eNOS Regulatory Mechanisms in Penile Vascular Function

阴茎血管功能中的 eNOS 调节机制

基本信息

批准号：
8039110
负责人：
Arthur Louis Burnett
金额：
$ 34.16万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2012-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8039110
关键词：
Accounting Acute Address Animal Model Basic Science Biochemical Biochemistry Biological Assay Biological Availability Biology Blood Vessels Blood flow Bone Marrow Transplantation Chemicals Coitus Cyclic GMP Cyclic GMP-Dependent Protein Kinases Development Disease Disease model Dysplasia Electrons Engineering Environmental sludge Erectile dysfunction Erythrocytes Fibrosis Functional disorder Gene Transfer Genes Hemoglobin Homeostasis Human Impairment Individual Intervention Investigation Light Measurement Mediator of activation protein Microscopic Modeling Molecular Molecular Abnormality Mus Neurotransmitters Nitric Oxide Nitric Oxide Synthase Nitrites Nitrogen Organ Oxidative Stress Oxygen Pain Pathway interactions Penile Erection Phenotype Physiological Physiology Plasma Priapism Production Recurrence Research Rho-associated kinase Role Science Series Sexual Dysfunction Sickle Cell Sickle Cell Anemia Signal Transduction Signal Transduction Pathway Source Testing Therapeutic Thinking Tissues Transgenes Transgenic Mice Work base cGMP-dependent protein kinase I erection human NOS3 protein in vivo inhibitor/antagonist insight intervention effect mouse model nitrosative stress operation penis phosphoric diester hydrolase psychological distress research study stem

项目摘要

DESCRIPTION (provided by applicant): Recent studies in the field of erection physiology have acknowledged that long-standing defective constitutive nitric oxide (NO) signaling in the penis may contribute significantly toward the pathophysiology of diverse erectile disorders including recurrent ischemic priapism, vasculogenic erectile dysfunction (ED), and penile fibrosis. The gaseous chemical NO is not just a physiologic mediator of penile erection, but it is also a homeostatic regulator involved in the steady state vascular biology of the penis. Accordingly, new directions in this research field involve investigating further this particular role of the chemical in the pathophysiology of erectile disorders. The primary hypothesis of this proposal is that "NO imbalance" occurs in the penile vasculature in association with various erectile disorders providing a molecular basis for their development. We have focused our investigation on the pathophysiology of recurrent priapism, an erectile disorder of repetitively occurring non-willful, excessive, and painful penile erection, which frequently results in permanent erectile tissue damage, erectile dysfunction, and psychological distress. We submit that specific molecular abnormalities are associated with this disorder, including 1) defective endothelial NO production sources; 2) altered circulating (hemoglobin and plasma) NO delivery; and 3) increased oxidative stress leading to NO degradation. Specific aims for the proposal are: 1) to determine whether NO signaling of vascular homeostasis is defective in the penis in association with recurrent priapism; 2) to investigate molecular mechanisms which contribute toward NO imbalance in the penis in association with recurrent priapism; and 3) to evaluate the effects of restoring NO bioactivity to the penis under conditions of recurrent priapism. Our proposed research work plan includes the use of experimental mouse animal models in combination with molecular and physiologic studies relevant to the NO-based signal transduction pathway in the penis and oxidative/nitrosative stress mechanisms. It is anticipated that findings produced by this study will provide a clearer understanding of the cellular and molecular mechanisms underlying recurrent ischemic priapism and provide a rational basis for its treatment. Recent studies in the field of erection physiology have acknowledged that long-standing defective constitutive nitric oxide (NO) signaling in the penis may contribute significantly toward the pathophysiology of diverse erectile disorders including recurrent ischemic priapism, vasculogenic erectile dysfunction (ED), and penile fibrosis. The primary hypothesis of this proposal is that "NO imbalance" occurs in the penile vasculature in association with various erectile disorders providing a molecular basis for their development. We submit that specific molecular abnormalities are associated with recurrent priapism including 1) defective endothelial NO production sources; 2) altered circulating (hemoglobin and plasma) NO delivery; and 3) increased oxidative stress leading to NO degradation. It is anticipated that findings produced by this study will provide a clearer understanding of the cellular and molecular mechanisms underlying this disorder and provide a rational basis for its treatment.

描述（由申请人提供）：在勃起生理学领域的最新研究已经承认，阴茎中长期有缺陷的原始氧化物（NO）信号传导可能对多种勃起性疾病的病理生理有显着贡献，包括复发性缺血性促血管，包括血管生成性勃起功能障碍（EDILE）和阴茎纤维化。气态化学NO不仅是阴茎勃起的生理介质，而且还是参与阴茎稳态血管生物学的稳态调节剂。因此，该研究领域的新方向涉及进一步研究该化学物质在勃起疾病的病理生理学中的特殊作用。该提议的主要假设是，在阴茎脉管系统中，“没有失衡”与各种勃起性疾病相关，为其发育提供了分子基础。我们将研究重点放在了复发性priApism的病理生理上，这种勃起性发生的无愿意，过度和疼痛的阴茎勃起，经常导致永久性勃起组织损害，勃起性功能障碍和心理困扰。我们认为特定的分子异常与这种疾病有关，包括1）内皮有缺陷的无生产来源； 2）循环改变（血红蛋白和血浆）无递送； 3）增加氧化应激导致没有降解。该提案的具体目的是：1）确定与复发性priapism相关的阴茎中没有血管稳态信号的信号； 2）研究分子机制，这些机制与复发性的priApism相关，导致阴茎不平衡； 3）评估在复发性priapism的条件下未恢复对阴茎的生物活性的影响。我们提出的研究工作计划包括使用实验小鼠动物模型与与阴茎中基于NO的基于NO的信号转导途径相关的分子和生理研究以及氧化/硝化应激机制。可以预料，这项研究产生的发现将对复发性缺血性培养基的细胞和分子机制有更清晰的了解，并为其治疗提供了合理的基础。在勃起生理学领域的最新研究已经承认，阴茎中长期有缺陷的原始氧化物（NO）信号传导可能对多种勃起性疾病的病理生理有显着贡献，包括复发性缺血性促血管，包括血管生成性勃起功能障碍（EDILE）和阴茎纤维化。该提议的主要假设是，在阴茎脉管系统中，“没有失衡”与各种勃起性疾病相关，为其发育提供了分子基础。我们认为，特定的分子异常与复发性培养主义有关，包括1）内皮缺陷无生产来源； 2）循环改变（血红蛋白和血浆）无递送； 3）增加氧化应激导致没有降解。可以预料，这项研究产生的发现将对这种疾病背后的细胞和分子机制有更清晰的了解，并为其治疗提供了合理的基础。