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

描述（申请人提供）：我的博士学位是在病毒发病机制和病毒性疾病的小鼠模型。我的主要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发病机制。在我的博士后研究期间，我在范德比尔特大学医学博士Stokes Peebles的实验室研究呼吸道合胞病毒（RSV）的发病机制。我的教育、培训和工作效率都得到了具有强大基础科学和临床背景的导师以及部门和机构环境的提高。我的近期目标是实现本提案的目标，并在生物医学研究机构获得助理教授的职位。我们报道了RSV 19株感染小鼠，而不是A2株感染小鼠，导致粘液产生、肺IL - 13表达和气道功能障碍。因此，19系RSV毒株是研究RSV诱导的粘液/气道功能障碍的模型。我们对19号系基因组进行测序，并鉴定出RSV诱导黏液的候选基因。目的1将利用RSV反向遗传学绘制足以引起感染诱导的粘液/气道功能障碍的19系基因组区域。我们发现不同的RSV临床分离株在小鼠中诱导不同的发病机制。与A2、line 19和A/2001/3 12菌株相比，RSV A/2001/2 20菌株在小鼠中诱导更高的肺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。目标2将利用RSV反向遗传学来绘制A/2001/2-20与A/2001/3 12（一种共循环RSV毒株）相比足以提高致病性的基因图谱。Aim 2还将确定IL 13和STAT6在A/2001/2-20发病机制中的作用。明确RSV毒株特异性发病机制和分子基础，将提高我们对RSV后遗症的认识。我的长期目标是在病毒发病机制领域成为一名富有成效的独立研究者，并为RSV发病机制提供见解，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对我的长期目标的假设。相关性：RSV在美国每年导致100万婴儿住院治疗，并且是婴儿毛细支气管炎和病毒性肺炎的主要原因。粘液产生是RSV疾病的一个显著特征，可导致气道阻塞、缺氧和机械通气。rsv诱导粘液的机制尚不清楚，这是本研究的重点。阐明这些机制将确定治疗的靶点。

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.