HETEROSPECIFIC CELL/CELL INTERACTIONS IN PROSTATE GROWTH

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DESCRIPTION The long-term goal of this research is to dissect the complex mechanistic interplay between hormone action and growth factor systems in the growth, differentiation and pathogenesis of the human prostate, focusing specifically on benign prostatic hyperplasia (BPH). The rationale for this idea is that neoformation of ductalacinar tissue in aged men in the pathogenesis of BPH occurs via stromal- epithelial interactions similar, if not identical, to those in fetal prostatic development. Stromal-epithelial interactions are proposed to be mediated via autocrine/paracrine growth factors. These long-term goals will be pursued by examining the following specific aims: (1) Characterization of androgenic and estrogenic response in chimeric human-rodent prostates, including determining the kinetics of androgenic and estrogenic response in human-rodent chimeric prostates. (2) Analysis of the cellular pathways of androgen and estrogen action in the human prostate. This will include (a) analysis of the cellular mechanism of androgen action on human prostatic epithelium, (b) analysis of the cellular mechanism of estrogen action on human prostatic epithelium, (c) in vivo analysis of growth factor/growth factor receptors in testicular feminization (Tfm)/wild type tissue recombinants, and (d) in vivo analysis of growth factor/growth factor receptors in estrogen receptor knockout (ERKO)/wild type tissue recombinants. (3) In vivo analysis of growth factors as mediators of stromal-epithelial interactions in growth and development of human prostatic epithelium focusing specifically on analysis of the role of insulin-like growth factor-1 (IGF-1) and EGF receptor in growth and development of human prostatic epithelium. (4) Analysis of the inter-relationships between different growth factor families during normal and impaired prostatic epithelial growth. The project is based upon analysis of a novel in vivo chimeric tissue recombinant composed of human prostatic epithelium (huPRE) growing in association with normal or growth factor knockout transgenic rat or mouse urogenital sinus mesenchyme (UGM). Growth factor/receptor expression will be assessed by species specific RT-PCR, which can simultaneously and independently assess gene expression in epithelium versus stroma. Growth factor/receptor expression will also be assessed by RNase protection, Western blot, Northern blot and immunocytochemistry. Concepts derived from the analysis of basic cellular mechanisms of prostatic growth will be applied to the pathogenesis of BPH.