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）： 该提案的长期目标是培训主要研究者成为独立的医生-科学家。 主要研究者已经在华盛顿大学完成了儿科血液学/肿瘤学的奖学金培训，现在将通过教学学习和科学指导的结构化计划来建立她的初步实验室经验。 Robert Strieter，细胞因子和肺生物学的世界级权威; Enrique Rozengurt，细胞信号专家;和Brian Hackett，肺发育生物学领域的专家，将指导首席研究员的科学发展。 此外，一个由发育生物学家和肺病学家组成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的儿科部门，以其长期的培训医生科学家的记录，将提供一个良好的，培育环境。 该研究计划旨在确定在某些肺部疾病中调节纤毛损失和顶端细胞骨架破坏的机制。 以细胞因子IL-13和IL-4增加为特征的各种呼吸道疾病，如哮喘和RSV感染，表现出纤毛丧失伴基体错误定位。 转录因子Foxj 1通过维持基底体锚定到顶端细胞骨架而对轴丝稳定性至关重要。 foxj 1的缺失导致纤毛的缺失和基体的错误定位。 在这个建议的具体目标是旨在阐明IL-13和IL-4在调节foxj 1表达的作用，以及它们在调节顶端细胞骨架和纤毛稳定性的作用。 将通过转染肺细胞系来检查IL-13和IL-4通过其信号转导途径对foxj 1启动子的调节以及STAT-6的激活。 将用IL-13和IL-4处理培养的分化的人气道上皮细胞，以检查对foxj 1、纤毛和顶端细胞骨架的影响。 野生型和STAT-6-/-小鼠中的RSV感染将用作模型，以检查响应RSV感染的异常粘膜纤毛清除中涉及的foxj 1、顶端细胞骨架和信号转导途径的调节。