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Identification of Host Drug Development Targets in Influenza Using Transposon Mutagenesis

使用转座子诱变鉴定流感宿主药物开发靶点

基本信息

批准号：
9089858
负责人：
Adam Lacy-Hulbert
金额：
$ 26.1万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089858
关键词：
Animals Antiviral Agents Antiviral resistance Bioinformatics Candidate Disease Gene Cell Death Cells Cessation of life Data Drug resistance Ebola virus Elements Epidemic Gene Expression Generations Genes Genetic Goals Health Healthcare High-Throughput Nucleotide Sequencing Host Defense Host Defense Mechanism Human Human Cell Line Immune system Individual Infection Infection prevention Influenza Influenza A virus Integration Host Factors Laboratories Lead Libraries Mediating Methodology MicroRNAs Modeling Morbidity - disease rate Mutagenesis Mutation Outcome Pathway interactions Phase Physiological Public Health RNA interference screen Resistance Resistance to infection Site Testing Therapeutic Therapeutic Intervention Transcript Untranslated RNA Up-Regulation Vaccination Vesicular stomatitis Indiana virus Viral Virus Virus Diseases Virus Replication Work antiviral immunity base care burden cell type chemotherapy combat drug development drug mechanism gene interaction genetic approach genome-wide influenzavirus innovation insight mortality mutant new therapeutic target novel novel therapeutics overexpression pandemic disease prevent programs resistance gene resistant strain screening seasonal influenza small molecule success targeted treatment therapeutic target viral resistance

项目摘要

DESCRIPTION (provided by applicant): The ongoing healthcare burden of seasonal Influenza, the emergence of strains resistant to existing treatments and the constant threat of new pandemic strains highlight the urgent need to identify new therapeutic targets against Influenza. The long term goal of our laboratory is to identify mechanisms of host defense against infection. The objective in this application is to identify host-encoded mechanisms of resistance to infection by Influenza. Based on emerging data and our preliminary studies, our central hypothesis is that the up-regulation of host 'restriction factors' that prevent viral entry restrict the ability of viruses to infect or replicate in host cells or increase the ability of cels to withstand viral-induced cytopathy represent an important strategy in host defense. Our rationale for the proposed work is that identification of such factors will provide a wealth of new targets fr therapeutic intervention, and that these may be less susceptible to resistance than viral-encoded targets. In the R21 phase we propose to use a novel unbiased forward-genetic approach to screen for host genes that confer resistance to Influenza infection. In the R33 phase, we will validate new host targets and use these insights to develop new anti-viral therapeutic strategies. Our screening approach is innovative because it allows identification of both host genes that, when overexpressed confer resistance ('restriction factors') as well as host genes required for infection, which are normally detected in conventional RNAi-based screens. The proposed work is significant because it has the potential to identify new targets, including non- coding RNA elements, which would be missed using existing approaches. Furthermore, our approach is responsive to the RFA because it is directed at identifying new host targets and therapeutic strategies to combat Influenza A and overcome resistance to existing antiviral agents.

描述(申请人提供)：季节性流感持续的医疗负担，对现有治疗方法产生抗药性的菌株的出现，以及新的大流行病毒株的持续威胁，突显了确定新的流感治疗目标的迫切需要。我们实验室的长期目标是确定宿主抵抗感染的机制。本应用的目的是识别宿主编码的抵抗流感感染的机制。根据新出现的数据和我们的初步研究，我们的中心假设是，上调宿主限制因子以阻止病毒进入，限制病毒在宿主细胞中感染或复制的能力，或增强CEL抵御病毒诱导的细胞病变的能力，这是宿主防御的重要策略。我们这项拟议工作的基本原理是，识别这些因素将为治疗干预提供大量新的靶点，而且这些靶点可能比病毒编码的靶点更不容易受到耐药性的影响。在R21阶段，我们建议使用一种新的无偏见的正向遗传方法来筛选对流感感染具有抵抗力的宿主基因。在R33阶段，我们将验证新的宿主靶点，并利用这些见解开发新的抗病毒治疗策略。我们的筛选方法是创新的，因为它允许识别当过度表达时授予抗性(限制因子)的宿主基因以及感染所需的宿主基因，这些基因通常在基于RNAi的传统筛查中被检测到。拟议的工作意义重大，因为它有可能确定新的靶点，包括非编码RNA元件，而使用现有方法将错过这些靶点。此外，我们的方法是对RFA做出反应，因为它旨在确定新的宿主靶点和治疗策略，以对抗甲型流感并克服对现有抗病毒药物的耐药性。