Intrinsic and innate barriers to respiratory virus infections

呼吸道病毒感染的内在和先天障碍

基本信息

批准号：
9415534
负责人：
Meike Dittmann
金额：
$ 24.9万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9415534
关键词：
A549 Adenoviruses Adopted Advisory Committees Antiviral Agents Antiviral Therapy Antiviral resistance Award Basic Science Bioinformatics Biological Assay Biological Models CRISPR/Cas technology Cells Child Communities Coronaviridae Coronavirus Counseling DNA Viruses Data Set Development Plans Drug Design Drug Targeting Ectopic Expression Elderly Environment Epithelial Ethics Family Family Picornaviridae Fibrinogen Future Gene Library Gene Targeting Genes Genetic Engineering Genetic Transcription Goals Grant Health Human Human Metapneumovirus Individual Influenza Influenza A virus Influenza B Virus Innate Immune System Integration Host Factors Interferons Intervention Laboratories Lead Learning Libraries Life Cycle Stages Lung Maps Mediating Membrane Glycoproteins Mentors Methodology Methods Modeling Para-Influenza Virus Type 3 Paramyxoviridae Paramyxovirus Pathway interactions Peptide Hydrolases Phase Physiological Plasminogen Activator Inhibitor 1 Positioning Attribute Process Property Protocols documentation RNA Viruses Research Research Personnel Resources Respiratory syncytial virus Rhinovirus Rice Role SARS coronavirus SERPINE1 gene Serpins Shapes Signal Transduction Stem cells Structure System Techniques Technology Training Translations Universities Vaccines Viral Virus Virus Diseases Virus Replication Writing airway epithelium base career career development comparative embryonic stem cell experience experimental study extracellular follow-up genome editing inhibitor/antagonist innovation insight medical schools member mortality new technology next generation novel novel strategies programs public health relevance respiratory infection virus respiratory virus screening skills success tissue culture tool transcription factor transcriptome transcriptome sequencing viperin virology

项目摘要

DESCRIPTION (provided by applicant): The primary research goal of this Pathway to Independence proposal is to dissect and characterize intrinsic and innate barriers to respiratory virus infections. Although respiratory viruses pose a major health burden, there is a paucity of effective, available antiviral strategies. Understanding the mechanisms by which individual host factors inhibit these viral infections may lead to new antiviral strategies. The recent discovery o several interferon-stimulated genes (ISGs) that inhibit viruses at late stages of their infectious cycles (viperin - budding; tetherin - detachment; plasminogen activator inhibitor 1 - maturation) validated such stages as attractive antiviral targets. In the mentored phase of this K99 award, the candidate will be trained in next-generation transcriptome profiling and bioinformatics to identify the late-acting antiviral program raised by ELF1, an ISG and transcription factor conferring broad antiviral resistance. In addition, based on her previous identification of late-acting inhibitors of influenza A virus, she will screen for antiviral ISG activity against a panel f other respiratory viruses, consisting of influenza B virus, human parainfluenzavirus, respiratory syncytial virus, human metapneumovirus, human rhinovirus and human adenovirus. Finally, the candidate will receive training on CRISPR/Cas9-mediated genome editing of embryonic stem cells (ESCs), and establish protocols to differentiate polarized human airway epithelium cultures from lung progenitor cells. These cultures will serve to validate findings from conventional tissue culture in a more physiologically relevant model system. Additional components of the candidate's comprehensive career development plan are courses and seminars in ethics and grant writing. The training phase will be carried out in the laboratory of Dr. Charles Rice at The Rockefeller University (RU), one of the world's leading laboratories in virology research. In addition to the significant resources and basic science expertise in this lab, the candidate will also benefit from RU's vibrant research community. A critical component of career development will be the close counsel of a highly experienced Advisory Committee, composed of Dr. Charles Rice, Dr. Jean-Laurent Casanova (both RU), and Dr. Adolfo Garcia-Sastre (Mt Sinai School of Medicine). The innovative skills and meaningful data sets obtained in the K99 training phase will set the stage for detailed mechanistic studies on ELF1 and other selected hits in the independent phase, and will be key to succeed as a young independent investigator in this highly competitive field of research. In all, the training will fulfill both the candidate's short-erm goals of adding new technologies, skills, and experience to her portfolio, and her long-term goals, to become an independent investigator with a research focus on the virus-host interplay in the context of the innate immune system.

描述（由适用提供）：独立建议途径的主要研究目标是剖析和表征呼吸病毒感染的内在和先天障碍。尽管呼吸道病毒构成了重要的健康伯恩，但有效的可用抗病毒药策略很少。了解各个宿主因素抑制这些病毒感染的机制可能导致新的抗病毒药策略。最近发现的几个干扰素刺激的基因（ISGS）在其感染周期的后期抑制病毒（viperin -upding; tetherin-脱离；纤溶酶原激活物抑制剂1-成熟）验证了这样的阶段，以验证像有吸引力的抗病毒靶标。在该K99奖的修订阶段，候选人将接受下一代转录组分析和生物信息学的培训，以识别ELF1提出的晚期抗病毒计划，ELF1（ISG和转录因子）赋予了广泛的抗病毒药性。 In addition, based on her previous identification of late-acting inhibitors of influencers of influenceza A virus, she will screen for antiviral ISG activity against a panel f other respiratory viruses, consisting of influenceza B virus, human parainfluenzavirus, respiratory syncytial virus, human metapneumovirus, human rhinovirus and human adenovirus.最后，候选人将接受有关胚胎干细胞（ESC）CRISPR/CAS9介导的基因组编辑的培训，并建立方案以区分极化的人类气道上皮培养物与肺祖细胞。这些培养物将用于验证传统组织的发现在更相关的模型系统中文化。候选人综合职业发展计划的其他组成部分是道德和授予写作的课程和半少数。训练阶段将在洛克菲勒大学（RU）的查尔斯·赖斯博士的实验室中进行，这是世界上领先的病毒学研究实验室之一。除了本实验室中的重要资源和基础科学专业知识外，候选人还将受益于RU充满活力的研究社区。职业发展的一个关键组成部分将是经验丰富的咨询委员会的密切建议，由查尔斯·赖斯（Charles Rice）博士，Jean-Laurent Casanova博士（RU）和Adolfo Garcia-Sastre博士（Sinai Mt Sinai医学院）组成。在K99培训阶段获得的创新技能和有意义的数据集将为ELF1和其他人在独立阶段进行详细的机械研究奠定阶段，并将在这一竞争激烈的研究领域中成为年轻的独立研究者成功的关键。总的来说，培训将实现候选人的短暂目标，即在她的投资组合中添加新技术，技能和经验以及她的长期目标，以成为一名独立的研究者，并在先天免疫系统的背景下进行了研究的重点。