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，GPIb1或VWF缺乏的小鼠，不仅在血栓形成中，而且在血小板发育、血栓形成前疾病状态、炎症和血管生成中，对这种受体-配体对的重要性提供了相当大的见解。也就是说，这些模型是有限的，因为没有信息可以收集到它们的结构-功能关系，也不能评估治疗药物的体内有效性，专门设计来破坏人类的这种相互作用。为此，我们现在运用几个实验室的知识和专业知识：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调节血小板-血管性血友病因子（VWF）在健康和疾病中的相互作用；2)通过生成和研究具有这种相互作用的机械和/或动力学性质特定改变的动物来验证所提出的生物物理机制。3)利用这些知识开发生物平台来测试专门用于抑制人类这种相互作用的疗法。我们相信，通过采用这种综合方法，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.