IDO-1介导的De novo NAD+合成激活在肺动脉高压中的作用和机制研究

肺动脉高压(PAH)的典型病理改变为肺血管细胞功能紊乱导致的肺血管重塑。我们发现PAH患者存在De novo NAD+合成激活，体外实验表明NAD+可导致肺血管细胞线粒体膜电位增加发生异常增殖，反之，抑制De novo NAD+合成限速酶IDO-1可限制NAD+合成降低线粒体膜电位纠正异常增殖。因此，我们提出科学假说：IDO-1介导的De novo NAD+合成激活导致肺血管细胞线粒体功能紊乱发生异常增殖和凋亡抵抗，促进PAH肺血管重塑。本项目将首先在体外明确调控IDO-1介导的De novo NAD+合成对肺血管细胞功能的影响和机制。然后将通过大鼠MCT-PAH模型研究抑制IDO-1(siIDO-1尾静脉注射或EPA灌胃)限制De novo NAD+合成激活治疗PAH的疗效和机制。预期结果有助于深入理解PAH的发病机理，并推动EPA(已用于癌症的三期临床试验)治疗PAH的临床试验的开展。

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling as a consequence of pulmonary vascular cells (PVCs) dysfunction. We originally found that there is an activation of De novo NAD+ synthesis in PAH patients. In vitro experiments showed that NAD+ could increase mitochondrial membrane potential and promote proliferation of PVCs, while inhibition of IDO-1 (the rate-limiting enzyme of De novo NAD+ synthesis) could limit the production of NAD+, reduce mitochondrial membrane potential, and halt proliferation of PVCs. Therefore, we propose the following hypothesis: IDO-1 mediated De novo NAD+ synthesis activation is involved in pulmonary vascular remodeling by inducing mitochondrial dysfunction in PAH. We first, in vitro, aim to investigate the impact and mechanism of IDO-1 mediated De novo NAD+ synthesis on the function of PVCs. After that, we will use monocrotaline (MCT) induced PAH in rats to investigate the efficacy and mechanism of De novo NAD+ inhibition by inbiting IDO-1 via siRNA IV injection or EPA ig. Our project will not only enhance our understanding in the pathogenesis of PAH, but also promote the initiation of clinical trials to investigate the efficacy of EPA (a drug already used in Phase III clinical trials for the treatment of cancer) for the treatment of PAH.