Multiscale Modeling of Blood Flow and Platelet Mediated Thrombosis

血流和血小板介导的血栓形成的多尺度建模

• 批准号: 9032130
• 负责人: DANNY BLUESTEIN
• 金额: $ 68.94万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032130
• 关键词: Accounting; Address; Adhesions; Adopted; Agonist; Algorithms; Anticoagulation; Antiplatelet Drugs; Arteries; Benchmarking; Binding; Biochemical; Biology; Biomechanics; Blood; Blood Circulation; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cause of Death; Cereals; Cessation of life; Chemicals; Clinical; Coagulation Process; Code; Communities; Complex; Computer Simulation; Coronary Arteriosclerosis; Coupled; Coupling; Cytoplasm; Cytoskeleton; Data; Databases; Deposition; Development; Devices; Engineering; Evaluation; Event; Experimental Models; Filopodia; Growth; Health Care Costs; Hemostatic Agents; High Performance Computing; Hybrids; In Vitro; Lead; Length; Life; Liquid substance; Measurement; Measures; Mechanics; Mediating; Membrane; Methodology; Modeling; Molecular; Outcome; Patients; Pattern; Platelet Activation; Platelet aggregation; Process; Property; Proteins; Protocols documentation; Pseudopodia; Quality of life; Risk; Scheme; Series; Shapes; Software Tools; Stimulus; Stress; Surface; Technology; Therapeutic; Therapeutic Embolization; Thrombin; Thrombosis; Thrombus; Time; Tissues; Translating; Vascular Diseases; base; biomechanical model; burden of illness; computing resources; cost; design; fluid flow; hemodynamics; improved; injured; innovation; interest; men who have sex with men; microscopic imaging; molecular dynamics; molecular scale; mortality; multi-scale modeling; multidisciplinary; nanoscale; next generation; novel; particle; public health relevance; receptor; research study; response; shear stress; simulation; tool; working group

 DESCRIPTION (provided by applicant): Cardiovascular diseases remain the leading cause of death in the developed world, accounting for near 30% of all deaths globally and 35% in the US annually. Coronary artery disease (CAD) with its associated thrombotic risk is responsible for 1 of 6 deaths in the US. Coincidentally, implantable blood recirculating devices, which have provided lifesaving solutions to patients with severe cardiovascular diseases, are burdened with thrombosis and thromboembolic complications, mandating complex life-long anticoagulation. The mechanisms underlying vascular disease processes and device-related thrombotic complications are intertwined. Thrombosis in vascular disease is potentiated by the interaction of blood constituents with an injured vascular wall and the non-physiologic flow patterns generated in cardiovascular pathologies initiate and enhance the hemostatic response by chronically activating the platelets. Similarly, device thrombogenicity is induced by pathological flow fields and contact with foreign surfaces. Upon activation platelets undergo complex biochemical and morphological changes. The coupling of the disparate spatio-temporal scales between molecular level events and the macroscopic transport represents a major modeling and computational challenge, which requires a multidisciplinary integrated multiscale numerical approach. Continuum approaches are limited in their ability to cover the smaller molecular mechanisms such as filopodia formation during platelet activation. Utilizing molecular dynamics (MD) to cover the multiscales involved is computationally prohibitive. In this application we offer to develop a comprehensive state-of-the-art multiscale numerical methodology that will be able to bridge the gap between the macroscopic transport and the ensuing molecular events. We will use an integrated Dissipative Particle Dynamics (DPD) and Coarse Grained Molecular Dynamics (CGMD) approach that allows platelets to continuously change their shape and synergistically activate by a biomechanical transductive linkage chain, interact with other blood constituents and clotting factors, aggregate, and interact and adhere to the blood vessels and devices. In this multiscale model, a mechanotransduction CGMD bottom platelet activation model is embedded into a DPD blood flow top model. The dynamic stresses of the macroscale model will be interactively translated to the micro to nanoscale model of the intra-platelet associated intracellular events. The model predictions will be validated in vitro in a carefully designed set of experiments. This will be achieved according to the following specific aims: We will develop a mechanotransduction model of platelet mediated thrombosis where a top/macro-scale model of flow-induced thrombogenicity using DPD at the µm-length and ms-time scales, in which multiple flowing platelets interact with each other and blood vessel walls or devices, will be fully coupled with a bottom/micro-scale model using CGMD at the nm-length and ps-time scales, in which platelets with multiple intracellular constituents evolve during activation as platelet lose their quiescent discoid shape and filopodia grow. The top and bottom models will be interfaced such that the hemodynamics will interactively respond to platelet shape change upon activation and platelet aggregation and thrombus is formed. The effect of modulating platelet mechanical properties via antiplatelet agents will be modeled as well. All model aspects will be validated in vitro in a series of carefully designed experiments characterizing the mechanical properties of platelets and using blood flow experiments where conditions leading to flow induced platelet activation will be replicated, as well as experiments where platelet-wall and platelet device interactions will be measured and where platelets will be pretreated with modulating agents. These data will be used to fine tune the large number of model parameters involved in this multiscale simulation and for validating the model predictions. An independent 3rd party evaluation of the model credibility is also included as an integral part of the project. e will also concentrate on the development of efficient algorithms adapted for ultra-scalable large HPC clusters to reduce prohibitive computation costs, so as to bring such ambitious large multiscale simulations within the reach of the multiscale modeling community at large and enable to adopt it to other relevant modeling needs and interests. To further enable these technologies, large sharable data base will be created where software tools, numerical codes, model and experimental data and protocols will be deposited and guidance will be provided for using them. The leaders of the project will be active in various MSM consortium working groups to further disseminate the project outcomes and share them with the modeling community. The methodology proposed represents a paradigm shift in the burgeoning field of multiscale simulations and its application to solving complex clinical problems at the interface of engineering and biology. Predicting the progression of arterial thrombosis under circulation conditions, providing tools for improved pharmacological management as compared to existing empirics-based treatments, and providing a modeling tool for developing the next generation of devices with reduced thrombogenicity may lead to reduced mortality rates, improved patients' quality of life, and an overall reduction of the financial burden of the ensuing healthcare costs.

 描述（由适用提供）：心血管疾病仍然是发达国家的主要死亡原因，占全球所有死亡人数的近30％，在美国年度占35％。冠状动脉疾病（CAD）及其相关的血栓形成风险是美国6例死亡中的1人。巧合的是，为严重心血管疾病的患者提供了可植入的血液循环装置，这些装置被血栓形成和血栓形成并发症燃烧，并强制使用复杂的终身抗凝性。血管疾病过程和与装置相关的血栓形成并发症的基础机制交织在一起。血栓形成在血管疾病中的血栓形成可能是由于血液成分与受伤的血管壁的相互作用以及心血管病理学中产生的非生理流动流动模式引发并通过长期激活血小板来增强止血反应。同样，装置血栓形成是由病理流场引起的，并与外国表面接触。激活后，血小板发生复杂的生化和形态变化。分子水平事件与宏观运输之间不同时空尺度的耦合代表了一个主要的建模和计算挑战，这需要多学科综合的多尺度数值方法。连续方法的覆盖较小分子机制（例如血小板激活过程中）等较小的分子机制的能力受到限制。使用分子动力学（MD）来覆盖所涉及的多尺度。在此申请中，我们提供 我们将使用集成的耗散粒子动力学（DPD）和粗粒分子动力学（CGMD）方法，使血小板能够继续改变其形状，并通过生物力学跨导托链接链进行协同激活，并与其他血液组成部分相互作用，并与其他血液组成部分相互作用，并与其他凝血因子，聚集因子，并相互作用，并与血管和血管相互作用并互相相互作用。在此多尺度模型中，机械转移CGMD底部血小板激活模型嵌入到DPD血流顶部模型中。宏观模型的动态应力将交互式转换为相关的细胞内事件的微观纳米级模型。模型预测将在一套经过精心设计的实验集中在体外进行验证。这将根据以下特定目的来实现：我们将开发一个血小板介导的血栓形成的机械转移模型，在该模型中，使用DPD在µm长度和MS时尺度上使用DPD的顶部/宏观尺度模型，其中多个流动血小板与彼此相互作用，并且与彼此相互作用，与血管壁上的模型相互作用。 NM长度和PS时间尺度，其中血小板在激活过程中构成多个细胞内的血小板，因为血小板失去了其静止的盘状形状，并且丝状质量生长。顶部和底部模型将在激活和血小板聚集时对血小板形状变化进行交互反应，并形成血栓形成。还将模拟通过抗血小板药物调节血小板机械性能的效果。在一系列精心设计的实验中，将在体外验证所有模型方面，这些实验表征了血小板的机械性能并使用血流实验，其中将复制导致流动诱导的血小板激活的条件，以及血小板壁和血小板壁和的实验 将测量血小板设备的相互作用，并使用调节剂预处理血小板。这些数据将用于微调该多尺度仿真中涉及的大量模型参数并验证模型预测。对模型信誉的独立第三方评估也被包括在项目的组成部分中。 E还将集中于适用于超级可观的大型HPC群集的有效算法的开发，以降低禁止的计算成本，以便将如此雄心勃勃的大型多尺度模拟带入大型多尺度建模社区的范围内，并有权将其采用到其他相关的建模需求和利益。为了进一步启用这些技术，将创建大型可共享的数据库，其中将存入软件工具，数值代码，模型和实验数据和协议，并提供用于使用它们的指导。该项目的领导者将活跃于各种MSM联盟工作组，以进一步传播项目成果并与建模社区分享。提出的方法代表了多个模拟的堤防领域的范式转移，以及在工程和生物学界面上解决复杂临床问题的应用。与现有的基于经验的治疗相比，在循环条件下预测动脉血栓形成的进展，为改善药物管理提供工具，并提供一种建模工具，用于开发具有降低血栓形成的下一代设备，可能会降低死亡率，改善患者的生活质量，并降低了随之而来的医疗费用的金融燃烧。