NAD-dependent Signaling and Pulmonary Vascular Remodeling in PAH

摘要 肺动脉高压（PAH）是一种罕见的、使人衰弱的、致命的疾病，目前没有 可用的治疗。有令人信服的证据表明，通过NAMPT的NAD依赖性信号传导是一种新的， PAH的治疗目标。为了便于翻译目前的体内和体外观察结果， NAMPT依赖性信号在PAH病理生物学中的作用，本提案将探讨以下假设： NAMPT/NAD信号轴调节PAH中的生理、细胞和分子途径，导致 肺血管重构SA 1试图确定肺动脉内皮细胞NAMPT在肺动脉粥样硬化中的作用。 调节与PH反应相关的代谢重编程。SA 2定义了NAMPT在以下方面的作用： 调节肺动脉内皮细胞的线粒体动力学。SA 3将寻求发现和验证 PAH易感性和预后的生物化学和遗传NAMPT中心生物标志物。

ABSTRACT Pulmonary arterial hypertension (PAH), a rare, debilitating and fatal disease for which there is currently no available cure. There is compelling evidence that NAD-dependent signaling via NAMPT is a novel and therapeutic target for PAH. To facilitate the translation of current in vivo and in vitro observations on the role of NAMPT dependent signaling in PAH pathobiology, this proposal will explore the hypothesis that the NAMPT/NAD signaling axis regulates physiologic, cellular and molecular pathways in PAH that result in pulmonary vascular remodeling. SA1 seeks to define the role of pulmonary artery endothelial cell NAMPT in the regulation on metabolic reprograming associated with the PH response. SA2 define the role of NAMPT in regulating mitochondrial dynamics in pulmonary artery endothelial cells. SA3 will seek discover and validate biochemical and genetic NAMPT-centric biomarkers of PAH susceptibility and prognosis.