THE SYMPATHETIC NERVOUS SYSTEM AND PROSTATIC HYPERPLASIA

交感神经系统和前列腺增生

• 批准号: 6524415
• 负责人: PAUL D WALDEN
• 金额: $ 23.75万
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524415
• 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，从而为未来治疗方法的开发以及该疾病的预防策略提供基础。在 BPH 中，成人前列腺基质和上皮细胞生长的正常调节受到干扰。很明显，雄激素虽然是必需的，但不足以促进前列腺的完全生长或前列腺增生症的发展。自主神经系统的交感神经系统通过交感神经递质去甲肾上腺素 (NE) 对 G 蛋白偶联 α1-肾上腺素受体 (α1-AR) 的作用来控制前列腺平滑肌张力。来自大鼠和人类模型的令人信服的证据表明，NE 对 alpha1-ARS 的作用可独立于雄激素刺激前列腺细胞增殖。此外，已知交感神经活性随着人类衰老而增加，并且人类 BPH 与异常交感神经传递的明确迹象相关，包括去甲肾上腺素能神经数量和编码三种 α1-AR 亚型的 mRNA 表达的变化。这些发现表明交感神经系统代表了重要的不依赖于雄激素的前列腺生长机制。我们的假设是，交感神经活动的增加是导致 BPH 的关键因素。我们进一步假设，交感神经活动的增加会导致 BPH 中观察到的 α1-AR 亚型 mRNA 的表达模式发生改变，进而导致细胞增殖增加。我们将通过剖析 NE 激活前列腺 α1-ARS 有丝分裂所涉及的机制来系统地检验我们的假设。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 alpha1-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，保留了完整组织中所见的细胞间相互作用。第二个系统是自发性高血压大鼠，这是一种表现出交感神经活动升高并伴有前列腺增生的动物模型。