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: 7779440
• 负责人: CURT M HORVATH
• 金额: $ 74.92万
• 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/7779440
• 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; 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，人类肺细胞中先天抗病毒药反应的调节机制和特定介体。一般来说，关于先天免疫系统的细胞病毒检测以及伴随细胞和全身反应的诱导基因表达事件的众所周知。但是，单个宿主可以以病毒特异性或细胞特异性方式证明对感染的抗性变异性。这些差异反应是许多因素的结果，包括在主要感染部位的基因表达的可变转录反应或转录后调节。该应用旨在通过基础研究和临床方法阐明新的范例，以阐明对流感病毒感染的先天细胞反应。一个具体的目的将研究以下假设：转录后基因调节在流感感染过程中调节规范抗病毒基因表达程序，并将通过检查其在感染肺细胞系中的生物发生和活性来解读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：流感病毒感染的主要部位气道粘膜中的差异基因表达与人类流感的临床表现的严重程度有关。在急性期和人流感感染的康复中，将分析气道粘膜样品的转录组，以鉴定与严重流感感染相关的新型基因表达模式和途径。此外，比较患有严重流行性流感的人与经历温和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有关的新型基因表达模式和途径。这些目标共同阐明了新的基本先天免疫机制，对抗病毒反应提供了更复杂的理解，以及潜在的抗病毒治疗靶标。