血浆血管性血友病因子（vWF）水平的异常可以引起多种病理状态（如出血、高凝状态、血栓形成等）。已经知道，血管内皮细胞的vWF分泌状态与血浆vWF浓度的稳态维持及血栓形成密切相关，但其具体的调控机制尚不完全清晰。申请人课题组在前期系统研究粘着斑与内皮细胞分泌关系时意外发现，斑联蛋白（Zyxin）参与vWF分泌的调控，并可能与cAMP介导的信号通路有关。本申请将进一步1）确定Zyxin调控内皮细胞释放vWF的作用及其方式；2）揭示Zyxin关联的上下游信号分子及其转导途径；3）运用基因敲除小鼠探讨Zyxin介导的信号通路在调节血浆vWF浓度及vWF关联血栓形成过程中的作用及机制。本项研究不仅能揭示内皮细胞vWF分泌调控的新机制，而且还可能为血浆vWF水平异常关联疾病的防治提供新的靶点和思路。

The abnormal vWF level in plasma may lead to the development of various pathological conditions such as bleeding，blood coagulation and thrombosis. Though endothelial vWF secretion is known to contribute to the maintenance of vWF homoeostasis in plasma phyisiologically and the development of thrombosis pathologically, the exact mechanism of endothelial vWF secretion is incompletely understood. During a screening study, the applicant team has found a critical role of Zyxin in the regulation of vWF release, which is likely associated with cAMP pathway. In this application, we will further 1)determine the role of Zyxin in the regulation of vWF secretion; 2)identify the Zyxin-associated molecules and their signaling cascades; 3) examine the role of Zyxin in vivo in the regulation of vWF level in plasma and vWF-dependent thrombosis, and their molecular mechanisms, using Zyxin gene knockout mice. This study will not only reveal a new mechanism mediated by Zyxin in the regulation of vWF secretion, but may also provide a potential target and insight in the prevention and treatment of the diseases related to abnormal vWF level in plasma.