Reaction and Transport Dynamics in Human Blood

描述（由申请人提供）：在给定基因型和表型的背景下，血凝块组装的动力学最终决定：血栓形成；血栓的溶栓敏感性；体外循环术中脑卒中；血管成形术后再狭窄；伤口愈合/炎症;深静脉血栓形成或肺栓塞的发病机制。在血液凝固过程中，活化的血小板和中性粒细胞通过十多种受体介导的途径形成同型和异型聚集体，同时触发凝血酶形成和纤维蛋白聚合。然而，在凝固的全血流动条件下，血小板-血小板和血小板-中性粒细胞结合导致聚集或沉积的强度和动力学，以及这些聚集物的生化反应性，我们对其定量了解较少。此外，在大多数实验中，仅持续几毫秒的事件的时间分辨率很少实现。体外高速成像实验将利用人类血细胞和蛋白质在受控的血液动力学和凝血条件下进行这些相互作用的动力学研究。这些实验的动力学数据将用于提高对人体血液现象的机械理解。通过定义血凝块在血流条件下如何组装的分子动力学，以及定义各种凝血情况的血流调节，对于给定的疾病进展，不调节凝血、出血和栓塞的风险将得到更定量的理解。具体目的是：目的1血小板和中性粒细胞受体在血栓形成过程中的相互作用；目的2活化血小板的凝血起始；目的3：探讨深静脉血栓形成抑制模型中红细胞粘附机制；目的4聚集和凝聚研究的计算工具。总的来说，这些研究试图提供基本的见解细胞-细胞相互作用和凝血生化发生在流动。

DESCRIPTION (provided by applicant): In the context of a given genotype and phenotype, the dynamics of blood clot assembly ultimately dictate: thrombosis; thrombolytic susceptibility of clots; stroke during cardiopulmonary bypass; restenosis after angioplasty; wound healing/inflammation; and pathogenesis of deep vein thrombosis or pulmonary embolism. During blood coagulation, activated platelets and neutrophils form homotypic and heterotypic aggregates through over ten receptor-mediated pathways while triggering thrombin formation and fibrin polymerization. Yet less is known quantitatively about the strengths and kinetics of platelet-platelet and platelet-neutrophil bonding that leads to aggregation or deposition under coagulating whole blood flow conditions or the biochemical reactivity of these aggregates. Furthermore, temporal resolution of events lasting only a few milliseconds is rarely achieved in most experiments. In vitro high speed imaging experiments will utilize human blood cells and proteins for kinetic studies of these interactions under controlled hemodynamic and coagulation conditions. Kinetic data from these experiments will be used to gain improved mechanistic understanding of human blood phenomena. By defining the molecular dynamics of how blood clots are assembled under flow conditions as well as defining the flow-regulation of various clotting scenarios, the risks of unregulated clotting, bleeding, and embolism will be more quantitatively understood for a given disease progression. Specific aims are: Aim 1 Platelet and neutrophil receptor interactions during thrombosis; Aim 2 Coagulation initiation on activated platelets; Aim 3 Red blood cell adhesion mechanisms in a depressed venous flow model of deep vein thrombosis; and Aim 4 Computational tools for aggregation and coagulation research. Overall, these studies seek to provide fundamental insight into cell-cell interacitions and coagulation biochemistry that occur under flow.