THE SYMPATHETIC NERVOUS SYSTEM AND PROSTATIC HYPERPLASIA

交感神经系统和前列腺增生

• 批准号: 2885738
• 负责人: PAUL D WALDEN
• 金额: $ 22.27万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2885738
• 关键词: alpha adrenergic receptor; benign prostate hyperplasia; biological signal transduction; cell growth regulation; clinical research; human subject; laboratory rat; male; molecular pathology; neuroregulation; norepinephrine; organ culture; pathologic process; receptor expression; sympathetic nervous system

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.

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，从而为未来治疗和预防这种疾病的策略的发展提供基础。在BPH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，但对于完全的前列腺生长或BPH的发展是不够的。自主神经系统的交感神经分裂通过交感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（alpha1-ARs）的作用来控制前列腺平滑肌张力。从大鼠和人类模型中也有令人信服的证据表明，NE对α 1- ars的作用独立于雄激素刺激前列腺细胞增殖。此外，已知交感神经活动随着男性年龄的增长而增加，人类BPH与交感神经传递异常的明确迹象有关，包括去甲肾上腺素能神经数量的改变和编码三种α 1- ar亚型的mrna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。我们的假设是交感神经活动增加是引起前列腺增生的关键因素。我们进一步假设，交感神经活动的增加导致BPH中α 1- ar亚型mrna的表达模式改变，从而导致细胞增殖增加。我们将通过剖析NE对前列腺α - 1- ars有丝分裂激活的机制来系统地验证我们的假设。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，保留了完整组织中细胞间的相互作用。第二个系统是自发性高血压大鼠，这是一种伴有前列腺增生的交感神经活动升高的动物模型。