PEAR1基因多态性在抗血小板疗效个体差异中的作用及其机制研究

Acute Coronary Syndrome (ACS) is a group of high-risk diseases caused by thrombosis.Platelets play an important role in thrombosis, so antiplatelet therapy is the core strategy for prevention and treatment of ACS. Clinical practices discover that the efficacy of antiplatelet therapy displays considerable inter-individual variability, some patients presenting poor curative efficacy of antiplatelet therapy and adverse outcomes. Platelet Endothelial Aggregation receptor 1 (PEAR1) is a newly reported protein which expresses on platelet membrane and plays an important role in platelet function. The aim of our study is to analyze whether PEAR1 gene polymorphisms are associated with variant antiplatelet therapy efficacy and investigate its mechanism of action. We will do research on the following aspects to elucidate the effect of PEAR1 gene polymorphisms on the mechanism of variant antiplatelet therapy efficacy:(1)explore whether the PEAR1 gene polymorphisms could lead to adverse clinical events(ischemic events, bleeding events,death) via a clinical trial on patients, thus make clear the effect of PEAR1 gene polymorphisms on patients prognosis under antiplatelet therapy; (2)analyze the influence of PEAR1 gene polymorphisms on platelet function through animal and cell experiments, so as to clarify the direct reason that cause variant antiplatelet therapy efficacy; (3)investigate the effect of PEAR1 gene polymorphisms on the molecular mechanism of affecting platelet function by testing the expression level of proteins and molecules in the signaling pathways, thereby explain the fundamental cause of variant antiplatelet therapy efficacy.Through our research work, we will expound explicitly the reason and mechanism of variant antiplatelet therapy efficacy caused by polymorphisms, thus provide theoretical basis for clinical individual therapy.

急性冠脉综合征（ACS）是一组因血栓形成导致的高危疾病，血小板在血栓形成中起着至关重要的作用，因此抗血小板治疗是防治ACS的核心。临床实践发现抗血小板疗效存在个体差异，部分患者疗效不佳。血小板内皮聚集受体1（PEAR1）是一种新发现的与血小板功能密切相关的血小板膜上蛋白。本课题将聚焦编码这种蛋白的PEAR1基因多态性在抗血小板疗效个体差异中起到的作用及其机制：从临床水平确证PEAR1基因多态性对抗血小板疗效的影响，为研究提供确切的临床证据；从动物、细胞水平明确PEAR1基因多态性对血小板功能的影响，阐明造成抗血小板疗效个体差异的直接原因；从分子水平探究PEAR1基因多态性影响血小板功能的机制，阐释造成抗血小板疗效个体差异的根本原因。本课题的完成，将从遗传学角度解释抗血小板疗效差异形成的原因，为临床个体化治疗提供理论基础。

抗血小板药物是冠状动脉粥样硬化性心脏病治疗的基石。然而，抗血小板疗效存在个体差异，导致部分患者预后无显著改善，基因多态性在其中起重要作用。既往关于抗血小板疗效差异的基因多态性研究多从抗血小板药物作用途径切入，鲜有针对血小板自身结构功能的研究。不受已有抗血小板药物干预的血小板膜蛋白可能是抗血小板疗效个体差异的潜在原因。本课题以血小板内皮聚集受体1（Platelet Endothelial Aggregation Receptor 1，PEAR1）为对象，从临床、动物、细胞水平展开研究。.临床研究确证了PEAR1基因多态性对血小板功能、抗血小板疗效个体差异及临床事件的影响。纳入405名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的冠心病患者，检测其血小板反应性及PEAR1 单核苷酸多态性（Single Nucleotide Polymorphism，SNP），发现PEAR1基因多态性与中国冠心病的血小板聚集功能显著相关；纳入647名接受PCI及阿司匹林加氯吡格雷的急性心肌梗死患者，检测其PEAR1 SNP并对临床事件进行12个月随访，发现PEAR1基因多态性与中国急性心肌梗死患者的临床预后显著相关。.动物水平方面，构建了PEAR1(+/-)基因敲除和PEAR1(-/-)小鼠品系，并可顺利、稳定繁殖后代。.细胞实验方面，纳入131名急性心梗PCI术后患者，实验发现相较阿司匹林治疗下血小板低反应患者，血小板高反应性患者血小板膜表面PEAR1蛋白表达水平更高，虽然未达到显著差异。此外课题组正在建立PEAR1干扰及过表达的人成巨核细胞白血病细胞系，用于探讨PEAR1在血小板产生、分化过程中的作用；正在建立PEAR1干扰及过表达的人冠脉内皮细胞模型，用与探讨血小板-内皮细胞相互作用导致血栓形成过程中PEAR1的作用。.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、新靶点。