MHV INDUCED APOPTOSIS AND RESISTANCE TO LETHAL HEPATITIS

我们建议利用暴发型肝炎病毒的小鼠模型 完全敏感品系的小鼠肝炎，小鼠肝炎病毒， 3号毒株(MHV-3)会产生一种致命的暴发型肝炎，其特征是 大量肝细胞坏死。相比之下，耐药品系的小鼠存活了下来 没有可检测到的肝损伤证据的感染。我们最近做了 观察到MHV-3在感染后迅速诱导细胞凋亡 来自A/J品系小鼠的巨噬细胞，在快速复制和 在Balb/c来源的巨噬细胞中高效表达。这种快速的细胞凋亡是 与抑制MHV诱导的合胞体形成从而抑制病毒有关 散开。我们建议确定通过以下方式快速诱导细胞凋亡 MHV-3仅限于巨噬细胞或也出现在其他类型的细胞中，并且 用生化方法描绘MHV-3诱导细胞凋亡的途径和调控因子 药理学和遗传学方法。尤其是半胱氨酸酶的作用， Bc1-2、p53、TNFa、Fas-FasL和dsRNA激活的蛋白激酶PKR，in 调控MHV-3引发的细胞自杀将被研究。此外，它是 建议研究细胞凋亡反应对抗药性的作用 MHV-3引发的致死性肝炎细胞凋亡途径的调控 我们建议研究细胞凋亡反应在抗药性中的作用 致命性肝炎。

We proposes to utilize the mouse hepatitis virus model of fulminant hepatitis In fully susceptible strains of mice, mouse hepatitis virus, strain 3(MHV-3) produces a lethal fulminant hepatitis characterized by massive hepatocellular necrosis. In contrast, resistant strains of mice survive the infection without detectable evidence of hepatic injury. We have recently observed that MHV-3 induces the rapid induction of apoptosis in infected macrophages derived from strain A/J mice, while replicating rapidly and efficiently in Balb/c derived macrophages. This rapid onset of apoptosis is correlated with inhibition of MHV induced syncytia formation and thus virus spread. We proposed to determine if the rapid induction of apoptosis by MHV-3 is confined to macrophages or also occurs in other cell types, and to delineate pathways and regulators of MHV-3 induce apoptosis using biochemical, pharmacologic, and genetic approaches. Specifically the role of caspases, bc1-2, p53, TNFa, Fas-FasL, and the dsRNA activated protein kinase PKR, in regulating MHV-3 triggered cell suicide will he studied. Furthermore it is proposed to investigate the role of the apoptotic response to resistance to lethal hepatitis by manipulating the apoptotic pathways triggered by MHV-3 we propose to investigate the role of the apoptotic response to resistance to lethal hepatitis.