RGS10甲基化对射血分数保留的左室舒张功能不全发病预警价值的队列研究及其表观遗传学调控机制

Left ventricular diastolic dysfunction with preservation of ejection fraction (LVDD-PEF) is one of the phenotypes and the very early stage of heart failure (HF),however, the long-term mortality of LVDD-PEF is extremely high. Based on a community-based study, we found that the DNA methylation level at promoter region (Pos: 121259187) of the G protein regulatory factor 10 (RGS10) in LVDD-PEF participants was significantly higher than that in the control group (p<0.001); Using in vitro assays, we further confirmed that the decrease of RGS10 induced by DNA methylation elevated levels of BNPand ANP, molecular marker of HF, which indicate that RGS10 DNA methylation might be the early warning factor of LVDD-PEF. This project will confirm the early warning value of DNA methylation, and deeply investigate the effect of RGS10 epigenetic mechanism on the occurrence of LVDD-PEF using clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 (CRISPR-Cas9). Methods of clinical Epidemiology, Biostatistics and molecular biology were used to explore the potential mechanism underlying G-protein signaling pathway. Our aim is to establish the functional model between RGS10, G protein signaling pathway and LVDD-PEF. The data will contribute to early clinical prevention, effect treatment and prognosis of HF, providing an important theoretical basis for the development of related drugs and precision medicine as well. All these will contribute to decrease the morbidity of HF and adverse cardiovascular events among community residents.

射血分数保留的左室舒张功能不全（LVDD-PEF）是心力衰竭（HF）的一个表型和极早期阶段，其远期病死率高且疾病负担极为严重。课题组以社区人群为对象，发现G蛋白调节因子10（RGS10）DNA甲基化与LVDD-PEF显著相关，体外实验证实甲基化修饰抑制RGS10表达，进而诱导HF分子标志物BNP、ANP表达增高，提示RGS10甲基化对LVDD-PEF发病具有预警价值。本研究拟通过对纳入人群进行5年随访探究RGS10甲基化对LVDD-PEF的预警价值；利用CRISPR-Cas9靶定DNA去甲基化技术验证RGS10致LVDD-PEF发生的表观遗传学机制；综合运用生物信息学手段，从多个维度构建RGS10表观遗传修饰致LVDD-PEF疾病发生的网络模型，揭示疾病病因网中的“黑匣子”现象，探究HF疾病发生、演进的机理，为HF的极早预防、不良结局预测、疾病治疗提依据。

项目为期四年，进展顺利，从人群、生物信息及分子水平对射血分数保留的左室舒张功能不全（left ventricular diastolic dysfunction with preserved ejection fraction, LVDD-PEF）危险因素及表观遗传学分子事件进行了全面分析，为LVDD-PEF疾病的预防、不良结局的预测以及相关药物的研制提供重要依据。项目期间，项目组成员参加国内、外学术交流9人次，其中课题重要研究成果，左室舒张功能不全的表观遗传学研究“Risk factors and epigenetic markers of left ventricular diastolic dysfunction with preserved ejection fraction in a community-based elderly Chinese population”于2019年10月31日，加拿大家庭医学论坛（温哥华）壁报交流。另一项研究成果在2021年4月2日第七届中国血压监测学术会议作大会汇报。课题负责人受邀国内学术交流7次，邀请同行交流2次。依托本项目且署名本项目，发表论文12篇，其中SCI论文7篇，核心期刊5篇。依托本项目，培养研究生10名，毕业4名（郑永韬、顾逸君、王润滋、李琦），其中李琦同学2021年获得国家优秀学生奖学金并获得上海市优秀毕业生。在读研究生蒋栋铭获2022年国家优秀学生奖学金。以科研促教学，项目执行期间，流行病学课程获得上海市重点课程、上海市一流本科课程