The main goal of this proposal is to investigate the molecular mechanisms of prostate growth in aging. The rationale for this proposal is that the mechanisms of neoformation of ductal-acinar tissue during the pathogenesis of benign prostatic hyperplasia (BPH) is similar (if not identical) to the process of ductal-acinar growth and development occurring during the organogenesis of the prostate in fetal and pubertal periods. This proposal is based on the hypothesis that the age- dependent endocrine control of prostatic cell growth is regulated by mesenchyme-epithelial cell interactions mediated by the local production and action of growth factors (KGF, TGFa, and TGFb). Based upon preliminary experiments, TGFa and KGF may up-regulate and TGFb down- regulate the prostatic epithelium growth. This hypothesis will be tested through pursuit of the following specific aims. 1. Analysis of paracrine mechanisms in the regulation of rat fetal prostatic growth and differentiation. Under this specific aim, rat fetal prostates (different ages) will be studied to determine growth kinetics, ductal morphogenesis, expression of differentiation markers and expression of KGF, TGFa and TGFb and their receptors.
Specific Aim number 2. Analysis of the growth promoting and morphogenetic effects of rat urogenital sinus mesenchyme (rat UGM) on growth-quiescent adult rat prostatic epithelium. Under this specific aim we will test the hypothesis that rat UGM can induce the growth and differentiation of growth-quiescent adult rat prostatic epithelium. To test this hypothesis, rat UGM will be associated with rat prostatic epithelium from adult rats (age 3, 6, 12, 18 and 24 months) and the resultant tissue recombinants will be grown in kidney capsules of male athymic nude mice and will be characterized for growth, differentiation and expression of KGF, TGFa and TGFb and their receptors.
Specific Aim number 3. Analysis of the inter- relationships between growth factor families during normal and impaired prostatic epithelial growth. Under this specific aim, we hypothesize that there is a complex interaction between androgen action and growth factors. Indeed, for some systems it has been shown that the actions of one growth factor may be mediated by other downstream signaling growth factors. To dissect this complex interplay between growth factors, various transgenic knockout mice will be utilized. The goal of this experiment is to elucidate the linkage between different growth factor pathways employing chimeric rat-mouse prostatic tissue recombinants.
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