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Collaborative Research: Blood Clotting at the Extreme -- Mathematical and Experimental Investigation of Platelet Deposition in Stenotic Arteries

合作研究：极端血液凝固——狭窄动脉中血小板沉积的数学和实验研究

基本信息

批准号：
1715156
负责人：
Jian Du
金额：
$ 15万
依托单位：
Florida Institute of Technology
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1715156&HistoricalAwards=false
关键词：
Collaborative Research Blood Clotting Extreme

项目摘要

This project brings together mathematical and computational scientists and bioengineers to study the fundamental biophysical and biochemical mechanisms underlying the formation of blood clots within stenosed (constricted) arteries. These are the blood clots responsible for most heart attacks and many strokes, and understanding how they can form under the extreme physical conditions in a stenotic artery may lead to new ideas for how to prevent them. The very fast blood flow in severely stenosed arteries means that many of the well-studied processes responsible for blood clotting in more physiologically typical situations can play at most a minor role in these arteries. Recent experiments, including ones from the laboratory of one of the current investigators, suggest the importance of a specific flow-sensitive protein in the blood in allowing blood platelets to clump together to form a clot in stenotic arteries. This project involves incorporating the hypothesized role of this protein into a novel and sophisticated computational model of arterial blood clot formation, developed by this project's other investigators, and to use the expanded model to characterize the conditions under which that protein's known properties could explain clot formation in stenotic arteries. Through comparisons of the new model's predictions with further laboratory experiments, the model will be refined and its predictive capabilities improved, and our understanding of how blood clots form under the extreme physical conditions in stenotic arteries will be increased. Because the challenges of forming a blood clot under the conditions in a stenotic artery are similar to those of stanching hemorrhage from a major artery, understanding of how such clots form may also aid in development of interventions to limit bleeding following trauma.Most arterial blood clots are formed by the adhesion of blood cells known as platelets to an injured blood vessel wall and by platelets? cohesion to one another. Platelet adhesion and cohesion are both accomplished through the formation of molecular bonds that involve specific proteins on the platelets? surfaces binding to other specific proteins on the vascular wall or in the blood plasma. To hold the platelets together, the bonds must collectively be able to withstand the forces imposed on the platelet clump by the blood flow. For many types of platelet-platelet bonds, a platelet can form that type of bond only if the platelet has already become activated in response to appropriate chemical or physical stimuli. The platelet activation process takes time. For a platelet moving through a highly constricted artery, there is not enough time to respond to activation stimuli and the forces that the fluid exerts on it if it tries to attach to the vessel wall are enormous. How clots form in this situation is poorly understood, but recent experiments lead to the hypothesis that bonds mediated by a uniquely flow-sensitive protein (von Willebrand factor) in the blood are critical. This project will explore that hypothesis through a combination of mathematical modeling, computer simulation, and laboratory experimentation. A novel multiphase model will be developed of the mechanical interactions between a viscous fluid representing the blood and a permeable, viscoelastic, fracturable material representing a growing platelet clot. Development of robust and efficient numerical methods will allow exploration of the model?s behavior. Model results will be compared with results from an in vitro physical model of a stenotic artery. The comparison will lead to model refinements and to the design and interpretation of the physical experiments. Such interplay between modeling and experiments provides a powerful engine for driving scientific discovery.

该项目将数学和计算科学家以及生物工程师聚集在一起，研究狭窄（收缩）动脉内血栓形成的基本生物物理和生化机制。这些是导致大多数心脏病发作和许多中风的血块，了解它们是如何在狭窄动脉的极端物理条件下形成的，可能会为如何预防它们带来新的想法。在严重狭窄的动脉中，血液流动非常快，这意味着许多在生理上更典型的情况下负责血液凝固的过程，在这些动脉中最多只能发挥次要作用。最近的实验，包括一位现任研究人员的实验室的实验，表明血液中一种特定的流动敏感蛋白在允许血小板聚集在狭窄的动脉中形成凝块方面的重要性。这个项目包括将这种蛋白质的假设作用纳入一个由该项目的其他研究人员开发的新颖而复杂的动脉血栓形成计算模型中，并使用扩展模型来表征这种蛋白质的已知特性可以解释狭窄动脉血栓形成的条件。通过将新模型的预测与进一步的实验室实验进行比较，该模型将得到改进，其预测能力将得到提高，我们对狭窄动脉在极端物理条件下血栓形成的理解将会增加。由于在狭窄动脉中形成血栓的挑战与大动脉止血的挑战相似，因此了解血栓如何形成也有助于开发限制创伤后出血的干预措施。大多数动脉血栓是由被称为血小板的血细胞粘附到受伤的血管壁和血小板形成的。相互间的凝聚力。血小板的粘附和内聚都是通过血小板上特定蛋白质形成的分子键来完成的。与血管壁或血浆中其他特定蛋白质结合的表面。为了将血小板固定在一起，这些键必须能够共同承受血液流动对血小板团施加的力。对于许多类型的血小板-血小板键，只有当血小板在适当的化学或物理刺激下已经被激活时，血小板才能形成这种类型的键。血小板活化过程需要时间。对于在高度收缩的动脉中移动的血小板来说，没有足够的时间对激活刺激做出反应，而且如果血小板试图附着在血管壁上，液体对血小板施加的力是巨大的。在这种情况下凝块是如何形成的尚不清楚，但最近的实验提出了一种假设，即血液中一种独特的流动敏感蛋白（血管性血友病因子）介导的键是至关重要的。这个项目将通过结合数学建模、计算机模拟和实验室实验来探索这一假设。一个新的多相模型将被开发的机械相互作用之间的粘性流体代表血液和渗透性，粘弹性，断裂的材料代表不断增长的血小板凝块。稳健而有效的数值方法的发展将允许对模型的探索。年代的行为。模型结果将与体外狭窄动脉物理模型的结果进行比较。这种比较将导致模型的改进以及物理实验的设计和解释。这种模型和实验之间的相互作用为推动科学发现提供了强大的引擎。