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

基本信息

批准号：
7530495
负责人：
Martin Lawrence Moore
金额：
$ 15.69万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/7530495
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

项目摘要

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。训练是在病毒疾病的病毒发病机理和小鼠模型中。我的研究的主要主题是利用小鼠模型和病毒遗传学来研究体内病毒发病机理。在我的博士后奖学金中，我正在研究范德比尔特（Vanderbilt）Stokes Peebles的实验室中的呼吸道合胞病毒（RSV）发病机理。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提高了我的教育，培训和生产力。我的直接目标是以该提案的目的进步，并在生物医学研究机构获得助理教授职位。我们报告说，RSV系19菌株的小鼠感染，但没有A2菌株导致粘液产生，肺IL 13表达和气道功能障碍。因此，RSV的线19株是研究RSV诱导的粘液/气道功能障碍的模型。我们对第19行的基因组进行了测序，并鉴定了诱导RSV粘液的基因候选物。 AIM 1将利用RSV反向遗传学来映射足以感染诱导的粘液/气道功能障碍的第19行基因组区域。我们发现不同的临床分离株RSV菌株会引起小鼠的差异发病机理。 RSV A/2001/2 20菌株比A2，19行和A/2001/3 12菌株诱导更高的肺IL 13和气道粘液表达，以及小鼠的疾病严重程度和组织病理学更大。 AIM 2将利用RSV反向遗传学来绘制A/2001/2-20的基因，与A/2001/3 12（一种共同循环的RSV菌株）相比，足以升高致病性。 AIM 2还将定义IL 13和STAT6在A/2001/2-20发病机理中的作用。定义机制和RSV菌株特异性发病机理的分子基础将提高我们对RSV后遗症的理解。我的长期目标是成为病毒发病机理领域的生产性独立研究者，并提供对RSV发病机理的见解，将RSV疾病转化为疗法和/或疫苗。我的研究将强调病毒免疫学和肺病的机制。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，并定义RSV基因型多样性如何影响RSV免疫发病。未来的方向部分描述了这里的特定目标将如何导致对我的长期目标的假设。相关性：RSV每年在美国导致> 100,000个婴儿住院，这是婴儿造成婴儿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诱导的粘液的机制尚不清楚，这是该提案的重点。阐明这些机制将确定疗法的靶标。