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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（由申请方提供）：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，小鼠缺乏GPIb 1或VWF提供了相当大的洞察力，这种受体-配体对的重要性，不仅在形成血栓，但在血小板的发展，血栓前疾病状态，炎症和血管生成。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，我们现在将几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性质如何调节健康和疾病中的血小板-血管性血友病因子（VWF）相互作用，2）通过产生和研究在这种相互作用的机械和/或动力学特性中具有特定改变的动物来验证所提出的生物物理机制，以及3）利用这些知识来开发生物平台，以测试设计用于在人体中特异性抑制这种相互作用的疗法。我们相信，通过采取这种全面的方法，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。公共卫生相关性：这项研究的相关性有3个方面：1）它解决了生物工程领域的一个关键障碍：用于测试生物物理机制的生物模型，所述生物物理机制被提出来控制参与细胞粘附的受体-配体对（例如血小板受体GPIb 1及其配体VWF）之间的相互作用，2）它将扩大我们对调节并因此将血小板-VWF相互作用限制在血管损伤部位的机制的科学理解，和3）它将导致产生更接近地模拟人类疾病的动物模型，并因此用作开发和测试在血栓形成前疾病状态中预防血小板-VWF相互作用的药物的生物平台。