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症(BPH)的发病机制，从而为未来该疾病的治疗和预防策略的发展提供基础。在良性前列腺增生症中，成人前列腺间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，但不足以促进前列腺的充分生长或良性前列腺增生症的发展。自主神经系统的交感神经部分通过交感性儿茶酚胺神经递质去甲肾上腺素(NE)作用于G蛋白偶联的α1-肾上腺素受体(α1-ARs)来控制前列腺平滑肌张力。也有来自大鼠和人类模型的令人信服的证据表明，去甲肾上腺素对α1-ARS的作用不依赖于雄激素而刺激前列腺细胞的增殖。此外，已知交感神经活性随着年龄的增长而增加，人类BPH与交感神经传递异常的明显迹象有关，包括去甲肾上腺素能神经的数量和编码三个α1-AR亚型的mRNAs的表达都发生了变化。这些发现表明，交感神经系统是一种重要的雄激素非依赖性前列腺生长机制。我们的假设是，交感神经活动增加是BPH发生的关键因素。我们进一步假设，交感神经活性的增加会导致BPH中α1-AR亚型mRNAs表达模式的改变，这反过来又会导致细胞增殖增加。我们将通过解剖NE激活前列腺α1-ARS有丝分裂的机制来系统地检验我们的假设。具体地说，我们将激活或抑制这一信号通路中的特定步骤，并检查对细胞增殖、细胞凋亡和α1-AR的影响。我们将利用两个模型系统进行这项研究。第一个是人类前列腺组织的器官培养系统，这是一个易于操作的系统，保留了在完整组织中看到的细胞与细胞之间的相互作用。第二个系统是自发性高血压大鼠，这是一种交感神经活性升高并伴有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.