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

限制血块生长机制的多尺度建模和实证研究

• 批准号: 8898196
• 负责人: Mark Alber
• 金额: $ 68.72万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-25 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898196
• 关键词: Address; Adherence; Adhesions; Affect; Algorithms; Binding; Biological; Biomedical Research; Blood; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Brain; Calibration; Carrier Proteins; Cause of Death; Cells; Cessation of life; Clinical; Coagulation Process; Complication; Computer Simulation; Coronary artery; Coupled; Coupling; Data; Development; Diffusion; Disease; Elements; Embolism; Environment; Evolution; Feedback; Fiber; Fibrin; Generations; Growth; Health; Hemorrhage; Hemostatic Agents; Human body; Image; Image Analysis; Incidence; Individual; Integrins; Ischemic Stroke; Kinetics; Length; Life; Ligands; Liquid substance; Lung; Measures; Mechanics; Mediating; Methods; Microfluidic Microchips; Microfluidics; Microscope; Modeling; Morbidity - disease rate; Motion; Movement; Myocardial Infarction; Names; Obstruction; Organ; Patients; Perfusion; Pharmacia brand of estropipate; Physicians; Physiological; Platelet Activation; Play; Process; Property; Proteins; Pulmonary Embolism; Reaction; Risk Estimate; Role; Running; Rupture; Series; Spectrum Analysis; Staging; Structure; Surface; System; Testing; Thermodynamics; Thick; Thrombosis; Thrombus; Time; Venous; Work; base; density; design; experience; fluid flow; laser tweezer; mortality; multi-scale modeling; novel; optical traps; pressure; prevent; protein transport; receptor; research study; response; shear stress; simulation; single molecule; three dimensional structure

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.

描述（申请人提供）：当血管破裂时，会形成主要由血小板和纤维蛋白组成的止血凝块，以限制血液流失。生理性血液凝固受到高度调节，但血管内可能形成病理性凝块（血栓）并限制血液流向器官，或者凝块碎片（栓子）可能脱落并被带到肺部，导致危及生命的并发症，称为肺栓塞。此外，冠状动脉中形成血栓，导致心脏病发作；脑血管中形成血栓，导致缺血性中风。高发病率和死亡率（仅静脉血栓栓塞性疾病每年约有 900,000 例发病和 300,000 例死亡）强调了研究限制血栓形成过程的生物医学重要性。然而，人们对阻止凝块生长的机制知之甚少。特别是，当前的血栓形成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化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) 的开发以及耦合 MBCME-3D 模拟和使用光镊和微流体室专门设计的实验，以研究 FNW 在调节血凝块生长中发挥的两个特定作用：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所导致的血液剪切力增加的常见临床情况进行详细检查，血管腔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，限制血栓的机制生长。更好地了解凝块的结构和特性以及凝块生长的机制及其在血流下的局限性，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个体患者患血栓性疾病的风险。此外，广义的 MBCME-3D 将能够详细模拟流体环境中生物细胞和蛋白质的运动 微观和中尺度多孔生物凝胶的研究将有助于开发用于生物医学研究的各种预测性多尺度计算模型。