DYNAMIC STUDIES OF COAGULATION AND THROMBOSIS

本研究的目的是应用最先进的流变学 技术和运输现象模型的研究具体问题 凝血和血栓形成 提出了五个具体目标， 调查 内皮细胞是血管的一部分， 由于血流产生的剪切应力和由于压力产生的机械应变 脉冲作用在柔性壁上。 应力和应变的作用 对细胞内花生四烯酸代谢和蛋白质合成的影响， 将确定分泌。 特定的靶蛋白已经被 组织纤溶酶原激活物，纤溶酶原激活物抑制剂- 1型、纤连蛋白和血管性血友病因子。 每一种蛋白质都是 在血栓形成中很重要，由内皮细胞合成。 初步 数据显示动脉剪切应力对TPA合成的显著影响， 分泌物 一个持续的问题是机械信号是如何 转导以影响细胞内的变化。 我们会用肾上腺素- 荧光视频显微镜和数字图像处理来研究压力 对钙通量和细胞内pH值的影响。同样，初步数据 显示了响应于流量变化的显著的钙瞬变。 我们 设备可以测定多细胞平均值和单细胞变化 in fluorescence荧光. 一个需要回答的重要问题是 应力（或应变）大小与应力（或应变）变化率的关系 应变）。 由于动脉血流固有地是脉动的，在体内， 我们的体外结果的应用将需要这些知识。 血管损伤模型血栓形成的生化调控 和生物材料表面进行研究。 我们的假设是 血液流动极大地调节了重要的 激活血栓附近的物种。 我们的结果清楚地预测了 凝血酶在血小板募集中的重要作用，即使在 肝素 我们将结合联合收割机落射荧光视频显微镜和 研究特定凝血因子作用的数学模型 以及附壁血栓形成和栓塞的流体力学。

The aim of this research is to apply state of the art rheological techniques and transport phenomena models to the study of specific problems in coagulation and thrombosis. Five specific aims are proposed for investigation. Endothelial cells which line blood vessels are subjected to shear stresses due to blood flow and mechanical strain due to the pressure pulse acting on the compliant wall. The effect of both stress and strain on intracellular arachadonic acid metabolism and protein synthesis and secretion will be determined. Specific target proteins have been identified tissue plasminogen activator, plasminogen activator inhibitor - type 1, fibronectin and von Willebrand factor. Each of these proteins is important in thrombosis and synthesized by endothelial cells. Preliminary data show dramatic effects of arterial shear stress on TPA synthesis and secretion. A continuing question is the problem of how the mechanical signal is transduced to effect intracellular changes. We will utilize epi- fluorescent video microscopy and digital image processing to study stress effects on calcium fluxes and intracellular pH. Again, preliminary data show striking calcium transients in response to changes in flow. Our equipment can determine both multicellular averages and single cell changes in fluorescence. An important question to be answered is the importance of stress (or strain) magnitude versus the rate of change of stress (or strain). Since arterial blood flow is inherently pulsatile, in vivo application of our in vitro results will require this knowledge. The biochemical control of thrombus formation on model damaged blood vessel and biomaterial surfaces will be investigated. Our hypothesis is that blood flow greatly modulates the local concentration of important activating species near growing thrombi. Our clearly results predicted an important role for thrombin in platelet recruitment even in the presence in heparin. We will combine epi-fluorescence video microscopy and mathematical modelling to study the role of specific coagulation factors and fluid mechanics in mural thrombus formation and embolization.