REGULATION OF THE CILIATED CELL PROGRAM IN AIRWAY PROGENITORS

气道祖细胞中纤毛细胞程序的调节

• 批准号: 8710697
• 负责人: Wellington V. Cardoso
• 金额: $ 42.07万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710697
• 关键词: Address; Adult; Appearance; Asthma; Bardet Biedel syndrome; Biology; Bronchial Tree; Cell Differentiation process; Cell Fate Control; Cells; Chronic; Chronic Obstructive Airway Disease; Cilia; Cystic Fibrosis; Development; Differentiation and Growth; Disease; Distal; Epithelial; Epithelial Cells; Equilibrium; Event; Fostering; Gene Expression Profile; Genes; Genetic Models; Goals; Growth Factor Receptors; Homeostasis; Ion Transport; Lead; Learning; Length; Life; Lung; Lung diseases; Mediating; Molecular; Morphology; Mucociliary Clearance; Mus; Organ; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Play; Primary Ciliary Dyskinesias; Process; Proteins; Regulation; Regulator Genes; Reporting; Respiratory System; Respiratory tract structure; Role; Secretory Cell; Signal Transduction; Site; Specific qualifier value; Structure of respiratory epithelium; System; Water; airway epithelium; biological systems; cell growth; ciliopathy; cilium biogenesis; environmental agent; gain of function; immunoregulation; in vivo; insight; loss of function; lung development; mutant; notch protein; postnatal; progenitor; programs; public health relevance; regional difference; response to injury; therapeutic target

DESCRIPTION (provided by applicant): The goal of this project is to investigate mechanisms responsible for the emergence and diversification of airway epithelial cells in the respiratory system. Multiciliated cells are a crucial component of the airway epithelium, being responsible for ciliary transport in concert with water and ion transport for optimization of airway clearance, in addition to being unique sites for expression of drug transporters and growth factor receptors. Altered number, morphology or function of ciliated cells is associated with a variety of diseases, including asthma, chronic obstructive pulmonary disease (COPD) and ciliopathies, such as primary ciliary dyskinesia (PCD). Our preliminary studies implicate Notch as a critical signal for ciliated versus secretory cell fate selection during development; moreover, E2F4 has been shown to be essential to form multiciliated cells in the respiratory epithelium. Recently the Hippo-YAP pathway has emerged as a major regulator of cell growth and differentiation, being also implicated in ciliogenesis. Nevertheless, how Notch, E2F4 and Hippo-YAP influence the molecular and cellular events associated with differentiation of the airway epithelium and how multiciliated cells become distinct regionally or in response to injury, is unclear. We propose to address these questions using gain and loss function genetic models and a well-established primary airway epithelial culture system. Thus, in this project we propose to: 1) Investigate the cellular and molecular events associated with initiation of ciliated cell fate in the developing airways, looking at the role of E2F4 and Notch signaling ; 2) Study the role of Hippo-YAP in ciliogenesis by manipulating YAP expression or phosphorylation in vivo and in primary airway epithelial cultures; 3) Study mechanisms that modulate the ciliated cell phenotype in airway progenitors of the developing lung, focusing on the Notch pathway.

描述（由申请人提供）：该项目的目标是研究呼吸系统中气道上皮细胞出现和多样化的机制。多纤毛细胞是气道上皮的重要组成部分，负责纤毛运输与水和离子运输，以优化气道清除。