骨形成蛋白受体2（BMPR2）是目前已知的最主要肺动脉高压（PAH）致病基因，突变类型众多，分子机制不清。我们课题组用时16年，初步描绘了中国PAH患者的BMPR2突变图谱，发现p.R491W为BMPR2热点突变，占比高达9.8%。我们从携带R491W突变的患者体内培养出诱导多能干细胞（iPSC），并成功构建了R491W突变大鼠模型。我们的最新研究表明DNA甲基化是调控BMPR2基因突变外显的重要因素，DNA甲基化转移酶1（DNMT1）在BMPR2基因突变导致PAH中可能发挥重要作用。本项目中，我们将利用自主构建的BMPR2突变敲入大鼠和患者来源的iPSCs，深入研究DNA甲基化及DNMT1在BMPR2基因突变致病中作用和机制，从表观遗传水平解释PAH发生机理，构建基因突变、表观遗传、PAH临床表型三者之联系，明确PAH发病的关键基因，为PAH早期预警和治疗提供潜在靶点。

Bone morphogenetic protein receptor 2 (BMPR2) is the most prominent pathogenic gene contributing to pulmonary arterial hypertension (PAH). The molecular mechanism underlying the causal relationship between BMPR2 mutation and PAH remains unclear. Over the past 16 years, our team kept focusing on the genetics research of PAH and have drawn the mutation atlas of BMPR2 gene for Chinese PAH patients. We found that p.R491W mutation is a BMPR2 hotspot mutation, affecting 9.8% in Chinese PAH patients. We have successfully cultured induced pluripotent stem cells (iPSC) from PAH patients with p.R491W mutation and generated a knock-in rat line carrying the p.R491W mutation. Most recently, we demonstrated that DNA methylation plays a critical role in regulating the penetrance of BMPR2 mutation. The DNA methyltransferase 1 (DNMT1), which was significantly decreased in the lung of BMPR2 mutant rat, may protect pulmoanry vascular remodling. In this project, we plan to explore the function of DNA methylation and DNMT1 in PAH using the BMPR2 mutant rat models and iPSC form patients. Our research will decipher the relationship between genetic mutation, epigenetic regulation and PAH phenotype, help to understand the pathogenesis of PAH at epigenetic level and identify novel targets for early warning and treatment of PAH.