能量限制保护血管稳态的表观遗传机制研究

Calorie restriction (CR) alleviates vascular oxidative stress and vascular inflammation, maintains vascular homeostasis and delays the onset and development of vascular diseases. However, the exact molecular mechanisms underlying the protective roles of CR in artery remain unclear. In the current project, we will establish a CR animal model on wild-type mice, ApoE-/- and Ldlr-/- mice, and eNOS-/-mice to evaluate the effects of CR on vascular functions. The differentially modified histone residues in aorta of mice affected by CR will be screened and analyzed. Whole genome chromatin immunoprecipitation followed by sequencing (ChIP-seq) and stable isotope labeling by amino acid in cell culture (SILAC) quantitative mass spectrometry techniques will be used to identify the differentially modified genes and differentially expressed proteins, respectively. The effects of histone modifications on vascular homeostasis and the development of vascular diseases will be evaluated in aorta of mice affected by CR. With the utilization of CR mimics and histone-modifying enzymes which mediate CR effects, we will further elucidate the epigenetic mechanisms underlying the changes in vascular homeostasis and diseases affected by histone modifications. Through this project, we will demonstrate the important roles of histone modifications in mediating protective effects of CR on vascular functions, and elucidate the epigenetic mechanisms underlying the maintenance of vascular homeostasis by CR. This project will hopefully provide new strategies for the clinical treatment of vascular diseases.

能量限制能够减轻血管氧化应激，降低血管炎症，维持血管稳态，延缓血管性疾病的发生发展。但其在维持血管稳态中的确切作用及分子机制还不清楚。本研究利用正常小鼠、代谢紊乱小鼠（ApoE-/-小鼠或者Ldlr-/-小鼠）和血管稳态失衡小鼠（eNOS-/-小鼠）建立能量限制小鼠模型和评价能量限制对于血管功能的作用。从组蛋白修饰的角度，筛选能量限制对血管组织的组蛋白修饰改变的位点，采用全基因组ChIP-seq结合SILAC定量质谱技术寻找相应的差异修饰的基因和差异表达的蛋白，阐述组蛋白修饰的改变对于血管稳态和血管性疾病的作用。利用能量限制模拟物以及介导能量限制效应的组蛋白修饰酶，进一步阐述组蛋白修饰的改变导致的血管稳态改变和血管性疾病的表观遗传机制。由此，明确组蛋白修饰的改变在能量限制保护血管功能中的重要作用，阐明能量限制维持血管稳态的表观遗传调控机制，以期为临床防治心血管疾病提供新的策略。

能量限制能够减轻血管氧化应激，降低血管炎症，维持血管稳态，延缓血管性疾病的发生发展。但其在维持血管稳态中的确切作用及分子机制还不清楚。本项目运用正常小鼠和代谢紊乱小鼠（ApoE-/-小鼠）建立能量限制小鼠模型和评价能量限制对于血管功能的作用。研究发现能量限制能够有效地保护血管功能以及维持血管稳态；进一步研究发现能量限制能够增加血管平滑肌中组蛋白去乙酰化酶SIRT1的表达，从而介导了能量限制对于血管的保护作用，能量限制通过增加SIRT1对于组蛋白H3K9和转录因子p53等去乙酰化而实现对于下游基因的抑制作用。进而，能量限制能够有效保护腹主动脉瘤等血管性疾病的发生。因此，研究表明 SIRT1可作为腹主动脉瘤疾病的潜在的干预靶点，为临床干预衰老所导致的血管疾病提供理论依据。本项目总体上发表标注项目基金号且申请人为通讯作者SCI文章17篇，其中影响因子大于 5 的研究论文9篇，其中有4篇影响因子大于 10。