CD226分子调控血小板功能参与动脉粥样硬化疾病的机制

Atherosclerosis is a serious diseases endangering human health. At present, there is still lack of effective prevention and control measures. Platelets can regulate thrombosis and vascular inflammation, thus involved in atherosclerosis and become the new focus of research field in recent years. CD226 molecule is also called "platelet and T cell activation antigen 1", it is highly expressed on platelets and T cells, its monoclonal antibody can effectively stimulate platelet and T cells activation. We found it seemed that the activation signal pathway of CD226 on platelet is not an isolated process, probably coupled to other molecules to regulate platelet function, or compete to combine downstream key molecules with other receptors, thus involved in the development of atherosclerosis disease. In this study, we try to clarify the molecular effects of CD226 on lipid metabolism and platelet activation, discuss the coordination mechanism of CD226 molecular with integrin αⅡbβ3 in regulating platelet function; use of CD226-/-ApoE-/- double knockout mice to explain the effect of CD226 on atherosclerosis, to observe the expression of CD226 in patients with atherosclerosis, to explore the possibility of CD226 as an indicator of disease, and detect the effects of human and mouse monoclonal antibody on platelet activation. The purpose of this study is to clarify the relation between CD226 molecule, lipid disorder and atherosclerosis, thus provide experimental basis for CD226 molecules as a therapeutic target to atherosclerosis in the future.

动脉粥样硬化是严重危害人类健康的疾病，目前仍缺乏有效的防治措施。血小板可以调控血栓形成和血管炎症等反应，在动脉粥样硬化疾病中发挥重要作用。CD226 分子又称"血小板与T 细胞活化抗原1"，该分子高水平地表达于血小板，其单抗能够刺激血小板的活化。我们发现，CD226对血小板的活化作用并非孤立的信号通路，很可能与其他分子相偶联激活血小板，或者竞争结合下游关键分子，从而参与动脉粥样硬化发生。为了明确CD226分子在血小板活化中的作用，寻找该分子与脂质代谢和动脉粥样硬化发病机制之间新的联系途径，本研究拟首先探讨CD226分子与整合素αⅡbβ3协同调控血小板功能的机制, 利用已构建的CD226-/-ApoE-/-双基因敲除小鼠，明确CD226分子对动脉粥样硬化的影响, 进一步观察血小板膜型CD226和血浆中可溶型CD226水平与人动脉粥样硬化疾病的关系，有望为动脉粥样硬化的防治开辟新的研究途径。

CD226分子又称“血小板与T细胞活化抗原”，该分子高表达于血小板，可能参与血小板的发育和活化，从而调节血栓形成和血管炎症，在动脉粥样硬化疾病中发挥重要作用。. 本课题研究发现，与对照野生型（WT）小鼠相比，CD226-/-小鼠的血小板数量明显减少，出血时间明显延长，FeCl3诱导的颈动脉血栓模型亦证实CD226-/-小鼠血栓形成时间延长，说明CD226分子对于血小板的生成和活化有显著的促进作用。值得注意的是，这些现象在老年雌性CD226-/-小鼠中更为显著。利用体外实验我们发现，干涉CD226分子影响巨核细胞的活化水平。进一步利用免疫共沉淀和质谱技术，本课题发现了包括BNDF在内的19个与CD226下游信号相关的分子。. 此外，内皮细胞功能障碍是动脉粥样硬化、2型糖尿病（T2DM）等代谢疾病的共同特征。本研究发现，CD226分子参与T2DM的疾病过程，CD226-/-小鼠的糖耐量明显由于WT小鼠，胰岛和脂肪等组织病理情况改善，其原因与CD226分子调节内皮细胞功能有关。高糖状态下炎症因子增加CD226分子表达，而干涉CD226可以影响炎症诱导的内皮细胞骨架重塑，增加内皮细胞葡萄糖转运体GLUT1表达，增加内皮细胞糖摄取能力，从而使血糖水平得到改善。. 通过本研究，我们证实CD226分子调控血小板活化，参与T2DM和动脉粥样硬化的疾病过程。