Regulation of Respiratory Epithelial Cell Homeostasis

描述(由申请人提供)： 急性和慢性呼吸道损伤和炎症导致呼吸道重塑和空域异常，从而导致儿童和成人肺部疾病的发病机制。介导气道重塑、纤维化和肺气肿的细胞和分子过程仍然知之甚少，但有助于常见肺部疾病的发病机制，包括COPD、CF、哮喘、BPD、肺纤维化和肺气肿。目前项目拨款的基本假设是，呼吸道上皮细胞动态平衡的破坏会导致气道功能和肺泡动态平衡的改变，进而导致许多慢性肺部疾病常见的气道重塑和肺气肿。提出了四个项目，以确定和表征目标/修饰基因和转录程序，这些基因和转录程序调节呼吸道上皮细胞的稳态机制(分化和细胞保护反应)。项目1将探索ERAD(内质网相关降解)相关转录在保护呼吸道上皮细胞免受SP-C突变引起的固有肺损伤中的作用，这些突变导致蛋白质错误折叠。项目2将确定与II型上皮细胞中SP-C缺乏相关的调节间质性肺疾病严重程度的基因。项目3将评估STAT-3保护上皮细胞免受高氧引起的外源性肺损伤的能力。项目4将研究上皮细胞转录因子FOXA1和FOXA2在调节出生后肺上皮细胞分化和肺泡化中的作用。这四个项目将得到两个核心的支持，这两个核心促进目标基因识别(微阵列/生物信息学核心)和转基因和基因靶标小鼠的形态分析(形态核心)。预计这一PPG将导致新的转录程序和信号通路的识别，这些程序和信号通路可能会显著影响我们对肺部疾病的理解，以及这些疾病治疗的新治疗目标。

DESCRIPTION (provided by applicant): Acute and chronic airway injury and inflammation cause airway remodeling and airspace abnormalities that contribute to the pathogenesis of pulmonary disease in children and adults. Cellular and molecular processes mediating airway remodeling, fibrosis and emphysema remain poorly understood, but contribute to the pathogenesis of common lung disorders, including COPD, CF, asthma, BPD, pulmonary fibrosis, and emphysema. The hypothesis underlying the current program project grant is that disruption of respiratory epithelial cell homeostasis leads to altered airway function and alveolar homeostasis which, in turn, contributes to airway remodeling and emphysema common to many chronic lung diseases. Four projects are proposed to identify and characterize target/modifier genes and transcriptional programs that regulate homeostatic mechanisms (differentiation and cytoprotective responses) of respiratory epithelial cells. Project 1 will explore the role of ERAD (ER associated degradation) associated transcription in protecting the respiratory epithelium against intrinsic lung injury arising from SP-C mutations that cause protein misfolding. Project 2 will identify genes that modulate the severity of interstitial lung disease associated with deficiency of SP-C in type II epithelial cells. Project 3 will assess the ability of STAT-3 to protect the epithelium against extrinsic lung injury caused by hyperoxia. Project 4 will examine the role of the epithelial cell transcription factors Foxa1 and Foxa2 in regulating epithelial cell differentiation and alveolarization in the postnatal lung. These four projects will be supported by two cores that facilitate target gene identification (Microarray/Bioinformatics Core) and morphologic analyses of transgenic and gene targeted mice (Morphology Core). It is anticipated that this PPG will lead to identification of new transcriptional programs and signal pathways that may significantly impact our understanding of lung disease and new therapeutic targets for the treatment of these diseases.