GPIb Alpha-VWF-A1 bond kinetics in health and disease

描述(申请人提供)：动物模型是研究止血和血栓形成的分子机制和遗传易感性的重要实验工具。特别是，缺乏GPIb1或VWF的小鼠已经相当深入地了解了这种受体-配体对不仅在血栓形成中的重要性，而且在血小板发育、血栓前疾病状态、炎症和血管生成中的重要性。也就是说，这些模型是有限的，因为无法收集到关于它们结构-功能关系的信息，也无法评估专门为破坏人类这种相互作用而设计的治疗剂的体内有效性。为此，我们现在将几个实验室的知识和专长应用到：1)对GPIba-VWF-A1键进行详细的生物物理分析，以了解这种相互作用的物理化学性质如何在健康和疾病中调节血小板-血管性血友病因子(VWF)相互作用；2)通过产生和研究具有这种相互作用的机械和/或动力学特性的特定改变的动物，验证拟议的生物物理机制；以及3)利用这些知识开发生物平台，以测试旨在专门抑制人类这种相互作用的治疗方法。我们相信，通过采取这一全面的方法，我们将避免与GPIba-VWF-A1相互作用中潜在的物种差异相关的陷阱。

DESCRIPTION (provided by applicant): Animal models are important experimental tools for investigating the molecular mechanisms and genetic susceptibilities underlying hemostasis and thrombosis. In particular, mice deficient in GPIb1 or VWF have provided considerable insight into the importance of this receptor-ligand pair not only in the formation of blood clots but in platelet development, prothrombotic disease states, inflammation, and angiogenesis. That said these models are limited as no information can be gleaned on their structure-function relationship nor can one assess the in vivo effectiveness of therapeutic agents specifically designed to disrupt this interaction in humans. To this end, we now apply the knowledge and expertise of several laboratories to: 1) perform a detailed biophysical analysis of the GPIba-VWF-A1 bond in order to understand how the physicochemical properties of this interaction may regulate platelet-von Willebrand Factor (VWF) interactions in health and disease, 2) validate proposed biophysical mechanisms by generating and studying animals with specific alterations in mechanical and/or kinetic properties of this interaction, and 3) exploit this knowledge to develop biological platforms to test therapies designed to specifically inhibit this interaction in humans. We believe that by taking this comprehensive approach, we will avoid pitfalls related to potential species differences in GPIba-VWF-A1 interactions.