血流剪应力对血小板和白细胞的激活及其信号通路的调控

在血管内皮细胞的损伤与炎症部位，活化了的血小板和白细胞的相互作用，可能诱导动脉粥样硬化斑块的形成和发展，并受到血流剪应力的调控。血小板和白细胞的激活，是止凝血和炎症反应中的关键事件，涉及尚不明晰的胞内力化学信号转导过程，为当前细胞分子生物力学中的前沿热点课题。本项目拟采用分子动力学模拟、荧光和流动腔实验技术，通过理论数值模拟与实验测量，研究分别由vWF和选择素介导的循环血小板和白细胞的激活、相关信号通路及其生物力学调控机制,旨在揭示在血小板和白细胞激活及其相互作用过程中发生的关键事件，如白细胞整合素LFA-1的活化，血小板整合素Mac-1的激活与血小板P-选择素的表达，细胞钙响应和信号转导分子间的相互作用等，以及蕴含在其中的生物力学调控机制和分子结构基础，旨在加深理解心脑血管疾病的生理病理过程，为心脑血管疾病患者的临床治疗和康复，相关分子药物靶点的发现和抗体药物的设计提供新的解决方案

In the inflammatory or injured site of vascular endothelial cell，the interaction of activated platelets and leukocytes may induce both formation and development of atherosclerotic plaque, and are regulated by blood flow shear stress. As unclear key events in the hemostatic and inflammatory responses, the activations of platelets and leukocytes are involved in intracellular mechanochemical signalling, and have become as a focus topic in cellular and molecular biomechanics. The present proposal is, experimemtally and numerically, to research the vWF-mediated platelet activation, the selectin-mediated leukocyte activation, and the involved mechanical regulation mechanism, with techniques of molecular dynamics simulation, fluorescence analysis and flow chamber experiment. The aim of the present proposal is to reveal the key events involved in activations of platelet and leukocyte, such as the activations of both leukocyte integrin LFA-1 and platelet integrin Mac-1, the expressing of platelet P-selectin, Ca+ responses in both platelet and leukocyte, and mechanical features and interactions of the signal molecules in the involved signal pathways, as well as the involved mechanical regulation mechanism and molecular structure foundation. This research will be useful in better understanding of physiological and pathological processes, in providing a new strategy for clinical treatment and rehabilitation, in discovery of new drug targets, and in development of new antibody drugs, for cardiovascular and cerebrovascular diseases.