MHV INDUCED APOPTOSIS AND RESISTANCE TO LETHAL HEPATITIS

MHV 诱导细胞凋亡和对致命性肝炎的抵抗

• 批准号: 6046117
• 负责人: JULIAN L LEIBOWITZ
• 金额: $ 19.21万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-15 至 2002-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6046117
• 关键词: BCL2 gene /protein; CD95 molecule; animal viral hepatitis; apoptosis; cysteine endopeptidases; disease /disorder model; double stranded RNA; genetic strain; host organism interaction; laboratory mouse; macrophage; microorganism immunology; murine hepatitis virus; p53 gene /protein; protease inhibitor; protein kinase; tissue /cell culture; tumor necrosis factor alpha; virus infection mechanism

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.

我们建议利用暴发性小鼠肝炎病毒模型 肝炎 在完全易感的小鼠品系中，小鼠肝炎病毒， 毒株 3（MHV-3）产生致命的暴发性肝炎，其特征为 大量肝细胞坏死。相比之下，抗药性小鼠品系却存活下来 感染没有可检测到的肝损伤证据。我们最近有 观察到 MHV-3 能快速诱导感染细胞凋亡 源自 A/J 品系小鼠的巨噬细胞，同时快速复制并 在 Balb/c 衍生的巨噬细胞中有效。这种细胞凋亡的快速发生是 与抑制 MHV 诱导的合胞体形成相关，从而抑制病毒 传播。 我们建议确定是否可以快速诱导细胞凋亡 MHV-3 仅限于巨噬细胞或也出现在其他细胞类型中，并且 使用生化技术描述 MHV-3 诱导细胞凋亡的途径和调节因子， 药理学和遗传学方法。具体来说半胱天冬酶的作用， bc1-2、p53、TNFa、Fas-FasL 和 dsRNA 激活蛋白激酶 PKR， 他将研究调节 MHV-3 引发的细胞自杀。此外，它是 提议研究细胞凋亡反应对耐药性的作用 通过操纵 MHV-3 触发的细胞凋亡途径来治疗致命性肝炎 我们建议研究细胞凋亡反应对耐药性的作用 致死性肝炎。

项目成果

Caspase inhibitors block MHV-3 induced apoptosis and enhance viral replication and pathogenicity.

Caspase 抑制剂可阻断 MHV-3 诱导的细胞凋亡并增强病毒复制和致病性。

• DOI: 10.1007/978-1-4615-1325-4_17
• 发表时间: 2001
• 期刊: Advances in experimental medicine and biology
• 作者: Leibowitz,JL;Belyavskaya,E
• 通讯作者: Belyavskaya,E