NOS Regulation in the Penis

NOS 对阴茎的调节

• 批准号: 8460813
• 负责人: Arthur Louis Burnett
• 金额: $ 34万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460813
• 关键词: Accounting; Address; Aging; Agonist; Animal Model; Biochemical; Biology; Blood Vessels; Body Regions; Cardiovascular system; Chemical Actions; Chemicals; Clinical Management; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diabetes Mellitus; Disease; Enzymes; Equilibrium; Erectile dysfunction; Fibrosis; Functional disorder; Genetically Engineered Mouse; Guanylate Cyclase; Health; Heme; Homeostasis; Intervention; Investigation; Ions; Knowledge; Laboratories; Literature; Location; Mediating; Mediator of activation protein; Modification; Molecular; Nervous system structure; Neurologic; Neurons; Neuropathy; Neurotransmitters; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pathologic; Pathway interactions; Penile Diseases; Penile Erection; Phosphorylation; Physiological; Physiology; Play; Post-Translational Protein Processing; Priapism; Process; Production; Protein Isoforms; Recurrence; Regulation; Research; Role; Science; Second Messenger Systems; Series; Services; Signal Pathway; Signal Transduction; Site; Source; Techniques; Testing; Therapeutic; Tissues; Work; base; clinical application; clinical practice; design; effective therapy; enzyme mechanism; erection; field study; human NOS3 protein; in vivo; insight; male; mouse model; nerve injury; neuron loss; neuroprotection; novel; novel therapeutics; penis; phosphoric diester hydrolase; relaxing factor; research study; response; second messenger; synthetic enzyme

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.

描述（由申请人提供）：阴茎勃起的疾病，其中包括男性勃起功能障碍，复发性缺血性priapism和阴茎纤维化，仍然令人垂涎的临床管理条件，目前可以通过有限的有效治疗选择来解决。该研究领域的科学研究已经认识到，一氧化氮（NO）是阴茎中主要的化学效应子的重要性，已被很好地描述为介导情节阴茎勃起的信号传导途径的主要介体。该领域的新兴进步进一步支持了阴茎中无功能的程度，以包括阴茎中的角色 体内稳态和共同调节行动，具有管理阴茎生物学的多种生化介体途径。可以想象，在调节的阴茎中进一步阐明任何行动都不会推动治疗前景。 NO生物学研究的最新重点集中在其合成酶的转化后修饰上，没有合成酶（NOS），该酶以影响体内各个区域的健康和疾病的方式影响化学物质的作用。这种研究水平适当地引入了阴茎功能的研究，并且可以合理地猜测，构成性NOS同工型的翻译后修饰在基本勃起生物学以及勃起功能障碍的病理生理学中发挥关键作用。该提议的中心假设是，构成性神经元和内皮NOS同工型的神经元NOS和S-硝基化磷酸化对阴茎中NO的信号传导和稳态活性产生了显着贡献。该提案研究了神经元NOS磷酸化在阴茎勃起的神经元调节中的作用（特定目的1）和在阴茎神经病的背景下作为阴茎组织神经保护的靶标（特定目标2）（特定的目标2）以及S-硝基丙二醇化的作用，在生理学方面（特定目标3）和Pathersic（Patheromic op opphys）和Pathery pressigic op ospoplys and pressigic op ospoplys and pathioly（4）和pen pressigic oppation in pathioly opopt（4）和patheralsy opphysic（4）。预计这些主要的NOS调节机制将为干预阴茎疾病的管理提供关键的新见解。