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

描述(由申请者提供)：这项指导性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(干扰素)合作解决丙型肝炎病毒(HCV)感染的机制。尽管干扰素被普遍用于治疗丙型肝炎病毒感染，但其作用机制却鲜为人知。该研究计划部分是基于候选人之前的筛选工作，以识别和表征具有先前未知抗病毒活性的I型干扰素刺激基因(ISGs)。此外，随着最近发现IL28B(一种III型干扰素)的基因变异与治疗诱导的丙型肝炎病毒清除有关，出现了新的模型，表明这两个干扰素系统在功能上相互依赖。实验目的是在具有临床意义的结果的背景下测试这些模型。将确定IL28B基因对经干扰素处理的丙型肝炎病毒感染者外周血单个核细胞产生IL28B的影响。这些样本的下一代测序将用于将IL28B基因型与干扰素引起的全球基因表达变化联系起来。这两个干扰素系统之间的功能相互作用将在基于细胞培养的丙型肝炎病毒感染的肝细胞模型中进行评估，随后将进行下一代转录组分析。基因图谱工作将与候选人先前的ISG筛查结合使用，以确定最强和/或最具临床相关性的效应者，以便在独立阶段进行后续的抗病毒作用机制研究。这项研究计划旨在补充一项全面的职业发展计划，其中包括与深度测序技术和翻译研究相关的新领域的指导。该奖项的指导阶段将在实验室或洛克菲勒大学的查尔斯·赖斯博士进行，洛克菲勒大学是世界上 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成立的丙型肝炎研究中心的一部分，这种环境还提供了进入充满活力的临床和翻译研究社区的途径。职业发展计划的关键是参加专业会议，定期与咨询委员会举行会议，以及提供伦理学、深度测序和临床/翻译研究技术指导的课程。总而言之，这项培训计划应该满足候选人的短期目标，即在已经广泛的实验体系中增加新技术和方法，以及长期目标，即在分子病毒学、病毒-宿主细胞相互作用和病毒发病机制方面运行独立的研究计划。 公共卫生相关性：丙型肝炎病毒(丙型肝炎病毒)是美国最常见的慢性血液传播感染，有严重的病理后遗症，包括肝炎、肝硬化和肝细胞癌。丙型肝炎病毒是疫苗不可预防的，而且经常对基于干扰素的现有治疗方法产生抗药性。更深入地了解干扰素是如何对抗丙型肝炎病毒的，可能会改进这种病毒感染和其他病毒感染的治疗方法。

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. PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, with severe pathological sequelae including hepatitis, cirrhosis and hepatocellular carcinoma. HCV is not vaccine preventable and is frequently resistant to available therapies, which are based on interferon. A greater understanding of how interferon acts against HCV may lead to improved treatments for this and other viral infections.