The long term objective of this project is to develop better methods for the prevention and treatment of lower urinary tract symptoms (LUTS) in men. Benign prostatic hyperplasia (BPH) occurs in a vast majority of men and contributes to the morbidity known as LUTS. Clinical treatment for LUTS ascribed to BPH in men is a significant cost in healthcare, adversely affecting quality of life, and contribute to the mortality risk in men and women. While the etiology of BPH remains largely unclear available data are consistent with the hypothesis that changing hormone levels, especially testosterone (T) and estradiol-17b (E2), are underlying causes of BPH and bladder outlet obstruction (BOO). In support of this idea the standard of care for men with enlarged prostates targets the androgenic pathway. However, as men age the amount of androgens significantly decrease while the estrogen to testosterone ratio increases. This posits that estrogens may be an important pathway in the manifestation or maintenance of BPH and associated BOO. New unpublished data from us and others implicates the testosterone metabolite E2 as a key mediator of BPH. However, little is known how estrogens may elicit their affects in the prostate and few models of BPH and BOO exist that will allow for the genetic and pharmacologic dissection of molecular pathways. In this regard, we have developed a new genetically tractable mouse model in which males treated with T+E2, to mimic the hormonal milieu in aging men, develop lower urogenital tract abnormalities consistent with BPH found in men. These criteria include: new glandular prostatic growth, prostatic urethral narrowing, progressively enlarged bladders, and urination patterns of high frequency and low volume. Our preliminary data implicate E2/estrogen receptor (ER)-signaling and specifically ER-a/a homodimerization as a key molecular determinant of lower urogenital tract abnormalities that are consistently found in men with BPH. Furthermore, we have observed increased expression of fibroblast growth factors (FGFs) and activated FGF receptors in human specimens of BPH and in our animal models. We hypothesize that abnormalities within the lower urogenital tract are mediated by inappropriate E2/ER-signaling in turn affecting paracrine acting estromedins to promote BPH and associated BOO.

Public Health Relevance

During the aging process nearly all men experience some form of lower urinary tract symptoms (LUTS), often due to benign prostatic hyperplasia (BPH). In addition to morbidity and quality of life issues, LUTS also significantly affects mortality risk by up to 50% in men and women. The proposed research addresses an urgent need in the urological field by performing estrogen hormone action mechanistic studies that underpin molecular pathways involved in BPH. The expectation of these studies is to develop therapeutic targets towards currently unknown pathways involved in BPH and hence prevent or treat this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093690-04
Application #
8719985
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Rankin, Tracy L
Project Start
2011-09-15
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$327,338
Indirect Cost
$109,838
Name
University of Wisconsin Madison
Department
Urology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Thomas, Samuel; Hao, Ling; Ricke, William A et al. (2016) Biomarker discovery in mass spectrometry-based urinary proteomics. Proteomics Clin Appl 10:358-70
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
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
Bauman, Tyler M; Vezina, Chad M; Ricke, Emily A et al. (2016) Expression and colocalization of β-catenin and lymphoid enhancing factor-1 in prostate cancer progression. Hum Pathol 51:124-33
Theberge, Ashleigh B; Yu, Jiaquan; Young, Edmond W K et al. (2015) Microfluidic multiculture assay to analyze biomolecular signaling in angiogenesis. Anal Chem 87:3239-46
Nicholson, Tristan M; Moses, Michael A; Uchtmann, Kristen S et al. (2015) Estrogen receptor-α is a key mediator and therapeutic target for bladder complications of benign prostatic hyperplasia. J Urol 193:722-9
Bauman, Tyler M; Becka, Alexander J; Sehgal, Priyanka D et al. (2015) SIGIRR/TIR8, an important regulator of TLR4 and IL-1R-mediated NF-κB activation, predicts biochemical recurrence after prostatectomy in low-grade prostate carcinomas. Hum Pathol 46:1744-51
Wynder, Jalissa L; Nicholson, Tristan M; DeFranco, Donald B et al. (2015) Estrogens and Male Lower Urinary Tract Dysfunction. Curr Urol Rep 16:61

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