ABCB1基因在P2Y12受体拮抗剂类抗血小板药物引发消化道出血中的作用及其分子机制研究

项目名称： ABCB1基因在P2Y12受体拮抗剂类抗血小板药物引发消化道出血中的作用及其分子机制研究

项目编号： No.81470486

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 袁晋青

作者单位： 中国医学科学院阜外医院

项目金额： 73万元

中文摘要： P2Y12拮抗剂在抗缺血方面使冠心病患者明确获益，但其引发的出血并发症尤其是消化道出血，常因属于心血管和消化的交叉学科内容，导致重视不足，更未见到相关机制研究。我们的前期临床研究发现肠道药物吸收相关基因ABCB1的多态性位点rs1045642与P2Y12拮抗剂引发的冠脉支架术后消化道出血显著相关。本项目以该基因多态性位点可能会增加P2Y12拮抗剂肠道吸收的科学假设为切入点，拟从细胞水平、整体动物水平深入研究P2Y12拮抗剂引发消化道出血的分子机制：（1）通过损伤肠道上皮细胞间紧密连接结构与自噬两个层面，诱导细胞凋亡，进而直接损伤肠道上皮屏障，引发溃疡后出血；（2）通过升高血药浓度，过度抑制血小板而增加出血风险；并最终以临床验证为研究结点。本项目将为P2Y12拮抗剂引发消化道出血的防治提供一种新思路、新靶点，为最大程度减少由于个体差异而导致的药物不良反应提供基础理论和研究依据。

中文关键词： 消化道出血；P2Y12拮抗剂；ABCB1基因；分子机制

英文摘要： P2Y12 inhibitors, including clopidogrel, prasugrel and ticagrelor, not only show definite antithrombotic effects for patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI), but also have associations with increased risk of bleedings. Gastrointestinal bleedings occur with higher frequency than other kind of bleedings and do great harm to patients. However, the mechanism of gastrointestinal bleedings remains unclear because both cardiologists and gastroenterologists may not attach importance to it. Our research group has demonstrated that the key gene affecting the absorption of P2Y12 inhibitors, ABCB1, harbors single nucleotide polymorphisms (SNP) rs1045642 significantly associated with gastrointestinal bleedings in patients with PCI in clinical level. Our study includes experiments of cultured cells and mice. With the hypothesis that the mutant allele carriers of rs1045642 may have increased absorption of P2Y12 inhibitors, we will do research on the following aspects to elucidate the molecular mechanism of gastrointestinal bleedings caused by P2Y12 inhibitors: (1) to investigate whether the increased absorption of P2Y12 inhibitors could disrupt intestinal epithelial barrier by damaging the structure of tight junctions, inducing autophagy and apoptosis, finally result in gastrointestinal bleedings in vivo and in vitro; (2) to demonstrate whether the increased exposure to P2Y12 inhibitors could suppress the platelet aggregation excessively to cause higher risk of bleeding. The aim of this study is to provide foundation for prevention and treatment of gastrointestinal bleedings caused by P2Y12 inhibitors in patients with ACS and PCI, guide the clinical medication, and decrease the adverse drug reactions on the individual difference.

英文关键词： gastrointestinal bleeding;P2Y12 inhibitors;ABCB1 gene;molecular mechanism