FIBRINOGEN, INFLAMMATION, AND ATHEROGENESIS

动脉粥样硬化越来越被认为是一种慢性炎症性疾病 进程。凝血因子纤维蛋白原(FGN)提供了一个关键的 损伤部位的临时基质，细胞可以在其中迁移和 履行止血和止血方面的专门职能 发炎。流行病学、组织学和实验品系 有证据表明，FGN可能计划在 动脉硬化。虽然血浆FGN水平升高与 心血管疾病的风险增加，目前尚不清楚 RGN是一种替代标记物或直接参与动脉粥样硬化的形成。 尽管FGN在健康和疾病中很重要，但其机制 FGN的主要分解代谢途径(S)的位置尚不清楚。 初步数据表明整合素Mac-1(CD11b/CD18) 单核细胞和肝细胞上的avb3(CD51/CD61)可以结合， 通过溶酶体组织蛋白D内化和降解FGN数据 自先前提交以来获得的证据提供了兔子模型的证据 FGN与Mac-1直接相互作用对血管损伤的影响 影响血管修复。这项提议的核心假设是 整合素是FGN水平的主要决定因素，它们的功能 在这方面受促炎症细胞因子和 尿激酶受体(微米级PAR)与血浆调节 FGN水平将直接影响动脉粥样硬化的发展。 提出了三个具体目标：(1)研究其形成机制 和对整合素介导的FGN周转的调节；我们建议 定义对相互作用重要的结构决定因素 FGN及其整合素受体及细胞因子的作用 关于FGN的降解。微米标准杆似乎是一个重要的 整合素的调节器。连接整合素的分子途径 微米级PAR的功能将在真核细胞中被剖析 导入野生型和突变型MAC-1和avb3；(2) 明确FGN在体内的分解代谢机制。血浆清除率 将进行实验以确定FGN的动力学 野生型受体(MAC-1和微米级PAR)的代谢- 和组织蛋白酶D减去缺陷小鼠。一个隔离的灌流 将利用大鼠肝脏制剂来研究黄连的影响。 FGN代谢中的细胞因子及其细胞类型的确定(S) 负责FGN的分解代谢；以及(3)研究FGN的作用 转基因小鼠动脉粥样硬化发病机制的研究进展 过表达人载脂蛋白B。纯合子FGN缺陷小鼠将 与表达人载脂蛋白B的小鼠杂交产生双倍 表达载脂蛋白B转基因并且是纯合子的转基因 或FGN缺乏症的杂合子。饮食诱导的动脉粥样硬化 病变面积将随着时间的推移进行量化，以确定FGN 在动脉粥样硬化形成的小鼠模型中，缺乏提供保护。 总的来说，这些实验旨在阐明FGN是否 在动脉粥样硬化中起病因学作用，如果是这样的话，提供了一个潜在的 针对FGN调控的药物设计的分子基础 级别。

Atherosclerosis is increasingly regarded as a chronic inflammatory process. The coagulation factor fibrinogen (FGN) provides a critical provisional matrix at sites of injury in which cells can migrate and carry out the specialized functions involved in hemostasis and inflammation. Epidemiologic, histologic, and experimental lines of evidence indicate the FGN may plan pathogenic roles in atherosclerosis. While elevated plasma FGN levels are associated with an increased risk of cardiovascular disease, it remains unclear whether RGN is a surrogate marker or directly participates in atherogenesis. Despite the importance of FGN in health and disease, the mechanism and site of the major FGN catabolic pathway(s) are unknown. Preliminary data demonstrate that the integrins Mac-1 (CD11b/CD18) on monocytes and avb3 (CD51/CD61) on hepatocytes can bind, internalize, and degrade FGN via lysosomal cathepsin D. Data obtained since the prior submission provide evidence in a rabbit model of vascular injury that interactions between FGN and Mac-1 directly influence vascular repair. The central hypotheses of this proposal are that integrins are a major determinant of FGN level, that their function in this regard is regulated by pro-inflammatory cytokines and the urokinase receptor (microns PAR), and that modulation of plasma FGN level will directly affect the development of atherosclerosis. Three specific aims are proposed: (1) to investigate the mechanism and regulation of integrin-mediated FGN turnover; we proposed to define the structural determinants important to the interaction between FGN and its integrin receptors and investigate the effect of cytokines on FGN degradation. Microns PAR appears to be an important regulator of integrins. The molecular pathways which connect integrin function with that of microns PAR will be dissected in eukaryotic cells transfected with wild-type and mutant forms of MAC-1 and avb3; (2) to define the in vivo mechanism of FGN catabolism. Plasma clearance experiments will be performed to determine the kinetics of FGN metabolism in wild-type, receptor (MAC-1 and microns PAR)- deficient; and cathepsin D minus deficient mice. An isolated perfused rat liver preparation will be utilized to investigate the effects of cytokines in FGN metabolism and to identify the cell type(s) responsible for FGN catabolism; and (3) to study the effect of FGN deficiency on the development of atherosclerosis in transgenic mice over-expressing human apoB. Homozygous FGN-deficient mice will be bred with mice expressing human apoB to generate double transgenics that express the apoB transgene and are either homozygous or heterozygous for FGN deficiency. Diet-induced atherosclerotic lesion area will be quantified over time to determine whether FGN deficiency affords protection in a murine model of atherogenesis. Collectively, these experiments are designed to clarify whether FGN has an etiologic role in atherosclerosis and, if so, provide a potential molecular basis for drug design aimed at the modulation of FGN levels.