ROLE OF MYB FOR AIRWAY EPITHELIAL CELL DIFFERENTIATION

MYB 在气道上皮细胞分化中的作用

• 批准号: 9268062
• 负责人: Steven Brody
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268062
• 关键词: Address; Adult; Affect; Asthma; Basal Cell; Candidate Disease Gene; Cell Differentiation process; Cells; Chromatin; Chronic; Chronic Obstructive Airway Disease; Data; Development; Disease; Distal; Elements; Epithelial; Epithelial Cells; Epithelium; Failure; Gene Expression; Health; Human; In Vitro; Individual; Injury; Lead; Link; Lung; Lung diseases; Maintenance; Metaplasia; Mitotic; Modeling; Molecular; Mus; Natural regeneration; One-Step dentin bonding system; Pathogenesis; Pathologic; Pathway interactions; Population; Process; Proliferating; Role; Secretory Cell; Stem cells; Symptoms; Validation; airway epithelium; base; cdc Genes; cell type; cilium biogenesis; genome-wide; in vivo; injured airway; injury and repair; lung development; lung injury; mouse model; notch protein; novel; progenitor; programs; public health relevance; reconstitution; remediation; repaired; restoration; self-renewal; stem; transcription factor; Address; Adult; Affect; Asthma; Basal Cell; Candidate Disease Gene; Cell Differentiation process; Cells; Chromatin; Chronic; Chronic Obstructive Airway Disease; Data; Development; Disease; Distal; Elements; Epithelial; Epithelial Cells; Epithelium; Failure; Gene Expression; Health; Human; In Vitro; Individual; Injury; Lead; Link; Lung; Lung diseases; Maintenance; Metaplasia; Mitotic; Modeling; Molecular; Mus; Natural regeneration; One-Step dentin bonding system; Pathogenesis; Pathologic; Pathway interactions; Population; Process; Proliferating; Role; Secretory Cell; Stem cells; Symptoms; Validation; airway epithelium; base; cdc Genes; cell type; cilium biogenesis; genome-wide; in vivo; injured airway; injury and repair; lung development; lung injury; mouse model; notch protein; novel; progenitor; programs; public health relevance; reconstitution; remediation; repaired; restoration; self-renewal; stem; transcription factor

 DESCRIPTION (provided by applicant): The pathways leading to airway epithelial cell differentiation and renewal are undergoing intense study as these programs are essential for repair following lung injury, and may be dysregulated leading to epithelial cell metaplasia in asthma and chronic obstructive airway disease. This project addresses the mechanism of normal restoration of the airway epithelium after injury. The current paradigm for airway epithelial cell regeneration is a one-step process, whereby regulatory factors direct a self-renewing P63+ progenitor cell to a differentiated type. In this project, we establish a new model based on our finding that the transcription factor Myb defines an essential intermediate stage in the progression from progenitor to specialized cell. Our findings suggest that the Myb+P63- cell is obligatory for the differentiation of a ciliated and secretory airway cell types. Myb is transietly expressed during lung development and in our primary-culture models, and is absent in the healthy adult lung. Myb is increased in our mouse models of lung injury and in airways of individuals with chronic obstructive lung disease. Depleting Myb in primary-culture of mouse and human airway epithelial cells abrogates differentiation. Accordingly, we generated mice with airway epithelial cell-specific deletion of Myb, and likewise found a failure to develop ciliated ad secretory cells. Genome-wide gene expression comparison between Myb deficient and sufficient cells identified programs for ciliated and secretory cell differentiation, and a reductin of Sox2 levels. Validation data demonstrated Sox2 was decreased in P63- airway epithelial cells, suggesting a Myb dependent requirement for Sox2. Together, these findings lead us to hypothesize that Myb regulates a program essential for the maintenance, repair and regeneration of differentiated airway epithelial cells. Using Myb targeted deficient mice and primary culture models, we propose to investigate (1) Myb-dependent cellular determinants for repair and regeneration using mouse injury models, and (2) identify Myb-dependent molecular programs for airway epithelial differentiation. The studies will establish a new model for understanding the pathogenesis of airways disease and define key elements as targets for reparative therapies.

 描述（由适用提供）：导致气道上皮细胞分化和更新的途径正在进行深入的研究，因为这些程序对于肺损伤后修复至关重要，并且可能导致哮喘和慢性阻塞性气道疾病导致上皮细胞上皮变质。该项目解决了受伤后气道上皮细胞正常恢复的机制。气道上皮细胞再生的当前范式是一个步骤，因此调节因素将自我更新的p63+祖细胞引导到差异化类型。在这个项目中，我们基于我们的发现，即转录因子MYB定义了从祖细胞到专用细胞的进展中的基本中间阶段。我们的发现表明，MYB+P63-细胞对分化纤毛和秘书的气道细胞类型是必不可少的。 MYB在肺部发育和我们的原发性培养模型中跨表达，并且在健康的成年肺中不存在。 MYB在我们的肺损伤的小鼠模型和慢性阻塞性肺部病人的气道中增加了。在小鼠和人类气道上皮细胞的初级文化中耗尽MYB会促成分化。根据，我们用MYB的气道上皮细胞特异性缺失产生了小鼠，并且同样发现未能发展出纤毛的AD秘书细胞。 MYB缺陷和足够细胞之间的全基因组基因表达比较确定了用于纤毛和秘书细胞分化的程序，并降低了SOX2水平。验证数据证明了SOX2在P63-气道上皮细胞中得到了改善，这表明对SOX2的MYB依赖性要求。总之，这些发现使我们假设MYB调节了一个对分化气道上皮细胞维持，修复和再生必不可少的程序。使用MYB靶向的缺乏小鼠和原发性培养模型，我们建议研究（1）使用小鼠损伤模型修复和再生Myb依赖性细胞确定剂，以及（2）确定用于气道上皮分化的MYB依赖性分子程序。这些研究将建立一个新的模型，以理解气道疾病的发病机理，并将关键因素定义为修复疗法的靶标。