Role of redox-sensitive signalling pathways linked to GPIIb-IIIa in platelet hyperactivity and thrombosis in diabetes

与 GPIIb-IIIa 相关的氧化还原敏感信号通路在糖尿病血小板过度活跃和血栓形成中的作用

• 批准号: 399500006
• 负责人: Dr. Sabine Kossmann
• 金额: --
• 依托单位: School of Biological Sciences
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/399500006?language=en
• 关键词: Role; redox; sensitive; signalling; pathways

Diabetes has become one of the major healthcare challenges of the 21st century and a leading cause of cardiovascular disease worldwide. Up to 70% of all diabetes-related deaths are due to cardiovascular disease, primary related to atherothrombosis. Diabetes enhances the atherosclerotic process in large arteries, increasing the risk of acute myocardial infarction, ischemic stroke and peripheral disease. In addition to developing more extensive atherosclerosis, diabetic individuals also exhibit a prothrombotic phenotype that manifest as an exaggerated accumulation of platelets at sites of plaque disruption. However, the mechanisms by which diabetes causes platelet hyperactivity and a prothrombotic phenotype remain incompletely understood. The Jackson laboratory (host institute) recently defined a new mechanism promoting arterial thrombus formation that involves biomechanical (rheology-dependent) platelet activation that leads to aggregation of discoid platelets. Preliminary data show evidence that this aggregation mechanism is dysregulated in diabetes, leading to excessive discoid platelet aggregation and thrombus formation in vivo. Oxidative stress seems to have a key role in amplifying discoid platelet aggregation in diabetes by altering the shear-sensitivity of the major platelet adhesion receptor αIIbβ3 (commonly referred to as GPIIb-IIIa). The hypothesis of this project is that this biomechanical prothrombotic mechanism is associated with alterations in redox-sensitive signal pathways linked to GPIIb-IIIa. Importantly, exaggerated platelet aggregation is not inhibited by conventional antiplatelet agents such as aspirin and clopidogrel, which may partly explain reduced efficacy of antithrombotic therapy in individual with diabetes. The specific aim in this proposal is to examine whether inhibiting platelet redox-sensitive signalling pathways reduces platelet hyperactivity and thrombosis in diabetes. To address the question the functional impact of several signalling inhibitors linked to GPIIb-IIIa activation on shear-dependent adhesion of diabetic platelets will be investigated by several in vitro approaches. Pharmacological inhibitors that are highly effective in vitro, will be examined for their ability to inhibit shear-dependent discoid platelet aggregation in vivo, using several thrombosis mouse models. Results of this project could help to identify entirely new approaches to reduce the prothrombotic function of diabetes.

糖尿病已经成为21世纪的主要医疗挑战之一，也是全球心血管疾病的主要原因。在所有与糖尿病相关的死亡中，多达70%是由于心血管疾病，主要与动脉粥样硬化血栓形成有关。糖尿病加剧了大动脉的动脉粥样硬化过程，增加了急性心肌梗死、缺血性中风和外周疾病的风险。除了发生更广泛的动脉粥样硬化外，糖尿病患者还表现出血栓前表型，表现为在斑块破裂处血小板过度聚集。然而，糖尿病导致血小板过度活跃和血栓前表型的机制仍不完全清楚。杰克逊实验室(主办机构)最近定义了一种促进动脉血栓形成的新机制，涉及生物力学(流变学相关)血小板激活，导致盘状血小板聚集。初步数据显示，糖尿病患者体内这种聚集机制失调，导致盘状血小板过度聚集和血栓形成。氧化应激似乎通过改变主要的血小板黏附受体αIIbβ3(通常被称为GPIIb-IIIa)的剪切敏感性，在糖尿病患者盘状血小板聚集的放大中发挥关键作用。该项目的假设是，这种生物力学血栓前机制与与GPIIb-IIIa相关的氧化还原敏感信号通路的改变有关。重要的是，阿司匹林和氯吡格雷等常规抗血小板药物不能抑制过度的血小板聚集，这可能是糖尿病患者抗血栓治疗效果降低的部分原因。这项建议的具体目的是检查抑制血小板氧化还原敏感信号通路是否可以减少糖尿病患者的血小板过度活动和血栓形成。为了解决这个问题，将通过几种体外方法来研究几种与GPIIb-IIIa激活有关的信号抑制剂对糖尿病血小板剪切依赖性黏附的功能影响。在体外高效的药物抑制剂将在体内使用几个血栓形成小鼠模型来检验它们抑制剪切依赖的盘状血小板聚集的能力。该项目的结果可能有助于确定降低糖尿病血栓前功能的全新方法。