eNOS Regulatory Mechanisms in Penile Vascular Function

描述(由申请人提供)： 最近在勃起生理学领域的研究已经承认，阴茎中长期存在的结构性一氧化氮(NO)信号缺陷可能在各种勃起疾病的病理生理学中起重要作用，包括复发性缺血性阴茎勃起、血管性勃起功能障碍(ED)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，也是参与阴茎稳态血管生物学的动态平衡调节剂。因此，这一研究领域的新方向涉及进一步研究这种化学物质在勃起障碍的病理生理学中的这一特殊作用。这一建议的主要假设是，与各种勃起障碍相关的阴茎血管系统没有发生失衡，这为它们的发展提供了分子基础。我们的研究集中在复发性阴茎勃起的病理生理学上，这是一种反复发生的非故意、过度和痛苦的勃起障碍，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)内皮NO产生来源的缺陷；2)循环(血红蛋白和血浆)NO传递的改变；以及3)氧化应激增加导致NO降解。该提案的具体目的是：1)确定阴茎血管内稳态信号是否与复发性阴茎异常勃起有关；2)研究导致阴茎不平衡与复发性阴茎异常勃起相关的分子机制；3)评估在复发性阴茎异常勃起条件下恢复阴茎无生物活性的效果。我们提出的研究工作计划包括使用实验小鼠动物模型，结合与阴茎中基于NO的信号转导途径和氧化/亚硝化应激机制相关的分子和生理学研究。预计本研究的结果将对复发性缺血性异常勃起的细胞和分子机制有更清晰的了解，并为其治疗提供合理的依据。 最近在勃起生理学领域的研究已经承认，阴茎中长期存在的结构性一氧化氮(NO)信号缺陷可能在各种勃起疾病的病理生理学中起重要作用，包括复发性缺血性阴茎勃起、血管性勃起功能障碍(ED)和阴茎纤维化。这一建议的主要假设是，与各种勃起障碍相关的阴茎血管系统没有发生失衡，这为它们的发展提供了分子基础。我们认为，特定的分子异常与复发性异常勃起有关，包括1)内皮细胞NO产生来源缺陷；2)循环(血红蛋白和血浆)NO传递改变；以及3)氧化应激增加导致NO降解。预计这项研究的结果将为更清楚地了解这种疾病的细胞和分子机制，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.