New Paradigms in Gene Regulation During Influenza Virus Infections

流感病毒感染期间基因调控的新范式

• 批准号: 8064308
• 负责人: CURT M HORVATH
• 金额: $ 72.67万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064308
• 关键词: Acute; Affect; Antiviral Agents; Antiviral Response; Antiviral Therapy; Award; Basic Science; Biogenesis; Cell Culture Techniques; Cell Line; Cells; Clinical; Convalescence; Disease; Epithelial Cells; Event; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Goals; Human; Human Genome; Immune; Immune response; Immune system; Individual; Infection; Influenza; Influenza Virus Infected Cells; Interferons; Lung; Mediator of activation protein; Messenger RNA; Methods; MicroRNAs; Mucous Membrane; National Institute of Allergy and Infectious Disease; Pathway interactions; Patients; Pattern; Phase; Post-Transcriptional Regulation; Predisposition; Proteins; Recording of previous events; Research; Resistance to infection; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Severities; Signal Transduction; Site; Susceptibility Gene; Testing; Tissue-Specific Gene Expression; Virus; Virus Diseases; Work; cytokine; design; drug development; experience; genome-wide; influenzavirus; novel; programs; response; therapeutic vaccine; viral detection

DESCRIPTION (provided by applicant): The long term objective for this project is to understand the regulatory mechanisms and specific mediators of innate antiviral responses in human lung cells following influenza virus infections. Much is known in general about cellular virus detection by the innate immune system and the inducible gene expression events that accompany the acquisition of cellular and systemic responses. However, individual hosts can demonstrate variability in resistance to infection in a virus-specific or cell-specific fashion. These differential responses are the result of many factors including variable transcriptional responses or post- transcriptional regulation of gene expression at the primary site of infection. This application is designed to elucidate new paradigms for innate cellular responses to influenza virus infection with both basic research and clinical approaches. One specific aim will examine the hypothesis that post-transcriptional gene regulation modulates canonical antiviral gene expression programs during influenza infections, and will decipher the roles of cytokine- and virus-induced microRNAs by examining their biogenesis and activity in infected lung cell lines. A second aim will test the hypothesis that differential gene expression in the airway mucosa, the main site of influenza virus infection, relates to severity of clinical presentation of human influenza. Transcriptomes of airway mucosal samples will be analyzed during acute phase and convalescence of human influenza infections to identify novel gene expression patterns and pathways related to severe influenza infections. In addition, comparison of airway mucosal transcriptomes between those predisposed to severe influenza and those who experienced milder disease will identify novel gene expression patterns and pathways related to susceptibility to influenza infections. Together these aims will elucidate new fundamental innate immune mechanisms, provide a more sophisticated understanding of the antiviral response, and potential new targets for antiviral therapy.

描述（由申请人提供）：该项目的长期目标是了解流感病毒感染后人类肺细胞先天抗病毒反应的调节机制和特定介质。关于先天免疫系统检测细胞病毒以及伴随细胞和全身反应获得的诱导基因表达事件，人们普遍了解很多。然而，个体宿主可以以病毒特异性或细胞特异性的方式表现出对感染的抵抗力的变异性。这些差异反应是许多因素造成的，包括可变的转录反应或原发感染位点基因表达的转录后调控。该应用旨在通过基础研究和临床方法阐明流感病毒感染的先天细胞反应的新范例。一个具体目标是检验转录后基因调控在流感感染期间调节经典抗病毒基因表达程序的假设，并通过检查受感染肺细胞系中的生物发生和活性来破译细胞因子和病毒诱导的 microRNA 的作用。第二个目标将检验以下假设：气道粘膜（流感病毒感染的主要部位）中的差异基因表达与人类流感临床表现的严重程度有关。将在人类流感感染的急性期和恢复期对气道粘膜样本的转录组进行分析，以确定与严重流感感染相关的新基因表达模式和途径。此外，比较易患严重流感的人和患有较轻疾病的人之间的气道粘膜转录组，将确定与流感感染易感性相关的新基因表达模式和途径。这些目标将共同阐明新的基本先天免疫机制，提供对抗病毒反应的更复杂的理解，以及抗病毒治疗的潜在新靶点。