参与扰动血流促进血栓形成信号途径的靶分子的初步筛选

Hemodynamic plays an important role in thrombosis at disturbance flow area of blood, promotes the formation of the blocked thrombus which could be a serious threat to patient's life. The current researches focus much more on the effects of high/low shear stress and shear stress gradient, but fewer on the effects of disturbance flow on platelet activation, adhesion and aggregation. Therefore, researches on the molecular mechanism of thrombosis induced by the disturbance blood flow could probably give a new pave of looking for new antithrombotic drug targets. Firstly, this project will establish the research methods for in-vitro and in-vivo experiments by using laminar flow as the control for the disturbed flow. Then, the selected 6 kinds of commonly used anti-platelet drugs or antagonists respectively have the effects on platelet activation, adhesion and aggregation signaling pathways. Find out which drug or its target molecular participates in the thrombosis arisen by the disturbed flow. Finally, verify the role of this selected molecule in the thrombosis by using megakaryocytic-specific knockout mice and the previous designed in vitro and in vivo experiments. In conclusion, these results will help us to understand the initial molecular mechanism in the thrombosis process promoted by the disturbance flow, and provide the theoretical evidences for new targets of anti-platelets.

血流动力学在血栓形成中发挥重要的作用，在血液扰动的区域，促进闭塞血栓的生成，严重威胁患者的生命。目前的研究多集中于高低切应力或切应力梯度对血小板激活、粘附和聚集的影响，对于流场的扰动及紊乱造成的影响的研究很少。因此，从血流扰动入手，探究其促进血栓形成的分子机理，寻找新的抗血栓药物靶点具有重要的临床意义。本项目首先通过体外实验和动物实验设计，以平稳流为对照，研究扰动流对促进血栓形成的作用。其次选定了6种常用抗血小板药物或者拮抗剂，分别针对血小板表面受体或者参与到血小板活化、粘附和聚集过程中的信号分子，筛选能有效抑制扰动流促血栓形成的药物及其靶分子。最后通过条件基因敲除小鼠的设计，验证该靶分子在此血栓形成过程中的作用。研究结果将有助于我们推断出扰动流促进血栓形成的初步分子机理，并为研发理想的抗血小板药物寻找新的作用靶点提供理论依据。

血流动力学在血栓形成中发挥重要的作用，在血液扰动的区域，促进闭塞血栓的生成，严重威胁患者的生命。目前的研究多集中于高低切应力或切应力梯度对血小板激活、粘附和聚集的影响，对于流场的扰动及紊乱造成的影响的研究很少。在该项基金的资助下，从血流扰动入手，探究其促进血栓形成的分子机理，寻找新的抗血栓药物靶点。.首先，在该课题的资助下我们建立了三个血栓模型，该模型不同于传统三氯化铁损伤的血栓模型，机械损伤模型更能模拟斑块破裂胞外基质暴露后诱发的血小板富集型血栓。其次，在该课题的资助下，我们深入探讨了血栓异质性构成与血栓造成血流扰动微环境之间的关系，以及通过基因敲除小鼠模型，验证了我们的假设。我们发现血小板TP对于血流紊乱相关的血小板聚集有影响，可能是血流紊乱作用下，血小板活化的特异性受体。上述研究成果产生2篇SCI文章（Thrombosis Research 1 篇， J. Med. Biol. Eng. 1篇），项目带头人均为通讯作者，并在国际会议上进行了相关的报道，受到国际同行一定的关注。