THE SYMPATHETIC NERVOUS SYSTEM AND PROSTATIC HYPERPLASIA

我们的长期目标是在分子水平上了解良性前列腺增生（BPH）的发病机制，从而为未来治疗方法的发展以及这种疾病的预防策略提供基础。在BPH中，成人前列腺中基质和上皮细胞生长的正常调节受到干扰。很明显，雄激素虽然是必要的，但对于前列腺的完全生长或BPH的发展是不够的。自主神经系统的交感神经分支通过交感神经儿茶酚胺神经递质去甲肾上腺素（NE）对G蛋白偶联α 1-肾上腺素受体（α 1-AR）的作用来控制前列腺平滑肌张力。还有令人信服的证据表明，从大鼠和人类模型的行动，NE对α 1-ARS刺激细胞增殖的前列腺独立的雄激素。此外，已知交感神经活性随着人的衰老而增加，并且人BPH与异常交感神经传递的明确指示相关，包括去甲肾上腺素能神经的数量和编码三种α 1-AR亚型的mRNA的表达的改变。这些发现表明，交感神经系统是一个重要的雄激素非依赖性前列腺生长机制。我们假设交感神经活动的增加是导致BPH的一个关键因素。我们进一步假设交感神经活性的增加导致BPH中α 1-AR亚型mRNA表达模式的改变，这反过来又导致细胞增殖的增加。我们将系统地测试我们的假设，通过解剖的机制，前列腺α 1-ARS的有丝分裂激活NE。具体来说，我们将激活或抑制该信号通路中的特定步骤，并检查对细胞增殖、细胞凋亡和α 1-AR的影响。第一个是人前列腺组织的器官培养系统，这是一个易于操作的系统，保留了完整组织中观察到的细胞-细胞相互作用。第二个系统是自发性高血压大鼠，一种显示交感神经活性升高伴前列腺增生的动物模型。

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.