危重血管性疾病血栓事件的发生 、发展及干预研究

Severe vascular diseases resulting from atherothrombosis such as myocardial infarction and stroke are the leading cause of death worldwide. However, there is a lack of effective prevention and treatment, demonstrating that the mechanism underlying atherothrombosis remains largely unknown. Platelet activation and coagulation stimulation are two key steps of thrombosis. This project aims to identify novel critical molecules in these two processes, and to characterize their integration network. First, utilizing the dynamic imaging system of thrombosis, we will observe the phenotype of gene knockout mice lacking the new molecules we have recently discovered, by which we will determine their specific roles in platelet function and coagulation activation. Combined with multiple approaches of proteomics, metabolomics, cell biology, molecular biology and biochemical methods, we will elucidate the mechanism for these new proteins. Further, we will evaluate the alternations of these molecules that are functionally associated with atherosclerotic plaque-related contents. The systemic analysis of the interaction among endothelial injury, platelet and coagulation activation will identify the driving factors for atherothrombosis, based on which we will develop the specific inhibitors against these factors and test their effect in inhibition of thrombosis. Collectively, this project will not only improve our understanding of the molecular network controlling atherothrombosis, but will also open new avenues for prevention and treatment of severe cardio-cerebrovascular diseases.

心肌梗塞和脑中风等危重血管性血栓疾病是人类主要死因，当前仍然缺乏安全有效的防治药物，其根源是对其主要诱因动脉粥样硬化血栓形成机制认识不清。虽然内皮损伤、血小板活化和凝血系统激活是动脉粥样硬化血栓形成的主要环节，但是三者的互作机制和调控网络等关键问题尚未解决。因此，本项目旨在发现新的调控血小板活化和凝血系统激活的关键分子，以及这些分子的协同机制。我们将建立小鼠动脉粥样硬化内皮损伤血栓模型，利用影像学技术动态定量评估血栓构成；应用基因敲除小鼠，判定关键分子在血小板活化和凝血系统激活的特异性作用，并结合组学、细胞分子生物学及生化方法，揭示这些关键分子的作用机制；利用病人动脉粥样硬化斑块和血栓样本鉴定这些关键分子的分布及作用；对发现的新作用靶点，将开发相应干预手段。通过上述研究，本项目将系统阐明动脉粥样硬化血栓中损伤内皮-血小板-凝血系统的互作机制及调控网络，为危重血管性血栓疾病开拓新的防治策略。

内皮损伤、血小板活化和凝血系统激活在动脉粥样硬化血栓形成中发挥重要作用，但是三者的互作机制和调控网络等关键问题尚未解决。项目通过建立小鼠动脉粥样硬化内皮损伤血栓模型，应用基因敲除小鼠，判定关键分子在血小板活化和凝血系统激活的特异性作用，结合组学、细胞分子生物学及生化方法，揭示关键分子的作用机制，并开发相应干预手段。研究过程中，发现支链氨基酸代谢能够调控TMOD3丙酰化修饰，进而影响整合素αIIbβ3介导的细胞骨架重构，调控血小板活化和血栓形成，这为代谢干扰动脉粥样硬化血栓形成提供了重要理论；发现酰基甘油激酶在血小板产生活化中的关键作用机制，为血小板增多症和减少症相关血栓和出血性疾病治疗提供了重要干预策略；发现MAPK通路关键上游分子MEKK3 通过ERK1/2和JNK2调控整合素αIIbβ3介导的内向外信号参与动脉血栓形成，揭示MEKK3可作为抗血栓药物的新靶点；发现PI3K/Akt通路中的mTORC2复合物能够协同PDK1/Gsk3β通路调节凝血酶受体和整合素αIIbβ3介导的血小板活化，参与心梗后微血栓和无复流的形成，为心梗PCI术后无复流的预防和治疗提供重要靶标；发现血浆激肽酶-激肽系统不依赖于FXII的Kal-HK-BK活化新途径；发现Gas6受体Tyro3、Axl和Mertk参与血栓形成的关键机制。这些系列研究成果发表在Circulation、Blood等杂志上，得到国际上本领域著名专家的积极评价和广泛引证。本项目研究成果为危重血管性血栓疾病防治提供了新策略。

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