NAD-dependent Signaling and Pulmonary Vascular Remodeling in PAH

摘要 肺动脉高压(PAH)是一种罕见的、使人衰弱的致命疾病，目前尚无治疗方法 可用的治疗方法。有令人信服的证据表明，通过NAMPT的NAD依赖信号是一种新的和 PAH的治疗靶点。为了便于翻译目前体内和体外观察到的 NAMPT依赖的信号在PAH病理生物学中的作用，这一建议将探索以下假设： NAMPT/NAD信号轴调节PAH中的生理、细胞和分子通路，从而导致 肺血管重塑。SA1试图确定肺动脉内皮细胞NAMPT在 与PH反应相关的代谢重编程的调节。SA2定义NAMPT在以下方面的角色 调节肺动脉内皮细胞线粒体动力学。SA3将寻求、发现和验证 以NAMPT为中心的生化和遗传生物标记物对PAH易感性和预后的影响。

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.