Model of Platelet Adhesion and Thrombus Formation

血小板粘附和血栓形成模型

基本信息

批准号：
8055354
负责人：
Thomas G Diacovo
金额：
$ 39.61万
依托单位：
CORNELL UNIVERSITY
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：
2010-03-08 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8055354
关键词：
Acute Adhesions Adhesives Animal Model Animals Anticoagulants Antiplatelet Drugs Arterial Fatty Streak Aspirin Bernard-Soulier Syndrome Binding Blocking Antibodies Blood Blood Platelets Blood Vessels CD42b Antigens Cells Cereals Clinical Clinical Trials Coagulation Process Collagen Computer Simulation Data Defect Deposition Development Disease Dissociation Drug usage Embolism Event Experimental Models F2R gene Fibrinogen Flow Cytometry Frequencies Future Growth Hemorrhage Hemostatic function Human Imagery In Vitro Incidence Individual Inherited Injury Integrins Kinetics Ligand Binding Ligands Measures Mediating Modeling Molecular Multicellular Process Mus Mutant Strains Mice Myocardial Infarction Patients Pharmaceutical Preparations Phase Phenotype Plasma Platelet Activation Platelet Count measurement Platelet Glycoproteins Plavix Prevention Probability Property Risk Rupture Simulate Site Speed Stroke Surface System Testing Thrombasthenia Thrombin Thromboembolism Thrombosis Thrombus Transgenic Mice Work adhesion receptor base blood vessel occlusion clinical Diagnosis drug development hemodynamics in vivo in vivo Model injured intravital microscopy loss of function mouse model multi-scale modeling mutant predictive modeling prevent public health relevance receptor research study response shear stress simulation von Willebrand Disease von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): Platelets adhesion to sites of vascular injury is a key event not only in the prevention of excessive bleeding (hemostasis) but also in the formation of platelet-rich clots (thrombi) in response to atherosclerotic plaque rupture, which is a leading cause of heart attacks and stroke. In the latter case, the development of drugs that prevent platelet-mediated clot formation are often hampered by an inability to predict the extent to which hemostasis may be impaired. Unfortunately, no adequate computational model exists that could potentially aid clinicians in predicting which patients may be at risk for bleeding or acute thrombotic events based on direct cellular and molecular information. Part of the problem may result from an inability to study human platelet thrombus formation in vivo. That said, there is evidence demonstrating that the ability of platelets to initially stick to the injured vessel wall is controlled by the synergistic action of two distinct platelet adhesion receptors: 1) Platelet glycoprotein Ib alpha (GPIb1) that supports platelet translocation due to rapid rates of bond formation and dissociation with surface-immobilized von Willebrand factor (VWF), and 2) the integrin 1221 that supports firm adhesion of platelets to exposed collagen. A third platelet receptor, 1IIb23, binds to plasma fibrinogen and is critical for mediating platelet: platelet interactions that contribute to thrombus growth and stability. In this project, we propose to extend our successful multiscale simulation of platelet hydrodynamics and receptor-mediated aggregation in shear flow to consider the processes of multicellular thrombus initiation, growth, and rupture based on in vitro and in vivo models of platelet adhesion. Importantly, we have access to unique and powerful animal models developed by the Diacovo lab to observe human platelet-mediated thrombus formation under physiologically relevant conditions (i.e. in vivo), which will be used to validate and refine the computational model. Once developed, the multiscale platelet adhesion model will be applied to the prediction of clinical observations of defects in hemostasis such as von Willebrand disease (VWD), the most common inheritable bleeding disorder in humans. The resulting simulation will also provide a rigorous framework for incorporation of additional receptor: ligand interactions required for platelet activation such as GPVI: collagen, P2Y12:ADP, and PAR1:thrombin. This will enable us to apply our model to predicting possible deleterious consequences associated with the administration of antiplatelet drugs used to prevent thrombus formation in patients with diseased blood vessels. The proposed work is organized around three specific aims: Aim 1: Development of a multiscale model of platelet adhesion and thrombus initiation, incorporating GPIb1:VWF, 1221:collagen, and 1IIb23:fibrinogen interactions. Aim 2: Multiscale modeling of thrombus stability and rupture with embolus formation. Aim 3: Prediction of clinical bleeding phenotype based on molecular input parameters from in vitro and in vivo studies. PUBLIC HEALTH RELEVANCE: A predictive model of hemostasis (cessation of blood loss following injury) and thrombosis (pathological occlusion of blood vessels) based on molecular and cellular properties is currently lacking. We propose to develop a multiscale computer simulation that is validated with a unique experimental model in which human platelets can be observed in the realistic in vivo setting of a genetically modified mouse. The simulation will be first applied to the clinical investigation and diagnosis of hereditary bleeding disorders, and in the future will enable phenotype prediction of patients treated with anticoagulants such as aspirin and Plavix.

描述（由申请人提供）：血小板对血管损伤部位的粘附不仅是预防过多的出血（止血），而且在响应动脉粥样硬化斑块破裂而形成富含血小板的凝块（血栓）的过程中，这是心脏病发作和心脏攻击和Stroke的主要原因。在后一种情况下，通常无法预测止血症受到损害的程度，通常会阻碍预防血小板介导的凝块形成的药物的发展。不幸的是，没有足够的计算模型可能会帮助临床医生预测哪些患者可能会基于直接细胞和分子信息而有出血或急性血栓性事件的风险。问题的一部分可能是由于无法在体内研究人血小板血栓形成而导致的。 That said, there is evidence demonstrating that the ability of platelets to initially stick to the injured vessel wall is controlled by the synergistic action of two distinct platelet adhesion receptors: 1) Platelet glycoprotein Ib alpha (GPIb1) that supports platelet translocation due to rapid rates of bond formation and dissociation with surface-immobilized von Willebrand factor (VWF), and 2) the integrin 1221 that支持血小板对暴露胶原蛋白的坚固粘附。第三个血小板受体1IIB23与血浆纤维蛋白原结合，对于介导血小板至关重要：血小板相互作用有助于血栓生长和稳定性。在这个项目中，我们建议扩展我们成功对剪切流中血小板流体动力学和受体介导的聚集的多尺度模拟，以考虑基于体外和体内血小板粘附模型的多细胞血栓启动，生长和破裂的过程。重要的是，我们可以访问Diacovo Lab开发的独特而有力的动物模型，以在生理相关的条件下（即体内）观察人血小板介导的血栓形成，该模型将用于验证和完善计算模型。一旦开发，多尺度血小板粘附模型将应用于止血性缺陷的临床观察结果，例如von Willbrand疾病（VWD），这是人类中最常见的遗传性出血疾病。所得的模拟还将提供一个严格的框架，用于掺入其他受体：血小板激活所需的配体相互作用，例如GPVI：胶原蛋白，P2Y12：ADP和PAR1：pAR1：凝血酶。这将使我们能够将模型应用于预测与用于防止患有血管患者血栓形成的抗血小板药物有关的可能有害后果。提出的工作是围绕三个特定目的组织的：目标1：开发血小板粘附和血栓启动的多尺度模型，结合了GPIB1：VWF，1221：胶原蛋白和1IIB23：纤维蛋白原相互作用。目标2：通过栓塞形成的血栓稳定性和破裂的多尺度建模。目标3：基于体外和体内研究的分子输入参数的临床出血表型的预测。公共卫生相关性：目前缺乏基于分子和细胞特性的止血和血栓形成（血管的病理阻塞）的预测模型。我们建议开发一个多尺度计算机模拟，该模拟通过独特的实验模型验证，在该模型中可以在遗传修饰的小鼠的体内环境中观察到人血小板。该模拟将首先应用于遗传性出血疾病的临床研究和诊断，将来将使用阿司匹林和PLAVIX等抗凝剂治疗的患者进行表型预测。