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MECHANISMS OF ACTION OF INTERFERON

干扰素的作用机制

基本信息

批准号：
3186795
负责人：
MARIANO ESTEBAN
金额：
$ 14.36万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-09-30 至 1992-06-30
项目状态：
已结题

项目摘要

The antiviral and antiproliferative actions of interferons have been correlated with a number of enzyme activities (2-5A synthetase, endoribonuclease, protein kinase), which, when activiated, inhibit protein synthesis but the relevance of these enzymes to the inhibition of replication of RNA and DNA-containing viruses has not been elucidated. We have found in a vaccinia virus infected mouse L cell system that the interferon-mediated inhibition of viral protein synthesis in vivo correlates with activation of the 2-5A synthetase/endonuclease and degradation of viral RNAs. In contrast, in a number of mouse and human cells of different origins, vaccinia protein synthesis is not inhibited by interferon and a novel phenomenon has been discovered where vaccinia products block the 2-5A synthetase and protein kinase activities. In this proposal, experiments are described using vaccinia virus as a model system to elucidate: a) the in vivo role of the 2-5A synthetase/endonuclease system in the interferon-mediated inhibition of vaccinia virus protein synthesis; b) the mechanism by which a DNA virus such as vaccinia escapes blockade by the interferon system. To determine the in vivo role of the 2-5A synthetase/endonuclease on protein synthesis we will establish to what extent the integrity of viral and cellular RNAs is related to a block of translation, if specific degradation of certain RNAs occurs and if these events are the result of the formation of viral RNA during the course of infection. To define how vaccinia virus escapes inhibition by the interferon-mediated enzyme activities, we will characterize the nature and mode of action of vaccinia products with interfering properties present in cell-extracts and virions. To further define the vaccinia products with blocking effects on interferon action we will examine whether viral genes introduced into cells by DNA-mediated gene transfer can overcome specific interferon-mediated enzyme activities. By examining these cell-systems where the interferon response of the cells may be controlled by vaccinia gene(s) we may provide the means to define the mechanisms responsible for inhibition of replication of various viruses as well as the antiproliferative actions of interferons.

干扰素的抗病毒和抗增殖作用已被证实。与许多酶活性（2-5A合成酶，核糖核酸内切酶，蛋白激酶），当被激活时，其抑制蛋白合成，但这些酶的相关性，以抑制 RNA和含DNA病毒的复制尚未阐明。我们已经在牛痘病毒感染的小鼠L细胞系统中发现，干扰素介导体内病毒蛋白质合成抑制与2-5A合成酶/核酸内切酶的活化相关，病毒RNA的降解。相反，在一些小鼠和人类中，不同来源的细胞，牛痘蛋白质合成不受已经发现了一种新的现象，产物阻断2-5A合成酶和蛋白激酶活性。在这建议，实验描述使用牛痘病毒作为模型系统为了阐明：a）2-5A合成酶/内切核酸酶的体内作用干扰素介导的牛痘病毒蛋白抑制系统合成; B）DNA病毒如牛痘病毒逃逸的机制通过干扰素系统阻断。为了确定在体内的作用， 2-5A合成酶/核酸内切酶对蛋白质合成的影响，我们将建立什么在某种程度上，病毒和细胞RNA的完整性与阻断翻译，如果某些RNA发生特异性降解，事件是病毒RNA形成的结果，感染为了确定牛痘病毒是如何逃脱干扰素介导的酶活性，我们将表征性质，存在干扰特性的牛痘产品的作用方式细胞提取物和病毒体。为了进一步定义牛痘产品，阻断干扰素作用的影响，我们将研究病毒基因是否通过DNA介导的基因转移引入细胞可以克服特异性干扰素介导的酶活性。通过检查这些细胞系统其中细胞的干扰素应答可以由牛痘控制基因，我们可以提供定义机制的方法，抑制各种病毒的复制以及干扰素的抗增殖作用。