The impact of aging on prostate growth regulation is central to efforts to elucidate the genesis of BPH and identify factors which contribute to prostate cancer initiation and progression. Three growth perturbing influences afflict the prostate of the aging male: tonic androgen stimulation, oxidative stress, and environmental exposure to chemical or toxic compounds. Each of these influences alone can disrupt normal growth regulation but the compounding effect of these influences is likely to be much larger. Acting in combination over the lifespan of an individual, these influences are postulated to degrade the normal growth regulatory mechanisms charged with maintaining growth homeostasis. The unifying hypothesis of this O'Brien Center proposal is that aging and the environment produce acquired changes in prostate growth control that predispose to neoplasia. This proposal examines the pathways and mechanisms that mediate those effects. The proposed Center embraces seven research subprojects. Four subprojects will examine how androgen stimulation produces oxidative stress, elucidate how changes in cellular redox state produces epigenetic changes in gene regulation and growth regulation, and examine the effect of oxidative stress on gene imprinting. Three subprojects examine chemical influences on prostate growth. One examines the mechanism of action of green tea; a second focuses on the plantalkaloid sensitive hedgehog signaling pathway; and a third project, an NIEHS merit award included as a non-reviewed project, examines the effect of dioxin on prostate development. Two DR/P&F projects selected from a total of 9 submitted preproposals address the immunology of androgen withdrawal induced prostatitis and the potential to design small molecule inhibitors of key signal transduction pathways based on peptide motif analysis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center (P50)
Project #
5P50DK065303-05
Application #
7287295
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (M1))
Program Officer
Hoshizaki, Deborah K
Project Start
2003-09-30
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2009-08-31
Support Year
5
Fiscal Year
2007
Total Cost
$758,176
Indirect Cost
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Syed, Deeba N; Chamcheu, Jean-Christopher; Adhami, Vaqar M et al. (2013) Pomegranate extracts and cancer prevention: molecular and cellular activities. Anticancer Agents Med Chem 13:1149-61
Yu, Min; Bushman, Wade (2013) Differential stage-dependent regulation of prostatic epithelial morphogenesis by Hedgehog signaling. Dev Biol 380:87-98
Asim, Mohammad; Hafeez, Bilal Bin; Siddiqui, Imtiaz Ahmad et al. (2011) Ligand-dependent corepressor acts as a novel androgen receptor corepressor, inhibits prostate cancer growth, and is functionally inactivated by the Src protein kinase. J Biol Chem 286:37108-17
Vezina, Chad M; Hardin, Heather A; Moore, Robert W et al. (2010) 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits fibroblast growth factor 10-induced prostatic bud formation in mouse urogenital sinus. Toxicol Sci 113:198-206
Bhusari, Sachin S; Dobosy, Joseph R; Fu, Vivian et al. (2010) Superoxide dismutase 1 knockdown induces oxidative stress and DNA methylation loss in the prostate. Epigenetics 5:402-9
Khan, Naghma; Mukhtar, Hasan (2010) Cancer and metastasis: prevention and treatment by green tea. Cancer Metastasis Rev 29:435-45
Khan, Naghma; Afaq, Farrukh; Mukhtar, Hasan (2010) Lifestyle as risk factor for cancer: Evidence from human studies. Cancer Lett 293:133-43
Lipinski, Robert J; Bushman, Wade (2010) Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening. Toxicol In Vitro 24:1404-9
Ewald, Jonathan A; Desotelle, Joshua A; Wilding, George et al. (2010) Therapy-induced senescence in cancer. J Natl Cancer Inst 102:1536-46
Mehraein-Ghomi, Farideh; Basu, Hirak S; Church, Dawn R et al. (2010) Androgen receptor requires JunD as a coactivator to switch on an oxidative stress generation pathway in prostate cancer cells. Cancer Res 70:4560-8

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