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

凝血因子和血小板的联合炎症作用如何调节心血管疾病尚无证据。在之前的工作中，我们可以证明FIIa-FXI反馈激活环涉及血小板糖蛋白Ibα (GPIbα)在动脉高血压血管疾病中的生理作用，有趣的是在没有凝血的情况下。在FACT-GP VASC中，我将解开血管性血友病因子（vWF）， FXI， FIIa和GPIbα在血管炎症中的相互作用。使用缺乏vWF或FIIa与GPIbα结合的基因工程小鼠，以及创新的活体成像技术和凝血酶生成测定，我将揭示FIIa- fxi反馈放大回路的原理，这是促进血管炎症所必需的（Aim I）。利用反义寡核苷酸耗竭技术，我将定义pre-kallikrein和kininogen的作用，以剖析可能介导FXI抑制的血管保护作用的趋同或协同途径。接下来，我将把概念和技术转化为慢性心肌梗死模型，其特征是血管紧张素ii依赖性血管炎症。因此，我的目标是证明GPIbα的特定配体特性在没有受到干扰的伤口愈合或出血的情况下传递血管保护（aim II）。因此，我的研究进入了一个新的、很大程度上未知的科学领域。我的目标是建立GPIbα作为迄今为止未被发现的血管炎症的药物靶点。我的研究结果可能对患有心血管疾病的人产生重大影响，心血管疾病是全世界发病率和死亡率的主要原因。

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.