TRANSGENIC MICE AS A MODEL TO STUDY HEPATITIS C VIRUS IMMUNOPATHOGENESIS

这个项目的目标是确定是否表达了 丙型肝炎病毒核心蛋白改变机体免疫能力 系统导致肝炎，并通过以下方式导致免疫功能障碍 改变免疫系统产生效应器的能力。这个 第一个目标是确定核心蛋白是否在 肝细胞改变其识别CD8+和CD4+的能力 免疫效应器。这将通过以下方式实现： NS5特异性免疫效应器在转基因(TG)小鼠中的表达 NS5和核心蛋白控制下的一种肝细胞特异性 推动者。这些小鼠将被与表达NS5基因的小鼠进行比较 只存在于肝细胞中。第二个目标是基于赖博士的数据(项目 I)显示核心蛋白与成员的相互作用(S) 肿瘤坏死因子受体家族。表达核心蛋白的转基因小鼠 在CMV启动子控制下的蛋白质将被检测为免疫 缺陷与受体信号的改变有关。假说 最终目标的基础是丙型肝炎病毒感染PBMC和 骨髓细胞。我们的假设是核心的表达 巨噬细胞抗原提呈细胞或T细胞中的蛋白质 它们本身会导致免疫失调。这种改变免疫力的能力 反应性促进了丙型肝炎病毒的持久性。对这一目标的考验 假说最初将使用骨髓嵌合体来确定 核心蛋白的表达改变了免疫反应性。会的 通过核心蛋白在任一种植物中的特定表达而被追求 巨噬细胞或T细胞中使用细胞类型特异性启动子。这 该项目将建立一个小动物模型系统来研究 丙型肝炎的发病机制，这是该中心的主要目标之一。 该项目与项目I密切互动。

The goals of this project are to determine if the expression of the hepatitis C virus (HCV) core protein alters the ability of the immune system to cause hepatitis, and results in immune dysfunctions by altering the ability of the immune system to generate effectors. The first aim is to determine if expression of the core protein in hepatocytes alters their ability to be recognized by CD8+ and CD4+ immune effectors. This will be accomplished by adoptive transfer of NS5-specific immune effectors into transgenic (TG) mice expressing both NS5 and core protein under the control of a hepatocyte-specific promoter. These mice will be compared to mice expressing the NS5 gene only in hepatocytes. The second aim is based on Dr. Lai's data (Project I) showing the interaction(s) of the core protein with members of the tumor necrosis factor receptor family. TG mice expressing the core protein under control of the CMV promoter will be examined for immune defects related to alterations in receptor signaling. The hypothesis of the final aim is based on the findings that HCV infects both PBMC and bone marrow cells. Our hypothesis is that expression of the core protein in either macrophage antigen presenting cells or the T cells themselves leads to immune dysregulation. This ability to alter immune responsiveness facilitates HCV persistence. Tests of this aim hypothesis will initially use bone marrow chimeras to determine if expression of the core protein alters immune responsiveness. It will be pursued by specific expression of the core protein in either macrophages or in T cells using cell type specific promoters. This project will establish a small animal model system for studying the pathogenesis of HCV, which is one of the major goals of this center. This project interacts closely with Project I.