血管内皮衰老机制与标识及其向动脉粥样硬化演变的关键节点与干预策略研究

人口老龄化带来心脑血管疾病高发，造成极大的社会与医疗负担。动脉粥样硬化是缺血性心脑血管疾病的病理学基础。项目前期聚焦血管与血液系统衰老及动脉粥样硬化，系统阐释了遗传与表观遗传调控机制，解析了血管内皮响应血流剪切力，驱动动脉粥样硬化发生发展的分子机理。表观转录修饰可迅速响应内外环境的改变，维持细胞稳态。本项目紧扣重大研究计划项目指南，基于已经构建的特色衰老动物模型和老龄人群队列，聚焦Sirtuins、m6A、ac4C等表观修饰及酶与结合蛋白，多角度、多层次、系统地研究血管内皮衰老的表观调控网络，解析血管内皮响应湍流冲击，并与循环免疫细胞互作，维持血管稳态的分子机制，解构血管内皮衰老向动脉粥样硬化演变进的关键时空节点、分子网络和生物标识，建立涵盖结构、功能、循环细胞与分子的人体血管衰老评估体系，发现可有效干预血管衰老的表观修饰靶标和生物活性分子，为干预心脑血管疾病及衰老进程提供科学依据与策略。

Aging population has brought about a high incidence of cardiovascular and cerebrovascular diseases, resulting in a huge social and medical burden. Atherosclerosis is the pathological basis of ischemic cardiovascular and cerebrovascular diseases. We have been focusing on the mechanisms of potential intervention of vascular and immune aging and atherosclerosis, especially the genetic and epigenetic regulation, and the vascular endothelium responds to hemodynamics to drive atherosclerosis. Recent studies have found that epitranscriptomic modifications can rapidly respond to changes in the internal and external environment and thus to maintain cellular homeostasis. Based on the established aging animal models and aging population cohorts, focusing on Sirtuins, m6A and ac4C modifications and reader proteins, this project will (1) study the epitranscriptomic modification regulatory network of vascular endothelial aging from multiple perspectives and at multiple levels, (2) analyze the molecular mechanism of vascular endothelial response to turbulence, interaction with circulating immune cells, by which it maintains vascular homeostasis, (3) deconstruct the key nodes, molecular networks and biomarkers of the transition from vascular endothelial aging to atherosclerosis, (4) establish human vascular aging evaluation system covering structural, functional, cellular and molecular aspects, and (5) discover potential therapeutic targets to intervene in vascular aging. The expected data will provide scientific basis and strategies for the intervention of cardiovascular and cerebrovascular diseases and aging process.