SREBP2诱导内皮稳态失衡及肺动脉高压发生的机制研究

内皮细胞稳态失衡是肺动脉高压发生与发展的关键环节，作为核转录因子，固醇调节元件结合蛋白-2 (SREBP2) 在内皮细胞稳态失衡中起核心作用。我们前期研究发现，缺氧及氧化应激可诱导内皮细胞中SREBP2的表达，造成内皮细胞间质转化及NLRP3炎症小体激活等稳态失衡表现。因此我们推测在肺动脉高压的病理条件下，内皮细胞中的SREBP2通过转录及表观遗传机制调节肺动脉高压相关基因的表达，影响肺动脉的功能和稳态平衡。本研究拟①采用转录组学、表观遗传学及生物信息学方法，探讨在缺氧诱导的细胞模型中，SREBP2调控内皮细胞间质转化及NLRP3炎症小体的分子机制；②利用内皮细胞特异性SREBP2过表达和敲除小鼠，在体验证SREBP2对肺动脉高压发生与发展的关键作用；③探讨SREBP2抑制剂缓解肺动脉高压的可能性；④结合特发性肺动脉高压患者的肺组织样本，验证SREBP2及其下游调控网络在此疾病中的关键角色

Endothelial dysfunction is a key event involved in the pathogenesis of pulmonary arterial hypertension (PAH). The aberrant expression of sterol regulatory element binding protein 2 (SREBP2), acting as a transcription factor, can lead to endothelial dysfunction. We have identified that hypoxia and oxidative stress can induce the expression of SREBP2 in vascular endothelial cells, leading to functional impairment, including endothelial-mesenchymal transition (endoMT) and NLRP3 inflammasome activation. The guiding hypothesis of this research proposal is that SREBP2 regulates the expression of genes related to PAH at both the transcriptional and epigenetics levels, which in turn disrupts the homeostasis of pulmonary arteries. We propose the following aims: (1) To elucidate the molecular mechanism by which SREBP2 induces endoMT and NLRP3 inflammasome utilizing transcriptional, epigenetic, and bioinformatics approaches; (2) To study the role of SREBP2 in vivo by the use of endothelial-specific SREBP2 transgenic or knockout mice; (3) To examine whether SREBP2 pharmacological inhibitors can mitigate PAH onset; and (4) To validate that SREBP2 and its downstream targets are involved in human PAH with the use of idiopathic PAH specimens.