NOS Regulation in the Penis

描述（由申请人提供）：阴茎勃起障碍，包括男性勃起功能障碍、复发性缺血性阴茎异常勃起和阴茎纤维化，仍然是令人烦恼的临床管理状况，目前有效的治疗方案有限。在这一研究领域的科学调查已经认识到一氧化氮（NO）作为阴茎中的主要化学效应物的重要性，其已被很好地描述为介导偶发性阴茎勃起的信号传导途径的主要介质。这一领域的新进展进一步支持了NO在阴茎中的功能范围，包括在阴茎中的作用。 体内平衡和与支配阴茎生物学的多种生化介导途径的共调节作用。可以想象，进一步阐明阴茎调节NO作用的机制将推进治疗前景。最近围绕NO生物学研究的焦点集中在其合成酶NO合酶（NOS）的翻译后修饰上，其以影响身体各个区域的健康和疾病的方式影响化学物质的作用。这种水平的调查是适当的阴茎功能的研究，这是合理的推测，组成型NOS亚型的翻译后修饰发挥关键作用，在基本的勃起生物学以及勃起功能障碍的病理生理学。该建议的中心假设是，神经元型NOS的磷酸化和组成性神经元型和内皮型NOS亚型的S-亚硝基化对阴茎中NO的信号传导和稳态活动有显着贡献。该提案检查了神经元NOS磷酸化在阴茎勃起的神经元调节中的作用（具体目标1），以及在阴茎神经病变的背景下作为阴茎组织神经保护的靶点（具体目标2），以及S-亚硝基化/脱亚硝基化在阴茎生理（具体目标3）和病理生理（具体目标4）过程中的作用。表征这些主要的NOS调节机制有望为干预阴茎疾病的管理提供重要的新见解。 公共卫生相关性：阴茎勃起障碍，包括男性勃起功能障碍、复发性缺血性阴茎异常勃起和阴茎纤维化，仍然是令人烦恼的临床管理状况，目前有效的治疗选择有限。在这一研究领域的科学调查已经认识到一氧化氮（NO）作为阴茎中的主要化学效应物的重要性，其已被很好地描述为介导偶发性阴茎勃起的信号传导途径的主要介质。这一领域的新进展进一步支持了NO在阴茎中的功能范围，包括在阴茎中的作用。 健康状况和与其他化学品的相互作用，保持阴茎健康。该提案的中心假设是，决定NO功能的主要化学调节机制在阴茎中是活跃的，并且可以科学地靶向治疗阴茎疾病。该提案探讨了这些调节机制在阴茎生理学和病理生理学中的作用。

DESCRIPTION (provided by applicant): Disorders of penile erection, which includes male erectile dysfunction, recurrent ischemic priapism and penile fibrosis, remain vexatious clinical management conditions and are addressed with limited effective treatment options at present. Scientific investigation in this field of study has acknowledged the importance of nitric oxide (NO) as a major chemical effector in the penis having been well described as the principal mediator of a signaling pathway that mediates episodic penile erection. Emerging advances in this field have further supported the extent of NO function in the penis to include roles in penile homeostasis and co-regulatory actions with diverse biochemical mediatory pathways that govern penile biology. It is conceivable that further elucidation of the mechanisms in the penis regulating NO actions will advance therapeutic prospects. Recent focus surrounding the study of NO biology has centered on post- translational modifications of its synthetic enzyme, NO synthase (NOS), which influence actions of the chemical in ways that impact health and disease in various regions of the body. This level of investigation is appropriately brought to studies of penile function, and it is reasonable to conjecture that post-translational modifications of constitutive NOS isoforms exert critical roles in basic erection biology as well as erectile dysfunction pathophysiology. The central hypothesis of this proposal is that phosphorylation of neuronal NOS and S-nitrosylation of both constitutive neuronal and endothelial NOS isoforms contribute significantly to signaling and homeostatic activities of NO in the penis. The proposal examines the role of neuronal NOS phosphorylation in the neuronal regulation of penile erection (Specific Aim 1) and as a target for penile tissue neuroprotection in the context of penile neuropathy (Specific Aim 2) and the role of S- nitrosylation/denitrosylation in physiologic (Specific Aim 3) and pathophysiologic (Specific Aim 4) processes in the penis. Characterizing these major NOS regulatory mechanisms is expected to offer critical new insights for intervening in the management of penile disorders. PUBLIC HEALTH RELEVANCE: Disorders of penile erection, which includes male erectile dysfunction, recurrent ischemic priapism and penile fibrosis, remain vexatious clinical management conditions and are addressed with limited effective treatment options at present. Scientific investigation in this field of study has acknowledged the importance of nitric oxide (NO) as a major chemical effector in the penis having been well described as the principal mediator of a signaling pathway that mediates episodic penile erection. Emerging advances in this field have further supported the extent of NO function in the penis to include roles in penile health states and interaction with other chemicals that preserve penile health. The central hypothesis of this proposal is that major chemical regulatory mechanisms that determine NO function are active in the penis and can be targeted scientifically to treat penile disorders. The proposal examines the roles of these regulatory mechanisms in both physiology and pathophysiology of the penis.