CONVERSION OF IFN? NULL RESPONDER PHENOTYPE IN TO IFN RESPONDER PHENOTYPE

干扰素的转化？

• 批准号: 8357716
• 负责人: Robert E LANFORD
• 金额: $ 7.23万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357716
• 关键词: Antiviral Agents; Antiviral Response; Drops; Exhibits; Funding; Gene Expression; Genes; Grant; Hepatic; Hepatitis C virus; Human; Interferons; National Center for Research Resources; Pan Genus; Pathway interactions; Phenotype; Population; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Source; Testing; Transcript; United States National Institutes of Health; Viral Load result; Viremia; cost; design; inhibitor/antagonist; man; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Inhibitors of miR122 have recently been shown to reduce HCV viral load by up to 2.6 logs in HCV infected chimpanzees. Analysis of hepatic gene expression revealed that the drop in viremia was accompanied by a reduction in the levels of hepatic transcripts for interferon stimulated genes (ISGs) or the normalization of the IFN pathway. HCV chronically infected chimpanzees do not exhibit an antiviral response to exogenous IFN¿ and resemble null responders in the human population in this regard. The null response phenotype in chimpanzees and in man correlates with elevated hepatic ISG expression, while IFN responders have low baseline ISG transcript levels. Thus, the reduction in ISG transcript levels during therapy with miR122 inhibitors likely results in the conversion of the null IFN phenotype to the responder phenotype. This study is designed to directly test this concept and to demonstrate that IFN¿ induces hepatic ISG expression and an antiviral effect in chimpanzees treated with miR122 inhibitors.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 MiR122的抑制剂最近被证明可以将感染丙型肝炎病毒的黑猩猩体内的丙型肝炎病毒载量降低高达2.6个对数。肝脏基因表达分析显示，病毒血症的下降伴随着肝脏干扰素刺激基因(ISGs)转录水平的降低或干扰素途径的正常化。长期感染丙型肝炎病毒的黑猩猩对外源性干扰素不表现出抗病毒反应，在这一点上类似于人类种群中的零反应。在黑猩猩和人类中，零反应表型与肝脏ISG表达升高相关，而干扰素响应者的基线ISG转录水平较低。因此，在miR122抑制剂治疗期间，ISG转录本水平的降低可能导致无效的干扰素表型转化为应答者表型。这项研究旨在直接测试这一概念，并证明干扰素在用miR122抑制剂治疗的黑猩猩中诱导肝脏ISG表达和抗病毒作用。