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，主要由血小板和纤维蛋白组成的止血凝块形成，以限制血液的流失。生理性血凝块是受到高度调控的，但病理性血凝块（血栓）可能在血管内形成，限制血液流向器官，或者血凝块（栓子）可能脱落并被带到肺部，导致一种危及生命的并发症——肺栓塞。此外，在冠状动脉中形成凝块，导致心脏病发作，在脑血管中形成凝块，导致缺血性中风。高发病率和死亡率（每年仅静脉血栓栓塞性疾病的发病率约为90万，死亡人数约为30万）强调了研究限制血栓形成过程在生物医学上的重要性。然而，阻止凝块生长的机制尚不清楚。特别是，目前的血栓形成模型没有解决纤维蛋白网络（FNW）结构如何影响凝血因子的时空演变，以及FNW与血小板在限制血栓生长的流动条件下的相互作用。本研究结合三维多尺度血凝块建模环境（MBCME-3D）的开发，耦合MBCME-3D模拟和使用光学镊子和微流体室专门设计的实验，研究FNW在调节血凝块生长中的两个具体作用：1)阻碍蛋白质运输；2)在生理或病理条件下调节血小板- fnw结合动力学。这将导致对常见临床情况的详细检查，即对部分阻塞和血管腔狭窄的反应增加血液剪切，这被认为是一个至关重要的组成部分，影响纤维蛋白的产生和血小板的结合，限制血栓生长的机制。更好地了解凝块的结构和性质以及凝块生长的机制及其在血流中的局限性，将有助于医生通过确定调节血栓形成过程的参数的临界值来估计单个患者的血栓性疾病风险。此外，广义MBCME-3D将能够模拟生物细胞和蛋白质在流体环境中存在的详细运动

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.