Our long-term goal is to understand the pathogenesis of benign prostatic hyperplasia (BPH) on a molecular level thus providing the basis for the development of future therapies as well as preventative strategies for this disease. In BPH, the normal regulation of stromal and epithelial cell growth in the adult prostate is perturbed. It has become apparent that androgens, while necessary, are not sufficient for full prostate growth or for the development of BPH. The sympathetic division of the autonomic nervous system controls prostate smooth muscle tone through the action of the sympathetic catecholamine neurotransmitter norepinephrine (NE) on G-protein coupled alpha1-adrenoceptors (alpha1-ARs). There is also compelling evidence from rat and human models that the action of NE on alpha1-ARS stimulates cell proliferation in the prostate independently of androgens. Furthermore, sympathetic activity is known to increase with aging in man and human BPH is associated with clear indications of aberrant sympathetic neurotransmission including alterations both in the number of noradrenergic nerves and in the expression of the mRNAs encoding the three alpha1-AR subtypes. These findings indicate that the sympathetic nervous system represents an important androgen independent prostatic growth mechanism. It is our hypothesis that increased sympathetic activity is a critical factor in the causation of BPH. We further hypothesize that increased sympathetic activity results in the altered expression pattern of the alpha1-AR subtype mRNAs seen in BPH which in turn results in increased cell proliferation. We will systematically test our hypothesis by dissecting the mechanism involved in the mitogenic activation of prostatic alpha1-ARS by NE. Specifically we will activate or inhibit specific steps in this signaling pathway and examine the consequences on cell proliferation, cell apoptosis and alpha1-AR We will utilize two model systems for this study. The first is an organ culture system of human prostate tissue, a readily manipulable system that retains cell-cell interactions seen in the intact tissue. The second system is the spontaneously hypertensive rat, an animal model that displays elevated sympathetic activity with concomitant prostatic hyperplasia.
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