eNOS Regulatory Mechanisms in Penile Vascular Function

阴茎血管功能中的 eNOS 调节机制

• 批准号: 6867852
• 负责人: Arthur Louis Burnett
• 金额: $ 24.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867852
• 关键词: age difference; atherosclerosis; diabetes mellitus; electrostimulus; enzyme activity; homeostasis; immunocytochemistry; immunoprecipitation; impotence; isozymes; laboratory mouse; laboratory rat; mitogen activated protein kinase; nitric oxide synthase; pathologic process; penis erection; phosphorylation; posttranslational modifications; protein protein interaction; shear stress; swine; vascular endothelial growth factors; vascular endothelium; western blottings

DESCRIPTION (provided by applicant): Recently published work has supported the emerging concept that the vascular and sinusoidal endothelium and, specifically, endothelial nitric oxide synthase (eNOS) localized to this cellular structure play important roles in aspects of the vascular homeostasis and erection physiology of the penis. Investigations of eNOS in the penis have shown that the enzyme is activated by a specific phosphorylation mechanism under blood flow stimulation so that it releases the gaseous messenger molecule nitric oxide (NO) in a steady, continuous manner. This finding indicates that eNOS contributes significantly to NO-mediated penile erection, regulating the penile tumescence and erection maintenance phases of the erectile response. Further investigation has revealed that eNOS is deficient in the penis under various conditions associated with erectile dysfunction including diabetes and aging. These reports correspond with epidemiologic studies that have identified high rates of erectile dysfunction in individuals with cardiovascular diseases, leading to suggestions of a common pathogenic link: endothelial dysfunction. However, the precise mechanisms underlying the putatively defective endothelial function in the penis associated with vasculogenic erectile dysfunction remain poorly understood. It is hypothesized that the actions of eNOS in the penis under the control of various complex regulatory mechanisms have an impact on the endothelial-dependent biological functions of this organ. Accordingly, this research proposal centers on two areas, the investigation of several specific molecular mechanisms controlling eNOS actions in the penis in correlation with physiologic and pathophysiologic events of this organ, and the assessment of "activated" eNOS as a vasculoprotective molecular target for preserving penile vascular function. Specific aims are: (1) to characterize eNOS isoform-specific regulatory mechanisms (i.e., post-translational phosphorylation, protein-protein interactions) operating in the penis during physiologic penile flaccidity and erection in the rat; (2) to determine roles of eNOS isoform-specific regulatory mechanisms in the penis in the pathogenesis of atherosclerosis-associated erectile dysfunction using porcine and rodent animal models; (3) to determine roles of eNOS isoform-specific regulatory mechanisms in the penis in the pathogenesis of age-associated erectile dysfunction in the rat; and (4) to evaluate "activated" eNOS as a molecular target for improving erectile function using select interventions (i.e., growth factor therapy, pharmacoinduction, and gene transfer) in rodent animal models of vasculogenic erectile dysfunction. The work may advance treatments not only for erectile dysfunction, but also for disorders of endothelial dysfunction in general.

描述（由申请人提供）：最近发表的工作支持了新兴概念，即血管和正弦的内皮，特别是内皮一氧化氮合酶（ENOS），该氧化物合酶（ENOS）位于这种细胞结构中，在血管稳态和阴茎的勃起物理学方面起着重要作用。对阴茎中的eNOS的研究表明，该酶是通过血流刺激下的特定磷酸化机制激活的，因此它以稳定的，连续的方式释放了气态的信使分子一氧化氮（NO）。这一发现表明，eNOS对无介导的阴茎勃起显着贡献，调节勃起反应的阴茎肿瘤和勃起维持阶段。进一步的研究表明，在勃起功能障碍（包括糖尿病和衰老）相关的各种条件下，eNOS缺乏阴茎。这些报告与流行病学研究相对应，这些研究已经确定了心血管疾病患者中勃起功能障碍的高率，从而提出了常见的致病性联系的建议：内皮功能障碍。然而，与血管生成勃起功能障碍相关的阴茎中预处理缺陷的内皮功能的确切机制仍然尚不清楚。假设在各种复杂的调节机制的控制下，eNOS在阴茎中的作用会影响该器官的内皮依赖性生物学功能。因此，该研究提案集中在两个领域，研究与该器官的生理和病理生理事件相关的几种特定分子机制，以及该器官的生理和病理生理事件的相关性，以及评估“激活” eNOS作为维护阴茎血管血管功能的血管蛋白保护分子靶标的。具体目的是：（1）表征eNOS同工型特异性调节机制（即翻译后磷酸化，蛋白质 - 蛋白质相互作用）在Penis在Penies Penile Penile的宽敞性和大鼠勃起期间的作用； （2）使用猪和啮齿动物模型来确定阴茎中eNOS同工型特异性调节机制在阴茎中的作用； （3）确定eNOS同工型特异性调节机制在阴茎中的作用在大鼠中与年龄相关的勃起功能障碍的发病机理中； （4）在血管生成勃起功能障碍的啮齿动物动物模型中，使用精选干预措施（即生长因子治疗，药物诱导和基因转移）评估“活化”的eNOS作为改善勃起功能的分子靶标。这项工作不仅可以针对勃起功能障碍，而且还可以推进内皮功能障碍的疾病。