eNOS Regulatory Mechanisms in Penile Vascular Function

描述（由申请人提供）： 勃起生理学领域的最新研究已经认识到，阴茎中长期存在的结构性一氧化氮（NO）信号传导缺陷可能对各种勃起障碍的病理生理学有重要作用，包括复发性缺血性阴茎异常勃起、血管源性勃起功能障碍（艾德）和阴茎纤维化。气态化学物质NO不仅是阴茎勃起的生理介质，也是阴茎稳态血管生物学中的稳态调节剂。因此，在这一研究领域的新方向涉及进一步调查勃起障碍的病理生理学中的化学物质的这种特殊作用。该建议的主要假设是，“NO失衡”发生在阴茎血管系统中，与各种勃起障碍相关，为它们的发展提供分子基础。我们的研究集中在复发性阴茎异常勃起的病理生理学上，这是一种反复发生的非故意的、过度的和痛苦的阴茎勃起的勃起障碍，经常导致永久性勃起组织损伤、勃起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）缺陷的内皮NO生产源; 2）改变循环（血红蛋白和血浆）NO输送;和3）增加氧化应激导致NO降解。该提案的具体目的是：1）确定血管稳态的NO信号传导是否与阴茎异常勃起复发相关; 2）研究导致阴茎异常勃起复发相关的NO失衡的分子机制; 3）评估在阴茎异常勃起复发条件下恢复NO生物活性对阴茎的影响。我们建议的研究工作计划包括使用实验小鼠动物模型结合相关的NO为基础的信号转导途径在阴茎和氧化/亚硝化应激机制的分子和生理学研究。预计本研究的结果将提供一个更清晰的了解缺血性阴茎异常勃起复发的细胞和分子机制，并为其治疗提供合理的依据。 勃起生理学领域的最新研究已经认识到，阴茎中长期存在的结构性一氧化氮（NO）信号传导缺陷可能对各种勃起障碍的病理生理学有重要作用，包括复发性缺血性阴茎异常勃起、血管源性勃起功能障碍（艾德）和阴茎纤维化。该建议的主要假设是，“NO失衡”发生在阴茎血管系统中，与各种勃起障碍相关，为它们的发展提供分子基础。我们认为，特定的分子异常与复发性阴茎异常勃起有关，包括1）内皮NO产生源缺陷; 2）改变循环（血红蛋白和血浆）NO输送; 3）增加氧化应激导致NO降解。预计这项研究的结果将为这种疾病的细胞和分子机制提供更清晰的理解，并为其治疗提供合理的基础。

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.