; Mathewson, Kara et al. (2016) Comparison of Picrosirius Red Staining With Second Harmonic Generation Imaging for the Quantification of Clinically Relevant Collagen Fiber Features in Histopathology Samples. J Histochem Cytochem 64:519-29|
|Ricke, William A; Lee, Calvin W; Clapper, Tyler R et al. (2016) In Utero and Lactational TCDD Exposure Increases Susceptibility to Lower Urinary Tract Dysfunction in Adulthood. Toxicol Sci 150:429-40|
|Liu, Teresa T; Grubisha, Melanie J; Frahm, Krystle A et al. (2016) Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor Î² (ERÎ²) Response to 5Î±-Reductase Inhibition in Prostate Epithelial Cells. J Biol Chem 291:14747-60|
|Keil, Kimberly P; Abler, Lisa L; Altmann, Helene M et al. (2016) Influence of animal husbandry practices on void spot assay outcomes in C57BL/6J male mice. Neurourol Urodyn 35:192-8|
|Thomas, Samuel; Hao, Ling; Ricke, William A et al. (2016) Biomarker discovery in mass spectrometry-based urinary proteomics. Proteomics Clin Appl 10:358-70|
|Gharaee-Kermani, Mehrnaz; Moore, Bethany B; Macoska, Jill A (2016) Resveratrol-Mediated Repression and Reversion of Prostatic Myofibroblast Phenoconversion. PLoS One 11:e0158357|
|Hao, Ling; Greer, Tyler; Page, David et al. (2016) In-Depth Characterization and Validation of Human Urine Metabolomes Reveal Novel Metabolic Signatures of Lower Urinary Tract Symptoms. Sci Rep 6:30869|
|Bauman, Tyler M; Ricke, Emily A; Drew, Sally A et al. (2016) Quantitation of Protein Expression and Co-localization Using Multiplexed Immuno-histochemical Staining and Multispectral Imaging. J Vis Exp :|
|Jeong, Clara H; Gao, Liying; Dettro, Tyler et al. (2016) Monohaloacetic acid drinking water disinfection by-products inhibit follicle growth and steroidogenesis in mouse ovarian antral follicles in vitro. Reprod Toxicol 62:71-6|
|Mulligan, William A; Wegner, Kyle A; Keil, Kimberly P et al. (2016) Beta-catenin and estrogen signaling collaborate to drive cyclin D1 expression in developing mouse prostate. Differentiation 93:66-71|
Showing the most recent 10 out of 21 publications