ADRENERGIC REGULATION OF HUMAN PROSTATE GROWTH

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DESCRIPTION (Adapted from the Applicant's Abstract): Benign prostate hyperplasia (BPH) is primarily a disease of stromal proliferation. Smooth muscle (SM) is a major component of prostatic stroma. Therefore, it is likely that the progression of BPH requires smooth muscle proliferation. In many smooth muscle tissues, the state of contractile protein gene regulation is modulated during proliferation, with a loss of normal contractile proteins during active growth and a re-acquisition of contractile proteins once growth has been arrested. Little is known regarding the phenotypic modulation of stromal SM cells during the initiation and progression of BPH. In addition, the impact of therapy, specifically a blockade, on the SM phenotype is unknown. In preliminary studies, they have demonstrated that men with established BPH have evidence of a smooth muscle de-differentiation process, compatible with past but not ongoing SM proliferation. In addition, they have demonstrated that a blockade significantly affects the SM phenotype. They propose to characterize the expression of SM phenotypic markers, including myosin heavy chain and caldesmon, to determine whether the smooth muscle phenotype is altered during the natural history and progression of BPH. In addition, they will expand or preliminary studies to determine to what extent the SM phenotype is regulated by alpha adrenergic signal transduction pathways. They will utilize two unique tissue banks for these studies. First, a large number of normal and hyperplastic prostates from men of a variety of age groups banked as part of the UT Southwestern NIH O'Brien Center Repository and from the NIH Medical Therapy of Prostate Symptoms (MTOPS) clinical trial which will permit longitudinal observation of single patients in correlation with clinical outcome. Quantitative RT_PCR, immunohistochemical and morphometric analysis will be utilized to address the following specific aims: (1) to establish and validate methods of archived tissue analysis suitable for a multi-center trial; (2) to define changes in the SM phenotype which occur during the natural history of BPH; (3) to determine whether the SM phenotypes is modulated by alpha adrenergic signals; (4) using a prostate SM culture system, elucidate the regulatory role of alpha1A adrenergic stimulation in prostatic SM growth and differentiation.