Elucidation of molecular and cellular mechanisms of androgen action has been the long-term objective of this research project. Effects of androgens on growth and function of target organs are currently though to be mediated by both a direct action of the hormone and indirectly by androgen-stimulated synthesis and secretions of paracrine growth factors. An imbalance of these direct and indirect effects can potentially cause abnormal growth and function of target organs such as the prostate gland. The keratinocyte growth factor (KGF), a member of the fibroblast growth factor family, is produced by the prostatic stromal cells and serves as a paracrine mediator of androgen action on the prostatic epithelium. This renewal application is designed to induce prostates hyperplasia in transgenic mice, by creating an imbalance between the direct and indirectly acting hormonal mediators, in order to study the specific contributory roles of KGF and androgens on prostatic function and to examine intervention strategies to retard the hyperplastic growth of the gland. Specific research objectives include (i) Overexpression of the androgen receptor (AR) and KGF, targeted to prostatic epithelial cells by the probasin gene promoter. This objective is based on the hypothesis that the age-dependent development of porstaic hyperplasia in the human may initially be due to increase epithelial growth which subsequently leads to the formation of cysts and nodules with thickening of the surrounding stroma. (ii) Stimulation of abnormal prostatic wroth in mice overexpressing AR directed by KGF gene promoter. The hypothesis behind this objective is based on our previous finding of an age-invariant overexpression of AR in prostic stromal cells of the dog, an animal that shows continued enlargement of the prostate with aging. (iii) the third and the final specific aim of this application is to generate transgenic mice engineered to express an AR mRNA inactivating ribozyme in the prostatic epithelium constitutively, and under conditional induction mediated by RU486. The RU486- dependent binary switch model will allow a transient inactivation of AR in the epithelium without interference with the stromal function. Based on the initial data, a successful outcome of all of these research objectives is anticipated. Completion of these investigative tools for studying hyperplastic growth of the prostate gland.
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