Interactions between type I and III interferon during resolution of HCV infection

I 型和 III 型干扰素在 HCV 感染消退过程中的相互作用

• 批准号: 8639566
• 负责人: John W. Schoggins
• 金额: $ 14.71万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639566
• 关键词: Advisory Committees; Aftercare; Antiviral Agents; Area; Award; Basic Science; Biochemical; Biological Assay; Blood; Cell Communication; Cell Culture Techniques; Cells; Chronic; Cirrhosis; Clinical; Clinical Research; Clinical Treatment; Communities; Complement; Data; Development Plans; Environment; Ethics; Foundations; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genotype; Goals; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatocyte; Hospitals; Human; In Vitro; Infection; Influenza; Instruction; Interferon Type I; Interferons; Joint Ventures; Laboratories; Lead; Life Cycle Stages; Link; Mentored Research Scientist Development Award; Mentors; Mentorship; Messenger RNA; Methods; Modeling; Molecular Virology; National Research Service Awards; New York; Outcome; Patients; Peripheral Blood Mononuclear Cell; Phase; Presbyterian Church; Primary carcinoma of the liver cells; Production; Proteins; Reporting; Research; Research Technics; Resistance; Resolution; Resources; Reverse Transcriptase Polymerase Chain Reaction; Rice; Running; Sampling; Sendai virus; Small RNA; Source; Specificity; Spliced Genes; System; Technology; Testing; Training; Translational Research; Treatment outcome; United States; Universities; Vaccines; Validation; Variant; Viral; Viral Pathogenesis; Virus; Virus Diseases; Work; base; career development; clinically relevant; combinatorial; deep sequencing; design; follow-up; gene induction; genome wide association study; improved; macrophage; medical schools; meetings; new technology; next generation; next generation sequencing; novel; novel strategies; overexpression; programs; research study; response; screening; symposium; virology

DESCRIPTION (provided by applicant): The primary research goals of this Mentored Research Scientist Development Award proposal are to study the mechanisms by which types I and III interferon (IFN) cooperate to resolve hepatitis C virus (HCV) infection. Despite the ubiquitous use of IFN¿ for treatment of HCV infection, its mechanisms of action are poorly understood. The research plan is partly based on previous screening efforts by the candidate to identify and characterize type I IFN- stimulated genes (ISGs) with previously unknown antiviral activities. Additionally, with the recent discovery that genetic variation in IL28B (a type III IFN is associated with treatment-induced HCV clearance, new models have emerged suggesting a functional interdependence of these two IFN systems. The experimental aims are designed to test these models in the context of clinically- meaningful outcomes. The effects of IL28B genotype on IL28B production in IFN-treated peripheral blood mononuclear cells from HCV-infected patients will be determined. Next-generation sequencing of these samples will be used to correlate IL28B genotype to IFN¿-induced changes in global gene expression. The functional interplay between these two IFN systems will be assessed in cell culture-based hepatocyte models of HCV infection, followed by next-generation transcriptome profiling. The gene profiling efforts will be used in combination with the candidate's prior ISG screens to pinpoint the strongest and/or most clinically relevant effectors for follow up antiviral mechanism of action studies in the independent phase. This research plan is intended to complement a comprehensive career development plan that includes mentorship in new areas related to deep sequencing technologies and translational research. The mentored phase of this award will be carried out in the laboratory or Dr. Charles Rice at The Rockefeller University, one of the world's leading virology laboratories and a source of significant resources and basic science expertise. As part of the Center for the Study of Hepatitis C, a joint venture with Weill Cornell Medical College and New York Presbyterian Hospital, this environment also offers access to a vibrant clinical and translational research community. Critical to the career development plan are attendance at professional conferences, regular meetings with an advisory committee, and courses that offer instruction in ethics, deep sequencing, and clinical/translational research techniques. Summarily, this training plan should satisfy the candidate's short-term goals of adding new technologies and approaches to an already extensive experimental repertoire, and long term goals of running an independent research program in molecular virology, virus-host cell interactions, and viral pathogenesis.

描述（由申请人提供）：本指导研究科学家发展奖提案的主要研究目标是研究 I 型和 III 型干扰素 (IFN) 合作解决丙型肝炎病毒 (HCV) 感染的机制。尽管普遍使用干扰素（IFN）来治疗丙型肝炎病毒（HCV）感染，但其作用机制却知之甚少。该研究计划部分基于候选人之前的筛选工作，旨在识别和表征具有先前未知的抗病毒活性的 I 型 IFN 刺激基因 (ISG)。此外，随着最近发现 IL28B（III 型 IFN 的遗传变异与治疗诱导的 HCV 清除相关），新模型的出现表明这两种 IFN 系统在功能上相互依赖。实验目的旨在在具有临床意义的结果的背景下测试这些模型。IL28B 基因型对 IFN 处理的外周血中 IL28B 产生的影响 将测定 HCV 感染患者的单核细胞。这些样本的下一代测序将用于将 IL28B 基因型与 IFNτ 诱导的整体基因表达变化相关联。这两种干扰素系统之间的功能相互作用将在基于细胞培养的 HCV 感染肝细胞模型中进行评估，然后进行下一代转录组分析。基因分析工作将与 候选人之前的 ISG 筛选，以确定最强和/或最临床相关的效应器，用于独立阶段的后续抗病毒作用机制研究。该研究计划旨在补充全面的职业发展计划，其中包括与深度测序技术和转化研究相关的新领域的指导。该奖项的指导阶段将在洛克菲勒大学的查尔斯·赖斯博士的实验室进行，洛克菲勒大学是世界上最顶尖的大学之一。 领先的病毒学实验室以及重要资源和基础科学专业知识的来源。作为与威尔康奈尔医学院和纽约长老会医院合资的丙型肝炎研究中心的一部分，该环境还提供了进入充满活力的临床和转化研究社区的机会。对职业发展计划至关重要的是参加专业会议、与咨询委员会定期举行会议，以及提供伦理学、深度测序和临床/转化研究技术指导的课程。总之，该培训计划应满足候选人的短期目标，即在已经广泛的实验库中添加新技术和方法，以及在分子病毒学、病毒-宿主细胞相互作用和病毒发病机制方面开展独立研究项目的长期目标。