My goal as an independent researcher is to use a two-pronged approach to study prostate disease: (1) I will use the developing prostate as a model system for elucidating previously unrecognized signaling pathways that contribute to prostate growth and (2) I will investigate these signaling pathways in clinically relevant models of benign prostate hyperplasia or prostate cancer. My research focus in this proposal is to test the overarching hypothesis that ?-catenin is required for prostate ductal development in the embryonic mouse prostate anlagen, the urogenital sinus (UGS). The first two specific aims will investigate the function of ?-catenin during prostatic budding. They will test hypotheses that (1) androgens stimulate ?-catenin-mediated transcription in the UGS and that ?-catenin is required for budding, and (2) ?-catenin mediates cell adhesion during prostatic bud formation and that this action of ?-catenin is required for budding. The last aim investigates the regulation of ?-catenin during budding. It will test the hypothesis that (3) fibroblast growth factor 10 is required for stabilizing ?-catenin during prostatic budding. This research plan has a high probability of leading to the identification of ?-catenin as a central player in prostatic budding. My plan is to use the above results as preliminary data to apply, in year 3 of this award, for an RO1 or R03 grant focused on mechanisms of benign prostate hyperplasia or prostate cancer. As a K01 recipient, I will follow a career development plan with very specific research and development milestones for each award year. I will meet regularly with my mentors and advisory committee and complete didactic coursework in cancer biology. I will obtain experiential training in grant writing, Wnt/ ?-catenin signaling, benign prostate hyperplasia, and prostate cancer. This plan will stretch my research expertise and enhance my training in prostate disease research. The University of Wisconsin is an NIDDK-sponsored O'Brien Urology Research Center, an NCI-sponsored Comprehensive Cancer Center, and boasts nearly 40 prostate research labs, culminating in an ideal training environment for me as a future prostate scientist. Biological factors regulating growth during prostate development are also believed to be responsible for inappropriate growth during prostate disease. The proposed research will investigate how the ?-catenin protein interacts with male sex hormones to control prostate development, as these interactions might provide clues for how inappropriate prostate growth is activated during prostate disease.

Public Health Relevance

Biological factors regulating growth during prostate development are also believed to be responsible for inappropriate growth during prostate disease. The proposed research will investigate how the ?-catenin protein interacts with male sex hormones to control prostate development, as these interactions might provide clues for how inappropriate prostate growth is activated during prostate disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK083425-05
Application #
8451393
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$154,868
Indirect Cost
$11,472
Name
University of Wisconsin Madison
Department
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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
Georgas, Kylie M; Armstrong, Jane; Keast, Janet R et al. (2015) An illustrated anatomical ontology of the developing mouse lower urogenital tract. Development 142:1893-908
Keil, Kimberly P; Abler, Lisa L; Mehta, Vatsal et al. (2014) DNA methylation of E-cadherin is a priming mechanism for prostate development. Dev Biol 387:142-53
Keil, Kimberly P; Abler, Lisa L; Laporta, Jimena et al. (2014) Androgen receptor DNA methylation regulates the timing and androgen sensitivity of mouse prostate ductal development. Dev Biol 396:237-45
Bauman, Tyler M; Nicholson, Tristan M; Abler, Lisa L et al. (2014) Characterization of fibrillar collagens and extracellular matrix of glandular benign prostatic hyperplasia nodules. PLoS One 9:e109102
Keil, Kimberly P; Altmann, Helene M; Mehta, Vatsal et al. (2013) Catalog of mRNA expression patterns for DNA methylating and demethylating genes in developing mouse lower urinary tract. Gene Expr Patterns 13:413-24
Mehta, Vatsal; Schmitz, Christopher T; Keil, Kimberly P et al. (2013) Beta-catenin (CTNNB1) induces Bmp expression in urogenital sinus epithelium and participates in prostatic bud initiation and patterning. Dev Biol 376:125-35
Keil, Kimberly P; Mehta, Vatsal; Abler, Lisa L et al. (2012) Visualization and quantification of mouse prostate development by in situ hybridization. Differentiation 84:232-9
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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