A Stochastic Molecular Dynamics Method for Multiscale Modeling of Blood Platlet Pheonmena

血小板现象多尺度建模的随机分子动力学方法

• 批准号: 0506312
• 负责人: George Karniadakis
• 金额: --
• 依托单位: Brown University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0506312&HistoricalAwards=false
• 关键词: Stochastic; Molecular; Dynamics; Method; Multiscale

It is now well established that platelet aggregation is not only important for primary hemostasis but, when exaggerated, can also lead to the formation of occlusive thrombi, which form at sites of atherosclerotic plaque rupture, resulting in a heart attack, stroke or sudden death. Platelets are micron-size cells - smaller than red blood cells - and when activated they become adhesive for other activated platelets and they adhere to the vessel wall. Their strong interaction with nano-size proteins at the sub-endothelium matrix activates and reshapes them from passively traveling discoids to active spiny spheres. The length and time scales characterizing such interactions as well as platelet-blood flow interactions span several orders of magnitude.We propose a multiscale modeling methodology with focus on flow-modulated phenomena such as platelet adhesion and aggregation at the micron-scale, and including nanoscale effects representing the main protein interactions. We will develop an integrated approach by coupling multiscale representations of blood flow, ranging from a quasi 1D transient flow in compliant vessels at the largest scale, to unsteady 3D flows in curved and flexing vessels at the mm range, to multi micron-scale thrombus formation at a fissure in the lumen of such a vessel with an atherosclerotic plaque, to changes over short times (seconds and minutes) in the behavior of platelet structure, receptors and bonds in a developing thrombus-wall interaction. To this end, we will develop a new mesoscopic numerical method that bridges the gap between atomistic phenomena and large-scale phenomena to seamlessly connect length scales from 10 nm to a few mm. The new simulation approach will be validated systematically against experiments of varying biological and computational complexity.We also propose to establish a virtual center for multiscale modeling in order to provide modelers and experimentalists with quantitative information about molecular and cellullar processes that can be incorporated into simplified models. To this end, we plan to organize a workshop on multiscale modeling of biological processes during the second year of the proposed project. In our outreach program, we plan to engage pre-college women from the Providence area in computer and computational sciences. This will involve lectures by our medical collaborators as well as interactive learning at Brown's virtual immersive visualization facility.The potential impact of this work is great as it provides a new simulation capability for studying biomolecular interactions in blood vessels, organs and the entire arterial tree in a few hours instead of days or even weeks on a supercomputer. This, in turn, will allow fundamental studies at the molecular and cellular level and interaction with macroscales not currently possible with existing methodologies.

现在公认的是，血小板聚集不仅对初级止血很重要，而且当夸大时，还可能导致闭塞性血栓的形成，这些血栓形成于动脉粥样硬化斑块破裂的部位，导致心脏病发作、中风或猝死。血小板是微米大小的细胞--比红细胞小--当被激活时，它们会与其他激活的血小板粘连，并附着在血管壁上。它们与内皮下基质中的纳米蛋白质强烈相互作用，激活并重塑它们，使它们从被动移动的盘状转变为活跃的多刺球体。描述这种相互作用以及血小板-血流相互作用的长度和时间尺度跨越了几个数量级。我们提出了一种多尺度建模方法，重点关注微米尺度上的血小板黏附和聚集等血流调制现象，并包括代表主要蛋白质相互作用的纳米尺度效应。我们将开发一种综合的方法，将血液流动的多尺度表示法结合起来，从最大规模的顺应性血管中的准一维瞬时流动，到毫米范围内弯曲和弯曲血管中的非稳定3D流动，到此类血管管腔裂缝处具有动脉粥样硬化斑块的多微米尺度血栓形成，以及在不断发展的血栓与壁面相互作用中血小板结构、受体和键的行为在短时间(秒和分钟)内的变化。为此，我们将开发一种新的介观数值方法，弥合原子现象和大尺度现象之间的差距，无缝连接从10 nm到几毫米的长度尺度。新的模拟方法将与不同生物和计算复杂性的实验进行系统的验证。我们还建议建立一个多尺度建模的虚拟中心，以便为建模者和实验者提供关于分子和细胞过程的定量信息，这些信息可以合并到简化的模型中。为此，我们计划在拟议项目的第二年举办一次关于生物过程多尺度建模的研讨会。在我们的外展计划中，我们计划让普罗维登斯地区的大学前女性参与计算机和计算科学的研究。这将包括我们的医疗合作者的讲座以及布朗的虚拟沉浸式可视化设备的互动学习。这项工作的潜在影响是巨大的，因为它提供了一种新的模拟能力，可以在几个小时内研究血管、器官和整个动脉树中的生物分子相互作用，而不是在超级计算机上几天甚至几周。这反过来又将允许在分子和细胞水平上进行基础研究，以及与宏观尺度的相互作用，这是现有方法目前无法实现的。