BMPR2突变导致肺动脉高压的表观调控机制及干预研究

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.

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。

本课题组对BMPR2基因突变在肺血管重构中的作用和机制展开研究，完成以下工作：.1.绘制中国肺动脉高压患者BMPR2突变全景图（Int J Cardiol. 2020; 318:138-143）；.2.发现BMPR2以外的肺动脉高压全新易感基因PTGIS（JAMA Cardiol. 2020;5(6):677-684）；.3.构建BMPR2 R491W突变敲入大鼠，发现该大鼠模型在常压常氧下有15%会自发肺动脉高压，在低压低氧下会产生更加严重的肺动脉高压。初步明确了BMPR2突变在肺动脉高压发病的恶性作用，申报两项国家发明专利；.4.初步探索了BMPR2突变导致肺动脉高压的表观遗传机制，发现BMPR2突变导致肺动脉导致肺动脉高压的分子机制与DNA甲基化改变紧密相关。. 项目执行期间，课题组共发表7篇SCI论著，总影响因子41.6，单篇最高影响因子14.676。发表4篇中文核心期刊论文。所有论文均标引课题资助。申报两项国家发明专利。培养毕业3名研究生。BMPR2突变全景图的绘制和PTGIS等新基因的发现为肺动脉高压患者遗传检测和分子分型奠定科学基础。BMPR2突变大鼠模型为研究自发性肺动脉高压以及环境因素诱导的肺动脉高压提供了重要工具。2021年，本项目的部分内容被写入“国人肺动脉高压遗传特征及发病机制的探索与应用”，并获得2021年北京医学科技奖壹等奖（王晓建为第六完成人）。