VASODILATION AND GUANYLATE CYCLASE REGULATION

描述：本项目的长期目标是识别和 阐明参与控制的信号转导机制 肺血管张力通过调节肺动脉平滑肌的产生而介导， 细胞内松弛介质，cGMP，通过调节可溶性 如何各种氧化还原相关的综合理解的形式 这些过程与活性氧的代谢相互作用， 一氧化氮（NO）通过调节肺血管张力 涉及sGC调节的机制。 主要研究者 建议系统地评估调节sGC的相互作用， 活性及其在肺动脉平滑肌调控中的作用 力涉及：（1）内源性血管平滑肌的潜在作用 肌肉氧化还原系统，包括胞质NAD和NADP，谷胱甘肽， 微粒体和线粒体电子传递，重点是 确定H2 O2，O2.-和sGC上血红素的氧化还原状态是 这些过程控制活动的中心机制 sGC与血管张力的关系，（2）这些氧化还原之间的关系 系统和NO/O2。互动，重点是确定是否 巯基亚硝化是一个重要的信号传导过程，（3）评估 细胞氧化还原系统之间的相互作用如何检查， O2和NO源性物质参与诱发的音调反应 通过PO 2的变化，重点是确定sGC的调节是否 活性是主要的信号转导机制， 观察到的反应。 本提案中的大部分工作将 还应重点了解以下方面的功能和重要性： NADH-细胞色素b558 O2.-产生电子传递链， 调查人员在最近的项目工作中发现 在小牛肺动脉平滑肌中。 这是氧气产生系统 似乎是内源性活性O2物质的主要来源， 作为PO 2传感器调节sGC活性。 当前 建议将采用离体小牛肺动脉进行张力研究 用机械探针，测量内源性活性O2 种和cGMP的产生，以及动脉平滑肌亚细胞 馏分，以确定产生活化剂的氧化还原系统， sGC抑制剂。 本提案中审查的程序可 有助于进一步了解氧诱导调节的各个方面 正常生理过程中的肺循环， 循环暴露于肺血管病理生理学相关 随着活性氧和NO衍生物质的形成（例如急性 肺损伤/ARDS、缺血再灌注、高血压等）。

DESCRIPTION: The long-term goals of this project are to identify and elucidate the signal transduction mechanisms involved in the control of pulmonary vascular tone mediated by modulation of the production of the intracellular mediator of relaxation, cGMP, via regulation the soluble form of an integrated understanding of how various redox-related processes interact with the metabolism of reactive oxygen species and nitric oxide (NO) in the control of pulmonary vascular tone through mechanisms involving the regulation of sGC. The principal investigator proposes to systematically evaluate interactions that regulate sGC activity and its role in the control of pulmonary arterial smooth muscle force involving: (1) the potential role of endogenous vascular smooth muscle redox systems including cytosolic NAD and NADP, glutathione, microsomal and mitochondrial electron transport, with a focus on determining if H2O2, O2.- and the redox status of the heme on sGC are the central mechanisms through which these processes control the activity of sGC and vascular tone, (2) the relationships between these redox systems and the NO/O2.- interaction, with a focus on determining if thiol nitrosation is an important signaling process, and (3) to evaluate how interactions between the cellular redox systems examined, reactive O2 species and NO-derived species contribute to tone responses elicited by changes in PO2, with a focus on determining if the modulation of sGC activity is the primary signal transduction mechanism mediating responses that are observed. Much of the work in this proposal will also focus on developing an understanding of function and importance of NADH-cytochrome b558 O2.- producing electron transport chain, which the investigators have discovered during their recent work on this project in calf pulmonary arterial smooth muscle. This O2.- producing system seems to both be a major source of endogenous reactive O2 species and functions as a PO2 sensor that regulates sGC activity. The current proposal will employ isolated calf pulmonary arteries for tone studies with mechanistic probes, and measurements of endogenous reactive O2 species and cGMP production, and arterial smooth muscle subcellular fractions to identify the redox systems which generate activators and inhibitors of sGC. The processes examined in this proposal may contribute to further understanding aspects of oxygen-elicited regulation of the pulmonary circulation during normal physiology and when this circulation is exposed to pulmonary vascular pathophysiology associated with the formation of reactive oxygen and NO-derived species (e.g. acute lung injury/ARDS, ischemia reperfusion, hypertension, etc.).