TRANSGENIC MICE AS A MODEL TO STUDY HEPATITIS C VIRUS IMMUNOPATHOGENESIS

这个项目的目标是确定 丙型肝炎病毒（HCV）核心蛋白改变免疫系统的能力， 系统引起肝炎，并导致免疫功能障碍， 改变免疫系统产生效应物的能力。 的 第一个目的是确定核心蛋白的表达是否在 肝细胞改变其被CD8+和CD4+识别的能力 免疫效应子 这将通过收养转移来实现， 将NS5特异性免疫效应物导入表达NS5特异性免疫效应物和NS5特异性免疫效应物的转基因（TG）小鼠中。 NS5和核心蛋白在肝细胞特异性 启动子 将这些小鼠与表达NS5基因的小鼠进行比较 仅在肝细胞中。 第二个目标是基于赖博士的数据（项目 I）显示核心蛋白与核心蛋白的成员的相互作用， 肿瘤坏死因子受体家族 表达核心的TG小鼠 将检查CMV启动子控制下的蛋白质的免疫活性。 与受体信号改变有关的缺陷。 的假设 最终目的的一个基础是HCV感染PBMC和PBMC， 骨髓细胞 我们的假设是， 巨噬细胞抗原呈递细胞或T细胞中的蛋白质 导致免疫失调。 这种改变免疫系统的能力 反应性促进HCV持续存在。 为此目的进行的试验 假设最初将使用骨髓嵌合体来确定是否 核心蛋白的表达改变免疫应答。 它将 通过核心蛋白的特异性表达， 巨噬细胞或T细胞中使用细胞类型特异性启动子。 这 项目将建立一个小动物模型系统，用于研究 HCV的发病机制，这是该中心的主要目标之一。 该项目与项目I密切相关。

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.