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）：血小板粘附到血管损伤部位不仅是预防过度出血（止血）的关键事件，而且是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）的关键事件。是心脏病发作和中风的主要原因。在后一种情况下，预防血小板介导的血栓形成的药物的开发常常因无法预测止血可能受损的程度而受到阻碍。不幸的是，没有足够的计算模型可以帮助临床医生根据直接的细胞和分子信息预测哪些患者可能面临出血或急性血栓事件的风险。部分问题可能是由于无法在体内研究人类血小板血栓的形成造成的。也就是说，有证据表明，血小板最初粘附到受损血管壁的能力是由两种不同的血小板粘附受体的协同作用控制的：1) 血小板糖蛋白 Ib α (GPIb1)，由于速度快而支持血小板易位与表面固定的血管性血友病因子 (VWF) 形成键和解离的过程，以及 2) 支持血小板与暴露的胶原蛋白牢固粘附的整合素 1221。第三种血小板受体 1IIb23 与血浆纤维蛋白原结合，对于介导血小板与血小板相互作用至关重要，从而有助于血栓生长和稳定性。在这个项目中，我们建议扩展我们对血小板流体动力学和剪切流中受体介导的聚集的成功多尺度模拟，以考虑基于体外和体内血小板粘附模型的多细胞血栓起始、生长和破裂的过程。重要的是，我们可以使用 Diacovo 实验室开发的独特而强大的动物模型来观察生理相关条件（即体内）下人类血小板介导的血栓形成，这将用于验证和完善计算模型。一旦开发出来，多尺度血小板粘附模型将应用于预测止血缺陷的临床观察，例如冯维勒布兰德病（VWD），人类最常见的遗传性出血性疾病。由此产生的模拟还将提供一个严格的框架，用于纳入其他受体：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：凝血酶。这将使我们能够应用我们的模型来预测与服用用于预防患病血管患者血栓形成的抗血小板药物相关的可能的有害后果。拟议的工作围绕三个具体目标进行组织：目标 1：开发血小板粘附和血栓引发的多尺度模型，纳入 GPIb1：VWF、1221：胶原和 1IIb23：纤维蛋白原相互作用。目标 2：血栓稳定性和破裂与栓子形成的多尺度建模。目标 3：根据体外和体内研究的分子输入参数预测临床出血表型。公共卫生相关性：目前缺乏基于分子和细胞特性的止血（受伤后停止失血）和血栓形成（血管病理性闭塞）的预测模型。我们建议开发一种多尺度计算机模拟，该模拟通过独特的实验模型进行验证，在该模型中可以在转基因小鼠的真实体内环境中观察人类血小板。该模拟将首先应用于遗传性出血性疾病的临床研究和诊断，未来将能够对接受阿司匹林和波立维等抗凝药物治疗的患者进行表型预测。