血管衰老对于腹主动脉瘤发生发展的作用及其表观遗传机制

Aging is a major risk factor for abdominal aortic aneurysms (AAAs) and epigenetic alteration is associated with the initiation and progression of vascular aging and age-related vascular diseases. However, it still remains unclear about the molecular mechanisms underlying the regulation of epigenetic modification, especially for the histone modification on the initiation and progression of AAAs. In the current project, we will establish models for vascular aging with young wild-type mice, aged wild-type mice, apoe-/- mice, ldlr-/- mice and their littermates, to evaluate the effects of vascular cell senescence on vascular aging and the development of AAAs. The changes of modified histone residues will be screened and analyzed in aortas of vascular aging mouse models. Combining the data from RNA Sequencing (RNA-seq), stable isotope labeling by amino acid in cell culture (SILAC) quantitative mass spectrometry and whole genome chromatin immunoprecipitation followed by sequencing (ChIP-seq), we will establish weighted gene co-expression network to identify the key genes for histone modifications. We will also investigate the effects of histone modifications on gene regulation of vascular aging and AAAs, and thereby discovering histone-modifying enzymes that act as new regulators for vascular aging and AAAs. With the utilization of CRISPR/Cas9 to establish histone-modifying enzymes-null mice, we will further elucidate the epigenetic mechanisms underlying the changes in histone modifications, vascular aging and AAAs. Through this project, we will demonstrate the critical roles of histone modifications in mediating the effects of vascular aging and age-related vascular diseases, and elucidate histone-modifying enzyme-mediated epigenetic mechanisms. Therefore, this project will hopefully lay the foundations and provide new strategies for the clinical treatment of age-related vascular diseases.

衰老是腹主动脉瘤主要的危险因素，表观遗传调节在衰老和衰老相关的疾病中发挥重要作用，但是衰老过程中表观遗传的改变，特别是组蛋白修饰改变在腹主动脉瘤发生发展中的作用及其机制还不清楚。本研究利用正常年轻小鼠、老龄小鼠和代谢紊乱小鼠(ApoE-/-小鼠或者Ldlr-/-小鼠）建立血管衰老模型，评价血管细胞衰老在血管组织衰老及其导致的腹主动脉瘤发生发展中的作用。在此基础上，筛选血管衰老组织中组蛋白修饰变化，结合不同时间点的RNA、蛋白质和表观遗传层面的组学数据进行联合分析，构建权重基因共表达网络以研究衰老引起的血管组织发生改变的基因调控模式，阐述其在血管衰老和腹主动脉瘤发生发展中的作用；寻找新的调节腹主动脉瘤的组蛋白修饰酶，进一步阐述其对于组蛋白修饰的改变以及在血管衰老和腹主动脉瘤发生发展中的表观遗传机制。由此，为临床防治衰老相关的心血管疾病提供理论依据和新的策略。

衰老是主动脉瘤发生主要的危险因素，但是衰老过程中表观遗传的改变，特别是组蛋白修饰改变在主动脉瘤发生发展中的作用及其机制还不清楚。本项目评价细胞衰老在血管组织衰老及其导致的主动脉瘤发生发展中的作用，发现组蛋白去乙酰化酶SIRT1/6对于主动脉瘤等有重要的保护作用，其主要通过抑制组蛋白H3K9等去乙酰化实现对于下游基因的调节作用，表明 SIRT1/6可作为主动脉瘤疾病的潜在的干预靶点，为临床防治衰老相关的心血管疾病提供理论依据和新的策略。研究成果主要以论文形式体现，原计划在SCI杂志上发表影响因子大于5的研究论文3-4篇，其中2篇IF在20分左右，培养硕士、博士研究生3-5名，博士后2名。实际发表文章包括Nat Cell Biol. Circulation等IF大于 5 的SCI论文 7篇，其中IF大于10，20和30的研究论文各1篇。