Cytokine Regulation of the Pulmonary Epithelium

肺上皮细胞因子的调节

• 批准号: 7154784
• 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/7154784
• 关键词: Advisory Committees; Apical; Asthma; Biology; Cell Line; Cells; Cilia; Class; Cytoskeleton; Development; Developmental Biology; Environment; Epithelial; Epithelial Cells; Epithelium; Fellowship; Human; Infection; Interleukin-13; Interleukin-4; Laboratories; Learning; Lung; Lung diseases; Maintenance; Mentors; Modeling; Mucociliary Clearance; Mus; Pediatric Hematology/Oncology; Physicians; Principal Investigator; Regulation; Reporter; Research; Research Personnel; Research Proposals; Role; Scientist; Signal Transduction; Signal Transduction Pathway; Structure; Testing; Therapeutic; Tissues; Training; Transfection; Universities; Washington; authority; career; cytokine; design; experience; expression vector; kinetosome; pediatric department; programs; promoter; respiratory; response; 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)： 这项提议的长期目标是培训首席研究员成为一名独立的内科科学家。这位首席研究员已经在华盛顿大学完成了儿科血液学/肿瘤学方面的奖学金培训，现在将通过有组织的教学学习和科学指导计划，以她最初的实验室经验为基础。 世界一流的细胞因子和肺部生物学权威Robert Strieter、细胞信号专家Enrique Rozengurt和肺部发育生物学领域的专家Brian Hackett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儿科拥有长期培养内科科学家的记录，将提供一个极好的培养环境。该研究计划旨在确定某些肺部疾病中纤毛丢失和顶端细胞骨架崩溃的调节机制。各种呼吸道疾病，如哮喘和呼吸道合胞病毒感染，以细胞因子IL-13和IL-4增加为特征，表现为纤毛丢失，基底错位。转录因子Foxj1通过维持与顶端细胞骨架连接的基底体，对轴丝的稳定性起着至关重要的作用。缺少foxj1会导致纤毛缺失和基底体定位错误。本研究旨在阐明IL-13和IL-4在foxj1基因表达调控中的作用，以及它们在调节顶端细胞骨架和纤毛稳定性中的作用。IL-13和IL-4通过其信号转导通路对foxj1启动子的调控以及STAT-6的激活将通过肺细胞系的转染来检测。培养的、分化的人呼吸道上皮细胞将被IL-13和IL-4处理，以检测对FOXJ1、纤毛和顶端细胞骨架的影响。在野生型和STAT-6-/-小鼠中的RSV感染将作为一个模型来研究foxj1的调节，顶端细胞骨架和参与RSV感染的异常纤毛清除的信号转导通路。