Coagulation FACTors and platelet GlycoProtein Ib alpha: A thrombo-inflammatory hub inVASCular dysfunction and disease (FACT-GP VASC)

凝血因子和血小板糖蛋白 Ib α：血管功能障碍和疾病中的血栓炎症中心 (FACT-GP VASC)

• 批准号: 508032346
• 负责人: Professor Dr. Philip Wenzel
• 金额: --
• 依托单位: Zentrum für Kardiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/508032346?language=en
• 关键词: Coagulation; FACTors; platelet; GlycoProtein; Ib

There is a gap in evidence, how the combined inflammatory actions of coagulation factors and platelets modulate cardiovascular disease. In prior work we could demonstrate a physiological role of the FIIa-FXI fedback activation loop involving platelet glycoprotein Ib alpha (GPIbα) in the vascular disease of arterial hypertension, interestingly in the absence of clotting. In FACT-GP VASC, I will disentangle the interaction of von Willebrand Factor (vWF), FXI, FIIa and GPIbα in vascular inflammation. Using genetically engineered mice that either lack vWF or FIIa binding to the GPIbα as well as innovative intravital imaging techniques and thrombin generation assays, I will unravel what is afforded to permit the FIIa-FXI feedback amplification loop, which is necessary to propel vascular inflammation (Aim I). Making use of antisense oligonucleotide depletion techniques, I will define the roles of pre-kallikrein and kininogen to dissect converging or synergistic pathways that could mediate the vascular protective effects of FXI inhibition. I will next translate concept and techniques to the chronic myocardial infarction model, characterized by angiotensin II-dependent vascular inflammation. Thereby I aim to prove that particular ligand-properties of GPIbα convey vascular protection in the absence of perturbed wound healing or bleeding (Aim II). My research therefore enters new and largely uncharted scientific territories. I aim to establish GPIbα as a hitherto unclaimed druggable target in vascular inflammation beyond haemostasis. My results could have a major impact for people suffering from cardiovascular disease, the leading cause for morbidity and mortality worldwide.

证据存在差距，凝血因子和血小板的炎症作用如何调节心血管疾病。在先前的工作中，我们可以证明涉及血小板糖蛋白IBα（GPIBα）在动脉高血压的血管疾病中的FIIA-FXI FedBack激活环的身体作用，这很有趣。实际上，我将在血管感染中解开Von Willebrand因子（VWF），FXI，FIIA和GPIBα的相互作用。使用缺乏VWF或FIIA与GPIBα结合的基因工程小鼠，以及创新的插入式插入成像技术和凝血酶生成测定，我将揭开FIIA-FXI反馈放大环路所提供的东西，这是驱动血管感染所必需的（AIM I）。利用反义寡核苷酸的部署技术，我将定义前卡利依林和依诺原以剖析可以介导FXI抑制的血管保护作用的融合或协同途径的作用。接下来，我将将概念和技术转化为慢性心肌违规模型，其特征是血管紧张素II依赖性血管感染。因此，我的目的是证明GPIBα的特定配体 - 如果没有扰动的伤口愈合或出血（AIM II），则传达了血管保护。因此，我的研究进入了新的且在很大程度上未知的科学领域。我的目标是将GPIBα确立为止血性血管感染中隐藏的无人药物靶标。我的结果可能对患有心血管疾病的患者产生重大影响，这是全球发病率和死亡率的主要原因。