Multiscale modeling and empirical study of a mechanism limiting blood clot growth

描述（由申请人提供）：当血管破裂时，形成主要由血小板和纤维蛋白组成的止血凝块，以限制失血。生理性血液凝固受到高度调节，但病理性凝块（血栓）可能在血管内形成并限制血液流向器官或凝块碎片（栓子）可能分离并携带到肺部，导致称为肺栓塞的危及生命的并发症。此外，凝块在冠状动脉中形成，引起心脏病发作，在脑血管中形成，引起缺血性中风。高发病率和死亡率（每年仅静脉血栓栓塞性疾病就有约900，000例发病率和300，000例死亡）强调了研究限制凝块形成过程的生物医学重要性。然而，阻止凝块生长的机制知之甚少。特别是，目前的血栓发展模型没有解决纤维蛋白网络（FNW）的结构如何影响凝血因子的时空演变以及在限制血凝块生长的流动条件下FNW和血小板之间的相互作用。该提案结合了3D多尺度血凝块建模环境（MBCME-3D）的开发，并将MBCME-3D模拟与使用光镊和微流体室专门设计的实验相结合，以研究FNW在调节血凝块生长中的两个特定作用：1）阻碍蛋白质运输; 2）在生理或病理条件下介导血小板-FNW结合动力学。这将导致对血管腔部分阻塞和狭窄引起的血液剪切力增加的常见临床情况进行详细检查，这被认为是一个至关重要的组成部分，影响纤维蛋白的生成和血小板的结合，限制血凝块生长的机制。更好地了解血栓的结构和性质以及在血流条件下凝块生长的机制及其局限性，将有助于医生通过确定调节血栓形成的过程的参数的临界值来估计个体患者的血栓性疾病的风险。此外，广义MBCME-3D将能够详细模拟生物细胞和蛋白质在流体环境中的运动， 在微观和介观尺度的多孔陶瓷，这将有助于生物医学研究的各种预测多尺度计算模型的发展。

DESCRIPTION (provided by applicant): When a blood vessel ruptures, a hemostatic clot, consisting mainly of platelets and fibrin, is formed to restrict the loss of blood. Physiological blood clotting is highly regulated, but a pathological clot (thrombus) may form within a vessel and restrict blood flow to organs or clot pieces (emboli) can detach and be carried to the lungs, causing a life-threatening complication called pulmonary embolism. Also, clots are formed in coronary arteries, causing heart attacks, and in brain vessels, causing ischemic strokes. The high morbidity and mortality rates (about 900,000 incidences and 300,000 deaths annually just from venous thromboembolic disease) underscore the biomedical importance of studying processes limiting clot formation. However, the mechanisms stopping clot growth are poorly understood. In particular, current models of thrombus development do not address how structure of fibrin network (FNW) affect spatial-temporal evolution of blood coagulation factors and the interplay between FNW and platelets under flow conditions limiting blood clot growth. This proposal combines development of 3D Multiscale Blood Clot Modeling Environment (MBCME-3D) and coupling MBCME-3D simulations and specifically designed experiments using optical tweezers and microfluidic chambers, to study two specific roles that a FNW plays in regulating blood clot growth: 1) impeding protein transport; and 2) mediating platelet-FNW binding kinetics under physiological or pathological conditions. This will result in detailed examination of the common clinical scenario of increasing blood shear in response to partial obstruction and narrowing of the vessel lumen, which is considered a critically important component, affecting both the generation of fibrin and binding of platelets, mechanisms limiting blood clot growth. Better understanding of the structure and properties as well as the mechanisms of clot growth and its limitations under blood flow will help physicians to estimate risk of thrombotic disease for an individual patient by identifying critical values of parameters o processes regulating thrombogenesis. Additionally, the generalized MBCME-3D will be able to simulate in detail motion of biological cells and proteins in the fluid environment in the presence of porous biogels at the micro- and mesoscale which will contribute to the development of a variety of predictive multiscale computational models for biomedical research.