Model of Platelet Adhesion and Thrombus Formation

血小板粘附和血栓形成模型

• 批准号: 8209188
• 负责人: Thomas G Diacovo
• 金额: $ 39.31万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 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/8209188
• 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

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（由申请方提供）：血小板粘附于血管损伤部位不仅是预防过度出血（止血）的关键事件，也是响应动脉粥样硬化斑块破裂形成富血小板凝块（血栓）的关键事件，动脉粥样硬化斑块破裂是心脏病发作和卒中的主要原因。在后一种情况下，预防血小板介导的凝块形成的药物的开发通常由于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存在，可以潜在地帮助临床医生预测哪些患者可能有出血或急性血栓事件的风险，基于直接的细胞和分子信息。部分问题可能是由于无法在体内研究人类血小板血栓形成。也就是说，有证据表明，血小板最初粘附在受损血管壁上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（GPIb 1），其由于与表面固定的血管性血友病因子（VWF）的键形成和解离的快速速率而支持血小板易位，和2）支持血小板与暴露的胶原牢固粘附的整联蛋白1221。第三种血小板受体1IIb 23与血浆纤维蛋白原结合，对介导血小板：血小板相互作用至关重要，有助于血栓生长和稳定。在这个项目中，我们建议扩展我们成功的多尺度模拟血小板流体动力学和受体介导的聚集在剪切流中考虑多细胞血栓的启动，生长和破裂的过程的基础上，在体外和体内模型的血小板粘附。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，以观察生理相关条件下（即体内）的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被应用于预测止血缺陷的临床观察结果，如血管性血友病（VWD），这是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，用于掺入血小板活化所需的其他受体：配体相互作用，如GPVI：胶原蛋白，P2Y12：ADP和PAR 1：凝血酶。这将使我们能够应用我们的模型来预测与用于预防血管病变患者血栓形成的抗血小板药物给药相关的可能有害后果。拟议的工作是围绕三个具体目标：目标1：开发一个多尺度模型的血小板粘附和血栓形成，纳入GPIb 1：VWF，1221：胶原蛋白，和1IIb23：纤维蛋白原的相互作用。目的2：血栓稳定性和破裂伴栓子形成的多尺度建模。目的3：基于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（损伤后失血停止）和血栓形成（血管病理性闭塞）的预测模型。我们建议开发一个多尺度的计算机模拟，验证了一个独特的实验模型，在该模型中，人类血小板可以观察到在现实的体内设置的转基因小鼠。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，未来将能够预测接受阿司匹林和血小板等抗凝剂治疗的患者的表型。