Most research on benign prostatic hypertrophy (BPH) has focused on hormonal control because it has been well established that development, growth and maintenance of the prostate involve hormonal mechanisms. However, it is now clear that other factors in addition to androgens are involved in the development of BPH. Recently, we have determined that neural innervation of the prostate is required for normal prostatic structure and function. The present study will focus on the mechanisms of the trophic control of the prostate by autonomic innervation and its interaction with aging. The following hypotheses will be tested with the overall goal of determining if changes in autonomic innervation play a role in BPH: 1.Neural innervation is critical for prostatic growth and maintenance: We demonstrated that the prostate atrophies following total denervation. In this set of experiments, we will examine the effects of selective denervations to determine if the trophic role of autonomic innervation is mediated by sympathetic or parasympathetic fibers, the intrinsic serotonergic paraneurons or a combination of these neural factors. The morphological and functional effects of selective denervations will be studied by quantitative anatomical and biochemical methods. Age related changes in the trophic control by innervation will be studied by similar experiments in old rats. 2.The trophic effects of innervation are mediated by autonomic neurotransmitters: We will directly test whether the trophic effects are mediated by neurotransmitters by neurotransmitter following specific denervation will attenuate the denervation-induced atrophy. Second, we will determine if chronic administration of specific neurotransmitter antagonists can mimic the effects of denervation. The effect of neurotransmitters during aging will be studied. In the third set of experiments, we will apply known concentrations of neurotransmitter agonists to cultured rat prostatic cells and measure the resulting mitogenic, morphological and biochemical changes. 3.The trophic effects of innervation are regional: Significant regional effects should be observed in our denervation studies because of the regional pattern of BPH presentation and the fact that the ductal system is an important determinant of cellular growth. Therefore our denervation, autonomic antagonist and neurotransmitter stimulation studies will focus on regional effects in the three lobes of the prostate and on prostatic cells along the ductal system. Immunohistochemical studies will be performed to map the density of autonomic innervation throughout the prostate. The changes of the innervation with age will be documented.
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