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

基本信息

批准号：
7531048
负责人：
Tara L Sabo-Attwood
金额：
$ 10.8万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-22 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7531048
关键词：
Adenocarcinoma Asbestos Asthma Breathing Calcium Cell Differentiation process Cell Line Cells Chloride Channels Chronic Bronchitis Chronic Obstructive Airway Disease Chrysotile Clara cell 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-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 Transcription Factor AP-1 Transcriptional Regulation Transgenes Transgenic Mice Up-Regulation depressed fibrogenesis human MAP2K1 protein in vivo inhibitor/antagonist lung injury pollutant prognostic programs research study response therapeutic development transcription factor

项目摘要

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.

气道粘液分泌过多是许多肺部病变的一个突出特征。确定其作用空气中的颗粒物加剧肺部疾病是本次应用以及未来的重点提案。主要目标是揭示石棉改变的信号通路，调节表达 hclcal/mclcaS 和 muc5ac，这两个基因涉及粘蛋白的产生和/或分泌。这个假设将在 3 个具体目标上进行测试，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化生。第一个假设是 mclcaS 的表达和粘液产生的发展将与吸入温石棉的正常小鼠相比，CC10-dnMEK 小鼠的抑郁程度降低。此外，细支气管气道内的克拉拉细胞将获得产生和分泌粘液的能力继石棉侮辱之后。为了验证这一假设，我们将观察石棉诱导的肺基因变化小鼠上皮细胞表达上皮细胞特异性 dnMEK 转基因，该转基因先前在我们的研究中进行了表征实验室。第二个假设指出，石棉纤维通过以下方式诱导 hclcal 和 mucSac 的表达：改变表皮生长因子受体 (EGFR)/丝裂原激活蛋白激酶激酶 1 (MEK)/激活剂 Protein-1 (AP-1) 信号传导途径通过产生活性氧 (ROS)。我们的第三个假设是石棉诱导的 MucSac 的产生需要以下物质的存在和上调 hClcal，并且这种诱导依赖于通过 EGFR/MEK/AP-1 的信号传导。实验目标 2 和 3 将使用 MARK 信号传导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。阐明与肺损伤有关的关键基因石棉暴露后可能有助于制定治疗和预后策略与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致病性环境污染物的调节，以及这些事件如何导致疾病，例如纤维化、哮喘、慢性阻塞性肺病（COPD）、肺气肿和癌症。希望是这样的加强我们对这些疾病的基本了解将导致适当的风险评估和未来制定空气传播相关疾病的治疗策略。