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。

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.