Model of Platelet Adhesion and Thrombus Formation

描述（由申请人提供）：血小板粘附在血管损伤部位是一个关键事件，不仅在防止过度出血（止血），而且在动脉粥样硬化斑块破裂时形成富含血小板的血栓（血栓），这是心脏病发作和中风的主要原因。在后一种情况下，由于无法预测止血可能受损的程度，阻止血小板介导的凝块形成的药物的开发常常受到阻碍。不幸的是，目前还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来预测哪些患者可能有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。也就是说，有证据表明血小板最初粘附损伤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)，由于与表面固定的血管性血血病因子（VWF）的快速键形成和解离，支持血小板易位；2）整合素1221，支持血小板与暴露的胶原的牢固粘附。第三种血小板受体1IIb23与血浆纤维蛋白原结合，对调节血小板至关重要：血小板相互作用有助于血栓的生长和稳定。在这个项目中，我们建议扩展我们成功的血小板流体动力学和受体介导的剪切流聚集的多尺度模拟，以考虑基于血小板粘附的体外和体内模型的多细胞血栓的起始、生长和破裂过程。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下（即体内）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。一旦发展起来，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，如人类最常见的遗传性出血性疾病血管性血友病（VWD）。由此产生的模拟还将为血小板活化所需的额外受体：配体相互作用（如GPVI：胶原，P2Y12:ADP和PAR1：凝血酶）的结合提供严格的框架。这将使我们能够将我们的模型应用于预测与用于预防病变血管血栓形成的抗血小板药物管理相关的可能有害后果。提出的工作围绕三个具体目标组织：目标1：开发血小板粘附和血栓形成的多尺度模型，包括GPIb1:VWF， 1221：胶原蛋白和1IIb23：纤维蛋白原相互作用。目的2：血栓稳定性和栓塞破裂的多尺度建模。目的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。

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.