血小板膜受体蛋白ADRA2A基因对抗血小板疗效影响的机制研究

Acute Coronary Syndrome(ACS) is high-risk disease caused by thrombosis. Platelets play an important role in thrombosis, thus antiplatelet therapy is the most important strategy for prevention and treatment of ACS. It is discovered in clinical practice that some patients presenting poor curative efficacy of antiplatelet therapy and adverse outcomes. Traditional research focusing on mechanism of antiplatelet drug can't fully explain this phenomenon. It is a new research direction that mechanism associated with platelet structure and function, especially protein expressed on the membrane of platelet surface may play a crucial role in antiplatelet efficacy. The α2A-adrenergic receptor(ADRA2A) is one of these important proteins which expresses on platelet membrane without the influence of antiplatelet drug plays an important role in platelet aggregation. Our group demonstrated that ADRA2A gene which encoded ADRA2A protein was associated with high platelet aggregation. But the underling mechanism is unclear. Base on this observation, the aim of this study is to analyze whether ADRA2A gene are associated with antiplatelet therapy efficacy and explain the internal mechanism. We will focus on：(1) whether ADRA2A gene is associated with adverse clinical outcomes(including ischemic and bleeding events);(2) analyze the influence of ADRA2A gene on platelet aggregation in cell experiments; (3)investigate the molecular mechanism of ADRA2A gene on platelet aggregation by testing the expression level of proteins and molecules in the signaling pathway. Through our research, we will add new genetic evidence and provide theoretical basis for clinical individual antiplatelet therapy.

急性冠状动脉综合征（ACS）是由血栓形成诱发的高危疾病，血小板在其中发挥重要作用，抗血小板治疗是ACS防治的关键。部分患者抗血小板疗效不佳，预后不良。传统抗血小板药物途径机制不能完全解释。与血小板自身结构功能相关的蛋白途径，尤其是血小板表面的膜受体蛋白是新的研究方向。α2A肾上腺素受体（ADRA2A）是血小板表面的重要膜蛋白，与血小板功能密切相关，不受抗血小板药物影响。申请人已报道编码该蛋白的ADRA2A基因与血小板聚集功能增强相关，机制不清。本申请继续聚焦ADRA2A基因，深入探讨其对抗血小板疗效的作用及机制：（1）从临床水平，确证ADRA2A基因对抗血小板疗效的影响；（2）从细胞水平，探讨其对血小板聚集功能的作用，明确影响抗血小板疗效的直接原因；（3）从分子水平，探讨其影响血小板聚集功能的机制，阐释影响抗血小板疗效的根本原因。研究结果将为个体化抗血小板治疗提供新思路和新靶点。

冠状动脉内血栓形成是急性冠状动脉综合征发病的主要机制。血小板是冠状动脉内血栓的主要成分。因此，有效的抗血小板治疗是冠心病防治的关键。然而临床抗血小板疗效存在个体差异，影响预后。基因多态性在其中起重要作用。既往相关基因多态性研究多从抗血小板药物作用途径入手，而针对血小板自身结构功能的研究鲜有报道。不受抗血小板药物途径影响的血小板膜蛋白可能是突破口。本课题以血小板膜α2A-肾上腺素受体（alpha2A-adrenergic receptor, ADRA2A）基因为对象，从临床、细胞、分子水平展开研究。. 临床水平方面，纳入666例行经皮冠状动脉介入术 (Percutaneous Coronary Intervention，PCI)且接受阿司匹林加氯吡格雷双联抗血小板治疗(Dual Antiplatelet Therapy，DAPT)的中国冠心病患者，进行病例对照研究，确证了ADRA2A基因多态性位点rs11195419和rs3750625与冠心病患者PCI术后DAPT治疗下的MACCE的显著相关。细胞水平方面，纳入1024例行PCI且接受DAPT的患者，进行基因和血小板功能检测。研究发现ADRA2A基因多态性位点rs11195419及rs3750625与PCI术后DAPT治疗下，ADP诱导的血小板聚集抑制率降低显著相关。分子水平方面，纳入1001例行PCI治疗且接受DAPT治疗的患者，进行了初步ADRA2A基因与P2Y12基因关联的分子研究。研究发现ADRA2A多态性位点rs3750625及P2Y12多态性位点rs6809699联合携带与严重氯吡格雷抵抗发生风险增加显著相关。. 本课题从遗传学角度解释了抗血小板疗效差异形成的原因，为指导临床个体化治疗、改善患者预后提供了理论基础，为抗血小板药物的研发提供了新思路。