Pulmonary vascular-targeted NO therapeutic strategies

项目3：以肺血管为靶点的NO治疗策略 肺动脉高压(PAH)是一种小肺动脉疾病，其特征是 血管收缩、血管增殖和重塑。肺血管平滑肌的松弛 细胞及其异常增殖受到一氧化氮(NO)依赖反应的强烈调控 CGMP依赖的血管扩张和cGMP非依赖的抑制血管增殖的反应 和炎性细胞功能。值得注意的是，多环芳烃与生物利用度的降低和缺乏 内皮型一氧化氮合酶对一氧化氮生物合成受损的结果 内皮型一氧化氮合酶解偶联、L-精氨酸代谢紊乱和氧化还原依赖性消耗增加 不是的。我们假设，新的血管靶向、基于NO的治疗策略将增强 多环芳烃的治疗。研究计划将评估新欣赏的信号的作用机制。 在限制多环芳烃的背景下的调解人。具体地说，我们假设肺血管eNOS是 受凝血酶敏感蛋白-L负调控。在eNOS的下游，NO在生理上被氧化成 形成强大的NO信号代谢产物亚硝酸盐和硝基脂肪酸，动态调节NO 水平、依赖p21的血管增殖、第二相应激反应酶和过氧化物酶增殖物 激活受体-y信号。项目#3中提出的研究将提供重要的新机制 对于调节PAH发生的核心事件的洞察力和有前景的治疗策略。这些 Goals利用了最近与NO的形成、代谢和行动有关的高影响力的发现 物种和与中心计划目标的协同作用。总体而言，eNOS和NO的调节 TSP-CD47的抑制、硝基脂肪酸的补充和亚硝酸盐的治疗应用将是 在一系列目标中进行评估，从基础力学研究到高度发达的 转化型临床发展计划。这一发展将来自多环芳烃和多环芳烃的啮齿动物模型 COPD/PAH在PAH临床前核心灵长类动物模型和人类11a期的临床试验 COPD和HIV相关PAH患者的导尿术研究，在临床核心中进行评估。

Project 3: Pulmonary Vascular-Targeted NO Therapeutic Strategies Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries, characterized by vasoconstriction, vascular proliferation and remodeling. The relaxation of pulmonary vascular smooth muscle cells and their abnormal proliferation is strongly modulated by nitric oxide (NO)-dependent reactions inducing both cGMP-dependent vasodilation and cGMP-independent reactions that inhibit smooth muscle proliferation and inflammatory cell function. Notably, PAH is linked with both decreased NO bioavailability and a lack of responsiveness to NO, a consequence of impaired NO biosynthesis, endothelial nitric oxide synthase (eNOS) uncoupling, dysregulated L-arginine metabolism and increased redox-dependent consumption of NO. We hypothesize that new vascular-targeted, NO-based therapeutic strategies will enhance the treatment of PAH. The research plan will evaluate the mechanisms of action of newly-appreciated signaling mediators in the context of limiting PAH. Specifically, we hypothesize that pulmonary vascular eNOS is negatively regulated by thrombospondin-l. Down-stream of eNOS, NO is then physiologically oxidized to form the potent NO signaling metabolites, nitrite and nitro-fatty acids, which dynamically regulate NO levels, p21 dependent vascular proliferation, phase 2 stress response enzymes, and peroxisome proliferator activating receptor-y signaling. The studies proposed in Project #3 will provide important new mechanistic insight and promising therapeutic strategies for modulating events central to the genesis of PAH. These goals capitalize on recent high impact discoveries related to the formation, metabolism and actions of NOderived species and synergize with central program objectives. Overall, the modulation of eNOS and NO by TSP-CD47 inhibition, nitro-fatty acid supplementation and the therapeutic application of nitrite will be evaluated in a continuum of objectives ranging from basic mechanistic studies to a highly developed translational clinical development program. This development will flow from rodent models of PAH and COPD/PAH, to clinical testing in a Pre-Clinical Core primate model of PAH and in human phase lla catheterization studies in patients with COPD and HIV associated PAH, evaluated in the Clinical Core.