Growth and maintenance of prostate function is dependent on androgens; however, androgens also contribute to pathological conditions in the prostate. For example, men with decreased androgen levels, such as eunuchs, or men with 5-alpha reductase deficiency, do not suffer from many of the pathological consequences associated with prostate diseases. Previously, we observed that androgen exposure to prostate cells in culture leads to oxidative stress through the production of reactive oxygen species. Changes in cellular reduction/oxidation (i.e. redox) status through the production of reactive oxygen species are believed to contribute to a number of cellular maladies, including aging. The mechanism for androgen-induced oxidative stress in prostate cells is largely unknown, and the effects of androgen-induced changes in prostate cell redox status in vivo have not been determined. In cultured prostate cells, we have identified the activation of AP-1 through increased JunD activity as a mediator of androgen-induced oxidative stress. We hypothesize that androgen exposure produces changes in the redox status of the intact prostate gland mediated by JunD that may contribute to pathological changes in the prostate gland. These studies will use an innovative transgenic mouse model in which activation of the antioxidant (alt. electrophile) response element can be detected by expression of a human placental alkaline phosphatase reporter gene to assess changes in cellular redox status. In the first aim, we plan to test whether or not androgen-induced changes in the prostate gland alter the cellular redox status. The redox status of the prostate will be determined in mice after castration to produce androgen-depleted conditions. In addition, the redox status of the prostate gland will be examined after androgen restoration by implanting testosterone-releasing capsules. For the second aim, we will determine whether or not androgen-induced changes in the prostate gland produce changes in JunD expression within the distinct cellular compartments of the prostate, including the prostate stroma, basal epithelium, and luminal epithelium. In the third aim, we will produce transgenic mice in which JunD over-expression is targeted to the prostate gland. These mice will be used to determine whether or not JunD over-expression is sufficient to induce changes in prostate gland redox status that may lead to abnormalities within the prostate gland. These studies wil help determine the role of androgen-induced oxidative stress in the development of pathological conditions in the prostate gland.
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