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（应用程序提供）：季节性流感的持续医疗保健烧伤，对现有治疗的菌株的出现以及新的大流行菌株的不断威胁凸显了迫切需要确定针对流感的新治疗靶标。我们实验室的长期目标是确定宿主防御感染的机制。该应用程序的目的是确定宿主编码的抗性感染机制。基于新兴数据和我们的初步研究，我们的中心假设是，防止病毒进入的宿主“限制因素”的上调限制了病毒在宿主细胞中感染或复制的能力，或提高CELS承受病毒诱导的细胞质病的能力，代表了宿主防御中的重要策略。我们对拟议工作的理由是，识别此类因素将提供大量的治疗干预措施，并且这些因素可能比病毒编码的靶标不容易受到抵抗的影响。在R21阶段，我们建议使用一种新型的无偏向前遗传学方法来筛选会导致对流感感染的抗性的宿主基因。在R33阶段，我们将验证新的宿主目标，并使用这些见解来制定新的抗病毒治疗策略。我们的筛选方法具有创新性，因为它允许识别两个宿主基因，这些基因在过表达的会议抗性（“限制因素”）以及感染所需的宿主基因时，通常在常规的基于RNAi的筛查中被检测到。拟议的工作很重要，因为它有可能识别新目标，包括非编码RNA元素，使用现有方法将错过。此外，我们的方法对RFA有反应，因为它旨在确定新的宿主目标和治疗策略来对抗流感，并克服对现有抗病毒药的抵抗力。