Ligand interactions of platelet glycoprotein Ib-IX-V in thrombosis

循环血小板从流体相、非粘附状态到粘附、活化和聚集状态（血栓形成）的转变在对血管损伤的正常止血反应中以及在血栓性疾病如心脏病发作和中风中是关键的。一种独特的血小板受体，即糖蛋白Ib-IX-V复合物，是特别令人感兴趣的，因为它在流动血液中的高流体剪切应力（包括在冠状动脉硬化中发生的病理剪切应力）下引发血小板聚集或血栓形成。我们发表的和初步的结果表明，GPIb依赖的血小板与血管性血友病因子，GPIb-IX-V的主要粘附配体的相互作用，是依赖于剪切应力的水平。使用跨物种（人到犬）同源性交换方法，其中人序列在离散结构域内被相应的犬序列取代，已经鉴定出GPIb序列，其随着流体动力学剪切应力的增加而变得越来越重要。建议进一步定义在增加剪切下识别血管性血友病因子的GPIb的相互作用表面，并定义GPIb构象的剪切依赖性改变与其与其他促血栓形成或促炎性结合伴侣相互作用的能力之间的关系。

The transition of circulating blood platelets from a fluid-phase, non-adherent state to an adherent, activated and aggregated state (thrombus formation) is critical in the normal haemostatic response to blood vessel injury and in thrombotic diseases such as heart attack and stroke. One unique platelet receptor, the glycoprotein Ib-IX-V complex, is of particular interest, because it initiates platelet aggregate or thrombus formation at high fluid shear stress in flowing blood, including the pathological shear stress that occurs in a sclerotic coronary artery. Our published and preliminary results show how GPIb-dependent interaction of platelets with von Willebrand factor, the major adhesive ligand for GPIb-IX-V, is dependent on the level of shear stress. Using a cross-species (human to canine) homology-swap approach, where human sequence is replaced by the corresponding canine sequence within discrete structural domains, a sequence of GPIb has been identified which becomes increasingly important as hydrodynamic shear stress increases. It is proposed to further define the interactive surface of GPIb that recognizes von Willebrand factor at increasing shear, and to define the relationship between the shear-dependent alteration of GPIb conformation and its ability to interact with other pro-thrombotic or pro-inflammatory binding partners.