肺动脉高压（PAH）发病机制尚未完全阐明。BMPR2是目前已知PAH最主要致病基因，但目前无法仅依靠遗传筛查准确判断BMPR2基因突变携带者将来是否发生PAH。我们在前期工作中发现DNA甲基化参与PAH血管重构，并筛选出多个BMPR2修饰基因，其甲基化分型可协助BMPR2突变携带者进行早期预警，特异性和敏感性均超过80%。在此研究基础上，我们将建立PAH高危人群生物样本库和临床数据库，构建多能诱导干细胞和淋巴细胞株，验证DNA甲基化分型在PAH预警的作用，研发临床检测试剂盒；构建修饰基因转基因和基因敲除大鼠，联合BMPR2基因敲除和基因敲入大鼠模型，研究修饰基因与BMPR2交互作用，探讨DNA甲基化在PAH中的功能和机制。我们研究将从表观遗传水平解释PAH发生发展机理，构建遗传、表观遗传、PAH临床表型三者之联系，发现新PAH致病靶点，为PAH早期预警和开发新的治疗方法提供手段。

The pathogenesis of pulmonary arterial hypertension (PAH) remains unclear. BMPR2 is identified as the major predisposing gene for PAH, and carriers of BMPR2 mutation are at high risk of developing PAH. However, low penetrance and high heterogeneity make it hard to predict whether carriers will develop PAH through genetic counseling screening. Our preliminary experiments showed DNA methylation was involved in pulmonary vascular remodeling. By comparing the methylation of affected and unaffected BMPR2 mutation carriers, we have found several differentially methylated regions. Using methylation genotyping, we can identify high-risk carriers and make early warning, with specificity and sensitivity of both greater than 80%. Based on these studies, we will establish a bio-bank and a clinical database of high-risk PAH population, construct induced pluripotent stem cells and lymphocyte cell lines, develop clinical assay kits for clinical testing, and verify the predictive value of DNA methylation genotyping in PAH early warning. We will also identify the interaction of modifier genes and BMPR2 and explore the function and mechanisms of DNA methylation in PAH using genetic modified rat models. Our research will help to understand the integral functions of genetics and epigenetics in the pathogenesis of PAH, establish a novel network between genetics, epigenetics, and PAH phenotype, identify novel pathogenic targets, and develop methods of early warning and new treatment strategies for PAH.