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

描述(申请人提供)：我的博士培训是关于病毒发病机制和病毒疾病的小鼠模型。我研究的主要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。在我的博士后工作期间，我在范德比尔特医学博士斯托克斯·皮布尔斯的实验室研究呼吸道合胞病毒(RSV)的发病机制。我的教育、培训和生产力都得到了一位具有深厚基础科学和临床背景以及部门和机构环境的导师的帮助。我的近期目标是实现这项提案的目标，并在一家生物医学研究机构获得一个助理教授的职位。我们报道，感染RSV 19株而不是A2株的小鼠会导致粘液产生，肺组织IL 13表达，以及呼吸道功能障碍。因此，19株RSV是研究RSV诱导的粘液/呼吸道功能障碍的模型。我们对19系基因组进行了测序，并确定了RSV粘液诱导基因的候选基因。目标1将利用RSV反向遗传学来定位19系基因组的区域，该区域足以引起感染诱导的粘液/呼吸道功能障碍。我们发现，不同的RSV临床分离株在小鼠中诱导不同的致病机制。与A2、19系和A/2001/312株相比，RSV A/2001/220株诱导小鼠肺IL-13和呼吸道粘液的表达增加，疾病严重程度和组织病理学改变也更严重。目的2利用呼吸道合胞病毒反向遗传学定位A/2001/2-20株(S)的致病性强于A/2001/312株的致病性。AIM 2还将确定IL 13和STAT6在A/2001/2-20致病机制中的作用。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了解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员，并为RSV疾病的治疗和/或疫苗提供对RSV发病机制的见解。我的研究将重点放在病毒免疫学和肺部发病机制上。我的长期研究目标是阐明RSV导致粘液产生/呼吸道功能障碍的机制，并确定RSV基因多样性如何影响RSV的免疫致病机制。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：呼吸道合胞病毒每年导致美国10万名婴儿住院，是导致婴儿毛细支气管炎和病毒性肺炎的主要原因。黏液产生是呼吸道合胞病毒病的一个显著特征，导致呼吸道阻塞、缺氧和机械通气。呼吸道合胞病毒诱导的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.