Basis of Airway Epithelial Cell Survival

气道上皮细胞存活的基础

基本信息

批准号：
7510813
负责人：
Michael J Holtzman
金额：
$ 36.79万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7510813
关键词：
Acute Address Amphiregulin Apoptosis Appendix Behavior Biological Markers Biological Models Breathing Bronchiolitis Cell Communication Cell Death Cell Line Cell Survival Cells Collagen Condition Disease Epidermal Growth Factor Receptor Epithelial Epithelial Cells Epithelium Equilibrium Event Exhibits Exposure to Genetic Goals Goblet Cells Growth Factor Health Homologous Gene Human Hyperplasia Immune Immune Response Genes In Vitro Infection Inflammation Inflammatory Injury Ligands Lung Lung diseases Maintenance Manuscripts Mediating Metalloproteases Molecular Morphology Mus Oncogenes Pathway interactions Pattern Phosphotransferases Post-Transcriptional Regulation Principal Investigator Process Production Protein Overexpression Pulmonary Surfactant-Associated Protein D Receptor Signaling Retroviridae Role Signal Pathway Signal Transduction Smoke Stimulus Structure Surface Testing Trachea Transgenic Organisms Viral Viral Bronchiolitis Virus Virus Diseases airway hyperresponsiveness airway remodeling base bronchial epithelium caspase-3 caspase-9 cell type cigarette smoking human subject in vivo mouse model programs repaired research study respiratory virus response

项目摘要

A major goal of this PPG proposal is to understand the molecular basis for remodeling of lung structure during inflammation and disease. In that context, significant evidence now exists that airway epithelial cells may be specially programmed for normal immune defense (especially against respiratory viruses) and abnormally programmed in airway disease. For the present project, we have extended this line of reasoning to ask how epithelial behavior becomes abnormal. In that regard, we now find that transient paramyxoviral bronchiolitis in mice causes acute loss and then long-term hyperplasia of ciliated airway epithelial cells when the infection occurs in a susceptible genetic background. Similar to the pattern in airway disease, the hyperplastic epithelium in mice exhibits persistent activation of epidermal growth factor receptor (EGFR) signaling. Despite activation of growth factor signal and concomitant hyperplasia, there is no evidence of persistent proliferation of airway epithelial cells. This finding raises the unexpected possibility that prolonged cell survival is critical for remodeling and perhaps normal maintenance of epithelial structure. In support of that possibility, study of airway epithelial cells in culture indicates that ciliated cell survival depends on uninterrupted EGFR signaling. Although the precise determinants of this signal are still being defined, it appears that selective overexpression of upstream ligand (e.g., amphiregulin) and consequent activation of downstream kinases (especially PI3K and Akt) are critical for maintenance of function. Otherwise, the ciliated cells may proceed toward programmed cell death (via caspase-9 and caspase-3) in a manner that appears analogous to virus-inducible apoptosis. To test these proposals, we have the following specific aims-- I. Using genetically homogeneous mice, define the mechanism for long-term hyperplasia of ciliated epithelial cells after damage due to viral infection and other inflammatory stimuli. These experiments concentrate on the role of the EGFR signaling pathway in long-term virus-induced ciliated cell hyperplasia and compare this response to other conditions, especially exposure to inhaled cigarette smoke. II. Using isolated airway epithelial cells, define the components of the EGFR signaling pathway that mediate ciliated epithelial cell survival. These experiments concentrate on precisely defining the intricate signaling pathways that control the balance between ciliated epithelial cell death and survival and so determine the cellular makeup of the epithelial barrier.

该PPG提案的主要目标是了解炎症和疾病期间肺结构重塑的分子基础。在这种情况下，现在存在大量证据表明，气道上皮细胞可能专门针对正常的免疫防御（尤其是针对呼吸道病毒），并且在气道疾病中编程异常。对于本项目，我们扩展了这种推理，以询问上皮行为如何变得异常。在这方面，我们现在发现，小鼠的短暂性角臂支气管炎会导致急性损失，然后在纤毛的气道上皮细胞中长期增生感染发生在敏感的遗传背景中。与气道疾病的模式相似，小鼠的增生上皮表现出表皮生长因子受体（EGFR）信号的持续激活。尽管激活了生长因子信号和伴随增生，但没有证据表明气道上皮细胞持续扩散。这一发现提出了意外的可能性，即延长细胞存活对于重塑和可能的上皮结构的正常维护至关重要。为了支持这种可能性，培养中气道上皮细胞的研究表明，纤毛的细胞存活取决于不间断的EGFR信号传导。尽管该信号的确切决定因素仍在定义中，但似乎上游配体（例如，两极蛋白）的选择性过表达，并随之而来的激活下游激酶（尤其是PI3K和AKT）对于维持功能至关重要。否则，纤毛细胞可以以看起来类似于病毒诱导的细胞凋亡的方式进行编程的细胞死亡（通过caspase-9和caspase-3）。为了测试这些建议，我们有以下特定目标 - I.使用遗传均匀的小鼠，定义了因病毒感染和其他炎症刺激而损害后纤毛上皮细胞长期增生的机制。这些实验集中在EGFR信号通路在长期病毒诱导的纤毛细胞增生中的作用，并将这种反应与其他疾病进行比较，尤其是暴露于吸入的香烟烟雾中。 ii。使用孤立的气道上皮细胞，定义了介导纤毛纤毛上皮细胞存活的EGFR信号通路的成分。这些实验集中于精确定义复杂的信号通路，这些信号通路控制纤毛上皮细胞死亡与存活之间的平衡，从而确定上皮屏障的细胞组成。