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，复发性缺血性勃起和阴茎纤维化，仍然是令人烦恼的临床管理条件，目前有效的治疗方案有限。该领域的科学研究已经认识到一氧化氮（NO）作为阴茎主要化学效应物的重要性，并被很好地描述为介导间歇性阴茎勃起的信号通路的主要介质。该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

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.