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

健康和疾病中的 GPIb Alpha-VWF-A1 键动力学

基本信息

批准号：
8122201
负责人：
Thomas G Diacovo
金额：
$ 40.25万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8122201
关键词：
Accounting Acute Address Adhesions Animal Model Animals Antibodies Binding Biological Biological Assay Biological Models Biological Process Biomedical Engineering Biophysics Biotinylation Bleeding time procedure Blood Circulation Blood Clot Blood Platelets Blood Vessels Blood coagulation Bone Marrow Cell Adhesion Cell Adhesion Molecules Cell Culture System Chemicals Cleaved cell Collaborations Collagen Complex Coronary Defect Development Disease Dissociation Effectiveness Event Foundations Generations Genetic Predisposition to Disease Genetically Modified Animals Glean Health Hemorrhage Hemostatic function Human In Vitro Individual Induced Mutation Inflammation Injection of therapeutic agent Injury Insertion Mutation Kinetics Knowledge Laboratories Lead Length Ligands Light Massachusetts Mechanics Megakaryocytes Metalloproteases Microscopy Minor Modeling Molecular Mus Mutant Strains Mice Mutation Patients Pattern Pharmaceutical Preparations Phenotype Plasma Platelet Count measurement Platelet aggregation Play Positioning Attribute Preclinical Testing Procedures Process Production Property Protein Fragment Proteolysis Recombinant Proteins Recombinants Research Resolution Role Simulate Site Site-Directed Mutagenesis Solutions Spectrum Analysis Structure-Activity Relationship Surface Syndrome System Techniques Tertiary Protein Structure Testing Therapeutic Therapeutic Agents Thrombocytopenia Thrombosis Thrombus Time Value of Life Video Microscopy activator 1 protein analog angiogenesis aptamer arteriole base cerebrovascular design drug testing embryonic stem cell gain of function mutation human disease in vitro Assay in vivo injured insight intravital microscopy medical schools mouse model mutant prevent protein protein interaction public health relevance receptor response species difference therapy design tool von Willebrand Factor

项目摘要

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.

描述（由申请人提供）：动物模型是研究止血和血栓形成基础的分子机制和遗传敏感性的重要实验工具。特别是，缺乏GPIB1或VWF的小鼠对这种受体配体的重要性不仅在血块形成中，而且在血小板发育，血栓形成疾病状态，炎症和血管生成方面提供了广泛的见解。也就是说，这些模型受到限制，因为无法收集其结构功能关系的信息，也无法评估专门设计用于破坏人类这种相互作用的治疗剂的体内有效性。为此，我们现在将多个实验室的知识和专业知识应用于：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特性如何通过在健康和疾病中进行特定的机制，并研究其在健康机制中的变化，并如何调节血小板 - 沃尔布兰德因子（VWF），2）这种相互作用的动力学特性，以及3）利用这种知识来开发生物平台，以测试旨在专门抑制人类这种相互作用的疗法。我们认为，通过采用这种全面的方法，我们将避免与GPIBA-VWF-A1相互作用中潜在物种差异相关的陷阱。公共卫生相关性：这项研究的相关性是3倍：1）它解决了生物工程领域的关键障碍：生物学模型测试旨在控制细胞粘附涉及的受体配体对之间相互作用的生物物理机制，例如，诸如血小板受体GPIB1及其ligand vwf的限制范围的机制 - 限制了该机构的机制，以至于限制了该机构，以至于限制了该机构的范围。血管损伤部位，以及3）将导致动物模型的产生，这些模型更紧密地模仿了人类疾病，因此是开发和测试可预防血栓性疾病状态下血小板-VWF相互作用的药物的生物平台。