Systematic assessment of multi-walled carbon nanotubes in pulmonary disease

多壁碳纳米管在肺部疾病中的系统评估

基本信息

批准号：
8686856
负责人：
Nancy Lan Guo
金额：
$ 32.97万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-18 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686856
关键词：
Affect Alveolar Animal Model Animals Apoptosis Asbestos Biological Biological Assay Biological Markers Blood Tests Blood capillaries Blood specimen CCL2 gene Caliber Cell model Characteristics Cicatrix Coculture Techniques Communication Computer Simulation Cultured Cells Data Detection Development Diagnostic Dose Early Diagnosis Early treatment Endothelial Cells Environmental Health Epithelial Epithelial Cells Evaluation Exhibits Exposure to Fiber Fibrosis Future Gases Genes Genomics Health Hazards Health protection Human Hyperplasia In Vitro Inflammation Injury Intercellular adhesion molecule 1 Intervention Laboratories Lead Length Lesion Lung Lung diseases Malignant Neoplasms Malignant neoplasm of lung Measurement Measures Mesenchymal Messenger RNA MicroRNAs Modeling Molecular Molecular Analysis Molecular Profiling Molecular Target Mus Mutation Pathway interactions Patients Pattern Permeability Pharmaceutical Preparations Phosphorylation Pneumonia Production Pulmonary Fibrosis Reaction Time Reactive Oxygen Species Research Risk Risk Assessment Shapes Signal Pathway Signal Transduction Signal Transduction Alteration Structure of parenchyma of lung Systems Biology Testing Tissues Toxic effect Toxicology Vascular Endothelial Growth Factors angiogenesis base cancer initiation cancer risk capillary carcinogenesis cell type chemokine cytokine cytotoxicity effective therapy genome-wide in vitro Assay in vivo interdisciplinary approach mRNA Expression mouse model multi walled carbon nanotube nanoscale novel particle response screening treatment strategy tumor progression

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to identify novel biomarkers and molecular mechanisms of multi-walled carbon nanotube (MWCNT)-induced pulmonary diseases, including fibrosis, for early detection and treatment interventions. MWCNT have been widely used for various industrial applications. However, concern over potential MWCNT-induced toxicity has emerged, particularly due to the structural similarity between asbestos and MWCNT. In our preliminary studies, exposure of mice to MWCNT by pharyngeal aspiration results in significant pulmonary inflammation, damage, and fibrosis at 56 days post-exposure. We have identified MWCNT-induced gene signatures in the mouse model that could predict human lung cancer risk and progression. In the computational evaluation of more than 800 pathways, VEGF, ICAM-1, MCP-1, and TGF- are among the most significantly represented pathways in the mouse model. The involvement of these signaling pathways has been further validated in MWCNT-treated human small airway epithelial cells (SAEC). A co-culture model of SAEC with human microvascular endothelial cells (HMVEC) was recently developed by our laboratory to elucidate mechanisms for MWCNT-induced cellular response. Nevertheless, the long-term pulmonary responses to MWCNT in mice and their underlying molecular mechanisms remain to be resolved. Moreover, there are currently no clinically available biomarkers for early detection and no effective treatment inventions for MWCNT-induced pulmonary diseases, particularly lung fibrosis. We hypothesize that genomic profiling and computational toxicology analysis of in vitro and in vivo studies can identify novel mechanisms and biomarkers predictive of MWCNT-induced pulmonary injuries in humans, which will lead to early diagnostic detection and treatment interventions for MWCNT-induced pulmonary diseases, including fibrosis. We will utilize multidisciplinary approaches, including in vivo animal toxicology assays, in vitro cellular toxicology assays, and computational modeling, to establish in vitro genomic signatures predictive of MWCNT-induced pulmonary diseases in the in vivo animal model and in humans and to explore the potential molecular targets for early treatment interventions. Aim 1 will evaluate the pulmonary dose-response and time course responses to MWCNT exposure in mice for up to 1 year. Aim 2 will determine the molecular mechanisms of MWCNT- induced injuries to the lung using an alveolo-capillary co-culture model. Aim 3 will identify mechanism-based gene signatures predictive of MWCNT-induced human pulmonary diseases using in vivo, in vitro, and patient data for early detection and treatment interventions. Aim 4 will perform integrated analyses of MWCNT-induced mRNA and miRNA changes and identify miRNA markers for early detection of MWCNT-induced lung fibrosis using non-invasive blood tests. We anticipate that this project will transform toxicological research of MWCNT- induced pulmonary diseases into strategies for environmental health protection and intervention. Results will fill th gap between in vivo/in vitro MWCNT-induced toxicity studies and risk assessment in humans.

描述（由申请人提供）：本提案的目的是确定多壁碳纳米管（MWCNT）诱发的肺部疾病（包括纤维化）的新型生物标志物和分子机制，以进行早期检测和治疗干预。多壁碳纳米管已广泛用于各种工业应用。然而，人们对多壁碳纳米管潜在毒性的担忧已经出现，特别是由于石棉和多壁碳纳米管之间的结构相似性。在我们的初步研究中，小鼠通过咽部抽吸暴露于 MWCNT，导致暴露后 56 天出现明显的肺部炎症、损伤和纤维化。我们在小鼠模型中发现了多壁碳纳米管诱导的基因特征，可以预测人类肺癌的风险和进展。在对 800 多个通路的计算评估中，VEGF、ICAM-1、MCP-1 和 TGF- 是小鼠模型中最显着的代表性通路之一。这些信号通路的参与已在 MWCNT 处理的人小气道上皮细胞 (SAEC) 中得到进一步验证。我们的实验室最近开发了 SAEC 与人微血管内皮细胞 (HMVEC) 的共培养模型，以阐明 MWCNT 诱导的细胞反应机制。然而，小鼠对多壁碳纳米管的长期肺部反应及其潜在的分子机制仍有待解决。此外，目前临床上还没有用于早期检测的生物标志物，也没有针对MWCNT引起的肺部疾病，特别是肺纤维化的有效治疗发明。我们假设体外和体内研究的基因组分析和计算毒理学分析可以识别预测多壁碳纳米管引起的人类肺损伤的新机制和生物标志物，这将导致对多壁碳纳米管引起的肺部疾病的早期诊断检测和治疗干预，包括纤维化。我们将利用多学科方法，包括体内动物毒理学测定、体外细胞毒理学测定和计算模型，在体内动物模型和人类中建立预测 MWCNT 诱导的肺部疾病的体外基因组特征，并探索早期治疗干预的潜在分子靶点。目标 1 将评估小鼠暴露于 MWCNT 长达 1 年的肺部剂量反应和时程反应。目标 2 将使用肺泡毛细血管共培养模型确定 MWCNT 引起的肺部损伤的分子机制。目标 3 将利用体内、体外和患者数据来识别基于机制的基因特征，预测多壁碳纳米管诱发的人类肺部疾病，以进行早期检测和治疗干预。目标 4 将对 MWCNT 诱导的 mRNA 和 miRNA 变化进行综合分析，并识别 miRNA 标记，以便使用非侵入性血液检测早期检测 MWCNT 诱导的肺纤维化。我们预计该项目将把多壁碳纳米管引起的肺部疾病的毒理学研究转化为环境健康保护和干预的策略。结果将填补体内/体外多壁碳纳米管诱导的毒性研究和人类风险评估之间的空白。