动脉粥样硬化发生的血流动力学调控机制和干预策略研究

Cardiovascular diseases such as myocardial infarction and stroke are the leading cause of death worldwide. They are mainly resulted from vascular diseases including atherosclerosis. However, prevention and treatments to atherosclerosis are very limited. Shear stress, the tangential component of the hemodynamic forces acting on the vascular wall, has been shown to play crucial roles in the regulation of vascular endothelial function and atherogenesis. Our previous studies have discovered a series of hemodynamic regulators such as YAP/TAZ and DNMT1, and unveiled their roles in mediating the shear stress-regulated endothelial functions. In the proposed project we will extend the study and utilize interdisciplinary multi-omics technologies including epigenome, transcriptome, and metabonomics to investigate the dynamic regulatory networks in endothelial cells in response to atheo-protective and athero-prone shear stress. On the basis of the networks, we will elucidate the complex signaling pathways and key molecules in relation to the shear stress-modulated functional outcomes in endothelial cells by using our in vitro and in vivo experimental models. The discovered networks, pathways and molecules will then provide important information in screening and verification of novel therapeutic targets for vascular endothelial dysfunction. The results from the proposed research will help to identify new targets highly associated with the translational and clinical medicine research with great potentials for biotechnological development, thereby facilitating the development of new therapeutic strategies for atherosclerosis.

动脉粥样硬化（AS）是造成心肌梗塞和中风的主因。血流动力学异常是导致血管内皮功能紊乱和AS发生的重要机制。受血管重大研究计划培育项目资助，申请人及项目组成员在前期工作中发现了一系列剪切力调控关键分子：Yap/TAZ、DNMT1等，其对AS相关血管重构的发生发展具重要作用，结果发表在Nature等权威杂志。在前期工作基础上，本研究将采用基于表观遗传组、转录组、代谢组等多组学结合的手段，研究血管内皮细胞受不同流场剪切力作用后的动态调控网络及其可能的相互作用机制，揭示其演变规律；筛选并验证部分关键的分子通路和节点；利用发现的网络、通路和节点获取抗内皮损伤新作用靶点并将其用于AS干预研究。研究结果将揭示新的关键分子并阐明AS的血流动力学调控机制，为新的AS防治策略研究奠定基础。

动脉粥样硬化（AS）是可引起心脑血管疾病的常见血管病变，所致心肌梗塞和脑中风等心血管事件的发生是人类重要致死原因。然而目前AS的防治策略非常有限。血流动力学异常是导致血管内皮功能紊乱和AS发生的重要机制。申请人及项目组成员在前期工作中发现了一系列剪切力调控关键分子：Yap/TAZ、DNMT1等，其对AS相关血管重构的发生发展具重要作用。在前期工作基础上，本研究将采用基于表观遗传组、转录组、代谢组等多组学结合的手段，研究血管内皮细胞受不同流场剪切力作用后的动态调控网络及其可能的相互作用机制，揭示其演变规律；筛选并验证部分关键的分子通路和节点；利用发现的网络、通路和节点获取抗内皮损伤新作用靶点并将其用于AS干预研究。研究结果将揭示新的关键分子并阐明AS的血流动力学调控机制，为新的AS防治策略研究奠定基础。