PDI-GPIIb/IIIa受体参与糖尿病血小板活化的机制研究

Platelet activation is the main cause for the increase of cardiovascular events in diabetes patients. GPIIb/IIIa activation is the final step of platelet activation. It's unclear how diabetes pathogenesis activates platelet through GPIIb/IIIa receptor. Our team found that microparticle plays an important role in platelet activation in previous studies. However, the relationship between microparticle and GPIIb/IIIa activation in diabetes state has not been reported. The present study focuses on protein disulfide isomerase (PDI) and takes multiple cell-derived microparticles as carriers, using translational medicine research paradigm to investigate the corresponding factors for conformational change of GPIIb/IIIa in levels of cell, animal and patients. We intend to reveal the role of PDI-GPIIb/IIIa in platelet activation of diabetes, to determine the mechanism of platelet activation cascade signal transduction in diabetes, therefore, searching for the target which can be intervened and providing theoretical evidence and experimental basis for integrated prevention and therapy of diabetes-related cardiovascular diseases.

血小板活化是糖尿病患者心血管事件增加的主要原因。GPIIb/IIIa受体活化是血小板活化的最终途径。糖尿病如何通过GPIIb/IIIa受体活化血小板尚不清楚。本课题组通过前期研究发现微粒在血小板活化中发挥了重要作用，但是糖尿病状态下微粒与血小板GPIIb/IIIa受体活化的关系尚无相关报道。本课题从蛋白质二硫键异构酶（PDI）入手，以不同来源微粒为载体，拟在细胞、动物和临床患者等不同层面，采用转化医学的研究模式，探索引起GPIIb/IIIa受体空间构象改变的相关因素，阐明内皮细胞来源和血小板来源PDI与GPIIb/IIIa受体结合的作用，揭示PDI-GPIIb/IIIa受体在糖尿病血小板活化过程中的关键地位，确定糖尿病血小板活化级联放大信号的传导机制并寻找可干预的靶点，为实现糖尿病心血管疾病的综合防治提供理论依据和实验基础。

血小板活化是糖尿病患者心血管事件增加的主要原因。GPIIb/IIIa受体活化是血小板活化的最终途径。糖尿病如何通过GPIIb/IIIa受体活化血小板尚不清楚。近期有研究发现PDI能够介导血小板聚集和血栓形成，调控GPIIb/IIIa受体的活化。本课题组通过前期研究发现microparticles在血小板活化中发挥了重要作用，但是糖尿病状态下microparticles与血小板GPIIb/IIIa活化的关系尚无相关报道。本课题采用转化医学的研究模式，阐明内皮细胞来源和血小板来源PDI与GPIIb/IIIa受体结合的作用，揭示PDI-GPIIb/IIIa受体在糖尿病血小板活化过程中的作用，结果显示：（1）糖尿病状态下CD62p、PAC-1、血小板-白细胞聚集体升高，血小板活化水平增强；（2）糖尿病状态下Annexin阳性的microparticles、血小板源microparticles、内皮细胞源microparticles及microparticles携带PDI酶活性升高；（3）内皮细胞源microparticles增强CD62p、GPIIb/IIIa活化和血小板聚集，这一过程可以被PDI抑制剂RL90和芦丁部分抑制；（4）内皮细胞源microparticles活化血小板，使血小板表达PDI表达升高并释放更多的血小板源microparticles。研究结果为糖尿病血栓防治提供了新的潜在靶点。