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

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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. PUBLIC HEALTH RELEVANCE: The relevance of this research is 3-fold: 1) It addresses a critical barrier in the field of bioengineering: biological models to test biophysical mechanisms proposed to govern the interaction between receptor-ligand pairs involved in cell adhesion such as the platelet receptor GPIb1 and its ligand VWF, 2) it will expand our scientific understanding of the mechanisms that regulate and thus limit platelet-VWF interactions to sites of vascular injury, and 3) it will lead to the generation of animal models that more closely mimic human disease and thus serve as biological platforms for the development and testing of drugs that prevent platelet-VWF interactions in prothrombotic disease states.