BASIC AND CLINICAL STUDIES OF COAGULATION PROTEINS

这是一份由一组人提出的继续项目计划的建议 成立了研究基础和临床方面的研究人员 止血和血管生物学，重点是纤维蛋白原、纤维蛋白和 脉管壁。项目1的目标将是定义结构 纤维蛋白原与成纤维细胞生长因子-2相互作用的基础及表征 它的功能含义。具体的研究将确定 相互作用的缔合和解离速率常数， 确定涉及的结合部位，并确定是否有其他成员 成纤维细胞生长因子家族还与纤维蛋白原结合。其他研究将确定其影响 成纤维细胞生长因子-2与纤维蛋白原结合对蛋白水解性的影响 降解和表征结合的功能效应，包括 受体相互作用与血管生成。下一个项目将 将纤维蛋白原定性为细胞外基质的一种成分。 具体研究将确定纤维蛋白原的结构域和 纤维蛋白原组装成基质所需的细胞表面受体， 检查细胞反应，检查纤维蛋白原和细胞的结构域 纤维蛋白原组装成细胞所需表面受体 检测细胞对基质相关纤维蛋白原的反应，以及 确定纤维蛋白原沉积到预制基质中是否会改变 基质细胞的基因表达。Sporn博士的项目是基于最近 关于促凋亡和抗凋亡信号机制的观察 在感染立克次体的内皮细胞中。支持细胞凋亡的人 立克次体感染直接诱导的信号通路将是 具有确定细胞凋亡是否涉及已知信号的特征 涉及caspase或产生活性氧的信号转导途径 物种和对P53的依赖和依赖。其他研究将 确定感染是否保护细胞免受其他促凋亡细胞的侵袭 刺激和相关的细胞内感染，诱导细胞凋亡 核因子-kappaB在细胞培养和体外模型中的激活。费伊博士的 该项目将继续对因子VIII的相互作用进行详细研究 内在的张力酶复合体。功能和调控的相互作用 因子VIII和Tenase之间的关系将得到详细的表征。 将研究APC对Tenase的调节，包括APC的作用 内皮细胞结合。临床研究将调查诊断 和循环纤维蛋白(原)衍生物的预后意义，以及 在临床试验中也评估新的抗血栓策略 导管引导与全身纤溶治疗深静脉血栓形成的对比研究 Lys-纤溶酶原在外周静脉溶栓治疗中的应用 动脉闭塞和抗凝策略在预防心绞痛中的作用 中心静脉导管血栓形成。五个研究项目 将由两个核心设施提供支持，这两个设施专门用于管理和 组织培养。该计划的特点是有重点地处理重要的 止血和血管生物学中的问题 基础和临床科学家的专业知识 通力合作。

This is a proposal for continuation of a Program Project by a group of established investigators to study basic and clinical aspects of hemostasis and vascular biology with a focus on fibrinogen, fibrin and the vessel wall. The goal of Project 1 will be to define the structural basis of the interaction between fibrin(ogen) and FGF-2 and characterize its functional implications. Specific studies will determine associations and dissociation rate constants for the interaction, identify binding sites involved and determine if other members of the FGF family also bind fibrinogen. Other studies will determine the effect of binding of FGF-2 to fibrin(ogen) on susceptibility to proteolytic degradation and characterize the functional effects of binding including receptor interactions and angiogenesis. The next project will characterize fibrinogen as a component of the extracellular matrix. Specific studies will define the structural domains of fibrinogen and cell surface receptors required for assembly of fibrinogen into matrix, examine cell response, examine structural domains of fibrinogen and cell surface receptors required for assembly of assembly of fibrinogen into matrix, examine cell responses to matrix-associated fibrinogen and determine whether fibrinogen deposition into preformed matrix alters gene expression of matrix cells. Dr. Sporn's project is based on recent observations regarding both pro- and anti-apoptotic signaling mechanisms in endothelial cells infected with R.rickettsii. The pro-apoptotic signaling pathway directly induced by R. rickettsii infection will be characterized to determine if apoptosis involved known signaling transduction pathways involving caspase or generation of reactive oxygen species and dependency and dependency on p53. Other studies will determine if infection protects the cell from other pro-apoptotic stimuli and correlate intracellular infection, induction of apoptosis and NF-kappaB activation in cell culture and ex vivo models. Dr. Fay's project will continue detailed studies of factor VIII interactions in the intrinsic tenase complex. The functional and regulatory interactions between factor VIII and tenase will be characterized in detail. Regulation of tenase by APC will be investigated including the role of endothelial cell binding. Clinical studies will investigate diagnostic and prognostic implications of circulating fibrin(ogen) derivatives, and also evaluate new anti-thrombotic strategies in clinical trials of catheter-directed versus systemic fibrinolysis of deep vein thrombosis, lys-plasminogen as an adjunct for thrombolytic therapy of peripheral arterial occlusion and anti-coagulant strategies for prophylaxis of thrombosis with central venous catheters. The five research projects will be supported by two core facilities devoted to administration and tissue culture. The Program features a focused approach to important problems in hemostasis and vascular biology with a balance between the expertise of fundamental and clinical scientists working collaboratively.