Lower urinary tract symptoms (LUTS), including bladder voiding symptoms, are a common problem in aging men. Voiding symptoms occur in many cases due to bladder outlet obstruction (BOO). While the underlying causes of BOO are unclear and may be multi-factorial, BOO is often found in association with benign prostatic hyperplasia (BPH), another highly prevalent condition in aging men. While the etiology of BPH and BOO remain largely unclear, available data are consistent with the hypothesis that changing hormone levels in aging men and/or the reactivation of developmental growth-regulatory pathways are underlying causes of BPH and associated BOO. In support of the potential role of steroid hormones in BPH and BOO, our preliminary studies showed that male mice treated with testosterone + estradiol (T+E2) at doses that mimic the hormonal milieu in aging human males developed benign enlargement of the prostate that was associated with the appearance of proliferating foci along the urethra that resembled developmental prostatic buds, changes in the morphology of the prostatic peri- urethral region, and a high incidence of urinary retention indicative of BOO. Strikingly, the severity of hormone-induced urinary retention was more than 4-fold greater in 18-month-old mice compared to 2-month-old mice indicating that this model recapitulates the age-dependent susceptibility to BOO that is also seen in humans. The hormone-induced mouse model also exhibited gene expression changes in the prostate that have been reported to occur in human BPH associated with BOO, including the up-regulation of Secreted frizzled related protein 1 (Sfrp1). Using several approaches including the creation and study of Sfrp1 knockout and transgenic mice as well as in vitro experiments, our published and preliminary studies have implicated Sfrp1 signaling via the non-canonical WNT/JNK pathway as a pro-proliferative signal during prostatic development that can be co-opted to trigger abnormal proliferation in the adult prostate. These data suggest that Sfrp1 is likely to be a mediator of BPH pathology rather than merely a biomarker for BPH. We hypothesize that a sub-type of BPH associated with BOO is caused by the reactivation of developmental growth-regulatory pathways including SFRP1/JNK signaling. This hypothesis will be tested using a multi-disciplinary approach that will include an evaluation of mouse models and a collaboration with a surgical pathologist, Wei Huang M.D., who will assist us in evaluating developmental growth factor pathways and JNK signaling in human patient samples.

Public Health Relevance

Benign prostatic hyperplasia (BPH) and bladder outlet obstruction are common problems in aging men that often occur together and require medical intervention ranging from drug therapy to surgery. The limitations of current therapies create a need for additional treatment options for men suffering from BPH and bladder outlet obstruction. This project addresses the need for additional treatment options by conducting mechanistic studies that will identify new molecular pathways that drive the development of BPH and bladder outlet obstruction. It is anticipated that these molecular pathways will serve as future therapeutic targets in the clinical management of BPH and bladder outlet obstruction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091193-07
Application #
8328840
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Rankin, Tracy L
Project Start
2011-09-15
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
7
Fiscal Year
2012
Total Cost
$322,245
Indirect Cost
$105,245
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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
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
Powers, Ginny L; Hammer, Kimberly D P; Domenech, Maribella et al. (2015) Phosphodiesterase 4D inhibitors limit prostate cancer growth potential. Mol Cancer Res 13:149-60
Gamat, Melissa; Malinowski, Rita L; Parkhurst, Linnea J et al. (2015) Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate. PLoS One 10:e0139522
Greer, Tyler; Hao, Ling; Nechyporenko, Anatoliy et al. (2015) Custom 4-Plex DiLeu Isobaric Labels Enable Relative Quantification of Urinary Proteins in Men with Lower Urinary Tract Symptoms (LUTS). PLoS One 10:e0135415
Hammer, Kimberly D P; Alsop, James D; Buresh-Stiemke, Rita A et al. (2014) A novel method for somatic transgenesis of the mouse prostate using the Sleeping Beauty transposon system. Prostate 74:781-91
Bauman, Tyler M; Vezina, Chad M; Huang, Wei et al. (2014) Beta-catenin is elevated in human benign prostatic hyperplasia specimens compared to histologically normal prostate tissue. Am J Clin Exp Urol 2:313-22
Powers, Ginny L; Marker, Paul C (2013) Recent advances in prostate development and links to prostatic diseases. Wiley Interdiscip Rev Syst Biol Med 5:243-56
Buresh-Stiemke, Rita A; Malinowski, Rita L; Keil, Kimberly P et al. (2012) Distinct expression patterns of Sulf1 and Hs6st1 spatially regulate heparan sulfate sulfation during prostate development. Dev Dyn 241:2005-13
Keil, Kimberly P; Mehta, Vatsal; Branam, Amanda M et al. (2012) Wnt inhibitory factor 1 (Wif1) is regulated by androgens and enhances androgen-dependent prostate development. Endocrinology 153:6091-103

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