Mechanisms of Respiratory Syncytial Virus-Induced Mucus" Viral Strain Dependence

呼吸道合胞病毒诱导粘液的病毒株依赖性机制

• 批准号: 7772293
• 负责人: Martin Lawrence Moore
• 金额: $ 10.72万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-20 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772293
• 关键词: Affect; Air; BALB/cJ Mouse; Basic Science; Biomedical Research; Bronchiolitis; CD8B1 gene; Candidate Disease Gene; Cells; Chromosome Mapping; Clinic; Clinical; Comparative Study; Data; Dependence; Disease; Doctor of Philosophy; Environment; Fellowship; Fibrin; Functional disorder; Future; Genes; Genetic; Genome; Genotype; Goals; Histopathology; Hospitalization; Hypoxia; Immunologics; Immunology; Inbred BALB C Mice; Infant; Infection; Institution; Interleukin-13; Laboratories; Lead; Lung; Maps; Mechanical ventilation; Mediator of activation protein; Mentors; Modeling; Molecular; Mucous body substance; Mus; Nucleotide Mapping; Nucleotides; Obstruction; PTPN11 gene; Pathogenesis; Pathogenicity; Positioning Attribute; Production; Productivity; Reporting; Research; Research Personnel; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Role; STAT6 gene; Severity of illness; Site-Directed Mutagenesis; System; T-Lymphocyte; Testing; Training; Training and Education; Translating; Vaccines; Viral; Viral Pathogenesis; Viral Pneumonia; Virulence; Virus Diseases; airway hyperresponsiveness; airway obstruction; base; cell type; constriction; cytokine; improved; in vivo; insight; mouse model; novel; positional cloning; professor; programs; respiratory; virus genetics; virus pathogenesis

DESCRIPTION (provided by applicant): My Ph.D. training is in viral pathogenesis and mouse models of viral disease. The major theme of my research is utilizing mouse models and viral genetics to study viral pathogenesis in vivo. In my postdoctoral fellowship, I am investigating respiratory syncytial virus (RSV) pathogenesis in the laboratory of Stokes Peebles, MD at Vanderbilt. My education, training, and productivity are enhanced by a mentor with strong basic science and clinical backgrounds as well as the departmental and institutional environments. My immediate goals are to progress with the Aims of this proposal and obtain an assistant professor position at a biomedical research institution. We reported that infection of mice with the RSV line 19 strain, but not the A2 strain resulted in mucus production, lung IL 13 expression, and airway dysfunction. Thus, the line 19 strain of RSV is a model for investigating RSV-induced mucus/airway dysfunction. We sequenced the line 19 genome and identified RSV mucus-inducing gene candidates. Aim 1 will utilize RSV reverse genetics to map the region of the line 19 genome sufficient for infection-induced mucus/airway dysfunction. We found that distinct clinical isolate RSV strains induce differential pathogenesis in mice. RSV A/2001/2 20 strain induces higher lung IL 13 and airway mucus expression, as well as greater disease severity and histopathology in mice than the A2, line 19, and A/2001/3 12 strains. Aim 2 will utilize RSV reverse genetics to map the gene(s) of A/2001/2-20 sufficient for elevated pathogenicity compared to the A/2001/3 12, a co-circulating RSV strain. Aim 2 will also define the roles of IL 13 and STAT6 in A/2001/2-20 pathogenesis. Defining mechanisms and the molecular basis of RSV strain-specific pathogenesis will improve our understanding of the sequelae of RSV. My long-term objectives are to be a productive, independent investigator in the field of viral pathogenesis and provide insights into RSV pathogenesis that translate into therapies and/or vaccines for RSV disease. My research will emphasize viral immunology and mechanisms of pulmonary pathogenesis. My long-term research goals are to elucidate mechanisms by which RSV causes mucus production/airway dysfunction and define how RSV genotype diversity affects RSV immunopathogenesis. The Future Directions section describes how the Specific Aims here will lead to hypotheses towards my long-term goals. Relevance: RSV causes >100,000 infant hospitalizations in the US each year and is the leading cause of bronchiolitis and viral pneumonia in infants. Mucus production is a hallmark feature of RSV disease, leading to airway obstruction, hypoxia, and mechanical ventilation. Mechanisms of RSV-induced mucus are unknown and the focus of this proposal. Elucidation of these mechanisms will identify targets for therapies.

描述（由申请人提供）：我的博士学位。培训是在病毒发病机理和病毒疾病的小鼠模型。我的研究主题是利用小鼠模型和病毒遗传学来研究病毒在体内的致病机制。在我的博士后研究中，我在范德比尔特的Stokes皮布尔斯博士的实验室研究呼吸道合胞病毒（RSV）的发病机制。我的教育，培训和生产力得到了具有强大的基础科学和临床背景以及部门和机构环境的导师的提高。我的近期目标是与此建议的目标取得进展，并获得在生物医学研究机构的助理教授职位。我们报道了用RSV 19株系而不是A2株系感染小鼠导致粘液产生、肺IL 13表达和气道功能障碍。因此，19系RSV株是研究RSV诱导的粘液/气道功能障碍的模型。我们对19系基因组进行测序，并鉴定了RSV粘液诱导基因候选物。目的1将利用RSV反向遗传学来绘制足以引起感染诱导的粘液/气道功能障碍的19号系基因组区域。我们发现，不同的临床分离RSV株诱导小鼠不同的发病机制。RSV A/2001/2 20毒株在小鼠中诱导比A2、line 19和A/2001/3 12毒株更高的肺IL 13和气道粘液表达，以及更大的疾病严重程度和组织病理学。目的2将利用RSV反向遗传学来定位A/2001/2-20的基因，与A/2001/312（一种共循环RSV毒株）相比，该基因足以提高致病性。目的2还将明确IL 13和STAT 6在A/2001/2-20发病机制中的作用。明确RSV株特异性致病机制和分子基础将有助于我们更好地理解RSV的后遗症。我的长期目标是成为病毒发病机制领域的一名富有成效的独立研究者，并提供对RSV发病机制的见解，这些发病机制可转化为RSV疾病的治疗和/或疫苗。我的研究将侧重于病毒免疫学和肺部发病机制。我的长期研究目标是阐明RSV引起粘液产生/气道功能障碍的机制，并确定RSV基因型多样性如何影响RSV免疫发病机制。未来方向部分描述了这里的具体目标将如何导致我对长期目标的假设。相关性：RSV每年在美国导致> 100，000名婴儿住院，是婴儿细支气管炎和病毒性肺炎的主要原因。粘液产生是RSV疾病的标志性特征，导致气道阻塞、缺氧和机械通气。RSV诱导粘液的机制尚不清楚，也是本提案的重点。阐明这些机制将确定治疗的目标。