Cytokine Regulation of the Pulmonary Epithelium

肺上皮细胞因子的调节

• 批准号: 6860476
• 负责人: BRIGITTE N GOMPERTS
• 金额: $ 12.66万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6860476
• 关键词: apical membrane; biological signal transduction; clinical research; cytokine; cytoskeleton; gene expression; genetically modified animals; human tissue; immunoregulation; interleukin 13; interleukin 4; kinetosome; laboratory mouse; respiratory disorder; respiratory epithelium; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to train the principal investigator to become an independent physician-scientist. The principal investigator has completed fellowship training in pediatric hematology/oncology at Washington University and will now build on her initial laboratory experience through a structured program of didactic learning and scientific mentoring. Robert Strieter, a world-class authority on cytokines and lung biology; Enrique Rozengurt, a cell signaling expert; and Brian Hackett, an expert in the field of lung developmental biology, will mentor the scientific development of the principal investigator. In addition, an advisory committee of developmental biologists and pulmonologists will assist in providing research and career guidance. The Department of Pediatrics at UCLA, with its long track record of training physician-scientists, will provide an excellent, nurturing environment. The research proposal aims to identify the mechanisms regulating the loss of cilia and the breakdown of the apical cytoskeleton in certain pulmonary diseases. Various respiratory diseases such as asthma and RSV infection, which are characterized by increases in the cytokines IL-13 and IL-4, demonstrate loss of cilia with basal body mislocalization. The transcription factor, Foxj1, is essential for axoneme stability through its maintenance of basal body anchoring to the apical cytoskeleton. An absence of foxj1 results in an absence of cilia with mislocalization of basal bodies. The specific aims in this proposal are designed to elucidate the role of IL-13 and IL-4 in the regulation of foxj1 expression, as well as their role in regulating the apical cytoskeleton and cilia stability. The regulation of the foxj1 promoter by IL-13 and IL-4 through their signal transduction pathways and activation of STAT-6 will be examined by transfection of a lung cell line. Cultured, differentiated human airway epithelial cells will be treated with IL-13 and IL-4 to examine the effect on foxj1, cilia and the apical cytoskeleton. RSV infection in wild type and STAT-6-/- mice will be used as a model to examine regulation of foxj1, the apical cytoskeleton and the signal transduction pathways involved in abnormal mucociliary clearance in response to RSV infection.

描述（由申请人提供）： 该提议的长期目标是培训主要研究人员成为独立的医师科学家。 首席研究人员已完成华盛顿大学小儿血液学/肿瘤学的奖学金培训，现在将通过她的最初实验室经验来建立教学学习和科学指导的结构化计划。 罗伯特·斯特里特（Robert Strieter），世界一流的细胞因子和肺部生物学权威；细胞信号专家Enrique Rozengurt；肺发育生物学领域的专家布莱恩·哈克特（Brian Hackett）将指导主要研究者的科学发展。 此外，开发生物学家和肺科医生的咨询委员会将协助提供研究和职业指导。 加州大学洛杉矶分校（UCLA）的儿科系拥有培训医师科学家的悠久记录，将提供一个良好的培养环境。 研究建议旨在确定调节纤毛损失的机制和某些肺部疾病中顶端细胞骨架的分解。 各种呼吸道疾病（例如哮喘和RSV感染）的特征是细胞因子IL-13和IL-4的增加，表明纤毛的损失而基础体内错误定位。 转录因子FOXJ1通过维持将基底体锚定在顶端细胞骨架上，对于轴突稳定性至关重要。 缺乏FOXJ1导致缺乏纤毛，基础体的错误定位。 该提案中的具体目的旨在阐明IL-13和IL-4在FOXJ1表达调节中的作用，及其在调节顶端细胞骨架和纤毛稳定性中的作用。 IL-13和IL-4通过其信号转导途径和Stat-6的激活对FOXJ1启动子的调节将通过转染肺细胞系进行检查。 培养的，分化的人类气道上皮细胞将用IL-13和IL-4处理，以检查对FOXJ1，纤毛和顶端细胞骨架的影响。 野生型和Stat-6 - / - 小鼠中的RSV感染将用作检查FOXJ1，顶端细胞骨架的调节以及响应RSV感染异常的粘膜胶质清除率的调节。