Mechanisms of Asbestos-Induced CIca1 and Mucin in Lung Epithelium

石棉诱导肺上皮细胞 CIca1 和粘蛋白的机制

• 批准号: 7335661
• 负责人: Tara L Sabo-Attwood
• 金额: $ 10.5万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-22 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7335661
• 关键词: Adenocarcinoma; Asbestos; Asthma; Breathing; Calcium; Cell Differentiation process; Cell Line; Cells; Chloride Channels; Chronic Bronchitis; Chronic Obstructive Airway Disease; Chronic Obstructive Asthma; Chrysotile; Clara cell; Depressed mood; Development; Disease; Distal; Environmental Pollution; Epidermal Growth Factor Receptor; Epithelial Cells; Epithelium; Event; Extracellular Signal Regulated Kinases; Fiber; Fibrosis; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Goals; Goblet Cells; Human; In Vitro; Lead; Link; Lung; Lung diseases; MAP2K1 gene; MAPK Signaling Pathway Pathway; Malignant Neoplasms; Messenger RNA; Metaplasia; Mitogen Receptors; Mitogen-Activated Protein Kinases; Mucinous; Mucins; Mucous body substance; Mus; Particulate; Particulate Matter; Pathology; Pathway interactions; Phenotype; Play; Process; Production; Proteins; Pulmonary Emphysema; RNA Interference; Reactive Oxygen Species; Receptor Signaling; Regulation; Research Personnel; Risk Assessment; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Testing; Therapeutic; Transcription Factor AP-1; Transcriptional Activation; Transcriptional Regulation; Transgenes; Transgenic Mice; Up-Regulation; fibrogenesis; human MAP2K1 protein; in vivo; inhibitor/antagonist; lung injury; pollutant; prognostic; programs; research study; response; transcription factor

Airway mucus hypersecretion is a prominent feature of numerous lung pathologies. Determining its role in exacerbation of lung disease by airborne particulates is the focus of this application, as well as future proposals. The primary goal is to unveil signaling pathways altered by asbestos that regulate the expression of hclcal/mclcaS and muc5ac, two genes involved in mucin production and/or secretion. This hypothesis will be tested in 3 specific aims which encompass both in vivo and in vitro approaches to elucidate signaling pathways that control the regulation of these genes, and their involvement in asbestos-induced mucus metaplasia. Out first hypothesis is that expression of mclcaS and development of mucus production will be depressed in CC10-dnMEK mice compared to normal mice exposed to chrysotile asbestosvia inhalation. Furthermore, Clara cells within the bronchiolar airways will acquire the ability to produce and secrete mucus following asbestos insult. To test this hypothesis, we will observe asbestos-induced gene changes in lung epithelial cells of mice expression an epithelial cell-specific dnMEK transgene previously characterized in our lab. The second hypothesis states that asbestos fibers induce the expression of hclcal and mucSac by altering epidermal growth factor receptor (EGFR)/mitogen activated protein kinase kinase-1 (MEK)/activator protein-1 (AP-1) signaling pathways through the generation of reactive oxygen species (ROS). Our third hypothesis is that the asbestos-induced production of MucSac requires the presence and up-regulation of hClcal, and that this induction is dependant upon signaling through the EGFR/MEK/AP-1. The experiments for Aims 2 and 3 will be carried out in human lung epithelial cell lines using inhibitors of MARK signaling pathways and si (small interference)-RNA constructs. Elucidation of critical genes involved in lung injury following asbestos exposure could aid in the development of therapeutic and prognostic strategies to treat asbestos-associated lung diseases. The long term goal of these studies is elucidating mechanisms of gene regulation by pathogenic environmental contaminants, and how these events lead to diseases such as fibrosis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, and cancer. The hope is that enhancing our basic understanding of these diseases will lead to appropriate risk assessment and future development of therapeutic strategies for airborne related diseases.

气道粘液过度分泌是众多肺病理的重要特征。确定其在 空气中颗粒物加剧肺部疾病是该应用的重点，以及未来 建议。主要目标是揭露由调节表达式的石棉改变的信号传导途径 Hclcal/McLCA和MUC5AC的两个基因参与粘蛋白产生和/或分泌。这个假设将会 在3个特定目的中进行测试，该目标包括体内和体外方法以阐明信号传导 控制这些基因调节的途径及其参与石棉诱导的粘液 Metaplasia。第一个假设是MCLCA的表达和粘液产生的发展将是 与暴露于石棉石棉吸入的正常小鼠相比，CC10-DNMEK小鼠的抑郁症。 此外，支气管气道中的克拉拉细胞将获得产生和分泌粘液的能力 遵循石棉侮辱。为了检验该假设，我们将观察石棉诱导的肺基因变化 小鼠的上皮细胞表达上皮细胞特异性的DNMEK转基因先前在我们的 实验室。第二个假设指出，石棉纤维通过 改变表皮生长因子受体（EGFR）/有丝分裂激活的蛋白激酶激酶1（MEK）/激活剂 通过活性氧（ROS）产生的蛋白-1（AP-1）信号通路。我们的第三个 假设是石棉诱导的粘液产量需要存在和上调 HCLCAL，并且这种诱导取决于通过EGFR/MEK/AP-1信号传导。实验 对于目标2和3，将使用标记信号的抑制剂在人肺上皮细胞系中进行 途径和Si（小干扰） - RNA构建体。阐明涉及肺损伤的关键基因 遵循石棉暴露可以帮助发展治疗和预后策略以治疗 石棉相关的肺部疾病。这些研究的长期目标是阐明基因的机制 病原环境污染物的调节，以及这些事件如何导致疾病，例如 纤维化，哮喘，慢性阻塞性肺疾病（COPD），肺气肿和癌症。希望是 增强我们对这些疾病的基本理解将导致适当的风险评估和未来 开发有关空气中相关疾病的治疗策略。