Cellular Determinants of Fibrin Structure and Stability

研究和相关的其他项目信息 6.项目总结/摘要 损伤后，携带组织因子（TF）的细胞暴露于血液，触发 血块形成血凝块由纤维蛋白网状结构稳定， 保护血凝块不受血液流动的影响fixtures也有免疫 在感染期间起作用并有助于伤口愈合。研究表明 纤维蛋白网络的形成或质量（结构和/或稳定性）异常 是异常血凝块（血栓形成和/或 出血）。我们和其他人已经表明，不同的细胞决定纤维蛋白的质量， 它们的促凝血活性和受体表达。有趣的是， 促凝血活性和受体产生的纤维蛋白密度更大，更稳定， 比远离细胞表面更远。我们假设空间位置 凝血酶产生的影响凝块的结构和稳定性。我们将使用激光扫描 共聚焦显微镜来表征调节纤维蛋白凝块结构近端的活性 并且远离凝血起始部位。我们将专门研究细胞的作用， 刺激、细胞和循环组织因子、可溶性凝血因子和细胞 受体决定凝块结构。我们将使用被动式和磁力驱动的 微珠技术和显微镜检查血管细胞如何调节纤维蛋白 网络渗透性、机械强度和抗纤维蛋白溶解性。最后我们将 使用透射电子显微镜比较在下形成的凝块中的纤维蛋白结构， 不同的剪切速率。我们预计我们的数据将 显示了不同止血和促血栓形成机制如何有助于凝血 静态和低剪切条件下的结构和稳定性。这些机制可能是 用于预防血管内血栓形成和/或栓塞的特异性靶点。

RESEARCH AND RELATED Other Project Information 6. PROJECT SUMMARY/ABSTRACT Following injury, tissue factor (TF)-bearing cells are exposed to the blood, triggering blood clot formation. Blood clots are stabilized by a web-like network of fibrin, which protects the clot from the rigors of flowing blood. Fibrin also has immunological functions during infection and contributes to wound healing. Studies have shown that abnormalities in the formation or quality (structure and/or stability) of the fibrin network are an established, independent risk factor for abnormal blood clots (thrombosis and/or bleeding). We and others have shown that different cells determine fibrin quality via their procoagulant activity and receptor expression. Interestingly, both cellular procoagulant activity and receptors produce fibrin that is denser and more stable near the cell than further away from the cell surface. We hypothesize that the spatial location of thrombin generation influences clot structure and stability. We will use laser scanning confocal microscopy to characterize activities that regulate fibrin clot structure proximal and distal to the site of clotting initiation. We will specifically investigate the roles of cell stimulation, cellular and circulating tissue factor, soluble clotting factors, and cell receptors in determining clot structure. We will use passive and magnetically-driven microbead techniques and microscopy to examine how vascular cells modulate fibrin network permeability, mechanical strength, and resistance to fibrinolysis. Finally, we will use transmission electron microscopy to compare fibrin structure in clots formed under different shear rates on freshly-excised human vessels. We anticipate our data will show how different hemostatic and prothrombotic mechanisms contribute to clot structure and stability in static and low shear conditions. These mechanisms may be specific targets for preventing intravascular thrombosis and/or embolism.