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.
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