Pulmonary vascular-targeted NO therapeutic strategies

项目3：肺血管靶向NO治疗策略 肺动脉高压（PAH）是一种小肺动脉疾病，其特征在于： 血管收缩、血管增生和重塑。肺血管平滑肌松弛 细胞及其异常增殖受到一氧化氮（NO）依赖性反应的强烈调节， cGMP依赖性血管舒张和cGMP非依赖性反应均抑制平滑肌增殖 和炎症细胞功能。值得注意的是，PAH与降低的NO生物利用度和缺乏 对NO的反应性，NO生物合成受损的结果，内皮型一氧化氮合酶 （eNOS）解偶联，L-精氨酸代谢失调和增加的氧化还原依赖性消耗 号我们推测，新的血管靶向，NO为基础的治疗策略将提高 治疗PAH。该研究计划将评估新认识的信号传导的作用机制， 在限制PAH的背景下，调节剂。具体来说，我们假设肺血管eNOS是 由血小板反应蛋白-1负调节。在eNOS的下游，NO然后被生理氧化成 形成有效的NO信号代谢物，亚硝酸盐和硝基脂肪酸，其动态调节NO 水平、p21依赖性血管增殖、2相应激反应酶和过氧化物酶体增殖物 激活γ受体信号。项目#3中提出的研究将提供重要的新机制 对调节PAH发生的核心事件的洞察力和有前景的治疗策略。这些 目标利用最近与NO衍生物的形成、代谢和作用有关的高影响力发现 并与中央计划目标协同增效。总的来说，eNOS和NO的调节 TSP-CD 47抑制、硝基脂肪酸补充和亚硝酸盐的治疗应用将是 从基本的机械研究到高度发达的 转化临床开发项目。这种发展将来自PAH的啮齿动物模型， COPD/PAH，在PAH的临床前核心灵长类动物模型和人类阶段IIa中进行临床测试 在COPD和HIV相关PAH患者中进行的导管插入术研究，在临床核心中进行评价。

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.