Project 3: Mouse Models of Smoking-related Diseases: What is the Best

项目 3：吸烟相关疾病的小鼠模型：什么是最好的

• 批准号: 8904705
• 负责人: Claire M Doerschuk
• 金额: $ 80.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904705
• 关键词: Address; Animal Model; Biological Assay; Cells; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cigar; Cigarette; Code; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Dehydration; Disease; Drug Metabolic Detoxication; Employee Strikes; Epithelial; Epithelial Cells; Foamy Macrophage; Gene Expression Profiling; Genes; Goals; Haemophilus influenzae; Health; Human; Immune; Immunophenotyping; Inflammation; Injury; Interstitial Lung Diseases; Liquid substance; Literature; Lung; Lung diseases; Lymphocyte Count; Malignant neoplasm of lung; Marketing; Matrix Metalloproteinases; Mediastinal lymph node group; Messenger RNA; Metaplasia; MicroRNAs; Modeling; Mouse Strains; Mucins; Mucociliary Clearance; Mucous body substance; Mus; Natural Immunity; Obstruction; Outcome; Pathology; Pathway interactions; Patients; Pneumonia; Population; Production; Proteins; Pulmonary Emphysema; Regulatory Pathway; Reporter; Research; Signal Pathway; Smoke; Smoking; System; Testing; Tobacco; Tobacco smoke; Toxic effect; Transgenic Mice; Water; Wild Type Mouse; Work; absorption; base; cell type; cigarette smoking; cytokine; human disease; in vivo; interest; lung injury; macrophage; mouse model; mucus hypersecretion; neutrophil; overexpression; tobacco exposure

Tobacco smoke has a devastating impact on health, particularly on lung health. It is the most common cause of chronic obstructive lung disease (COPD) and lung cancer. It also has synergistic effects on numerous other lung diseases, including interstitial lung disease and pneumonia. Most mouse models oftobacco smokerelated lung disease expose mouse strains to tobacco smoke. This model usually results in mild-to-moderate emphysema, but little or no evidence ofthe chronic bronchitis, which is a large component of COPD in humans. Our aim is to establish a model oftobacco smoke-induced lung injury that mimics that found in humans. This work will address the FDA CPT research interest, "Adverse Health Consequences". The goal ofthis project is to determine what animal models can be validated to establish standard toxicity changes and what magnitude observed within in vivo assays correlates with change in human health outcome (point 31). As described in Project 1, smoke exposure leads to decreased activity of CFTR, resulting in absorption of water from airway liquid, dehydration of mucus, and poor mucociliary clearance. Transgenic mice overexpressing Scnnib, the gene which codes forthe epithelial Na* chanriel subunit (pENaC), in the epithelial cells ofthe airways mimic this aspect oftobacco smoke, showing mucus cell metaplasia, mucus hypersecretion and obstruction, neutrophilic inflammation, large foamy macrophages, and increased numbers of lymphocytes in both the lumen and the walls ofthe ainways. These mice also show evidence of an MMP-12-dependent emphysematous component to the injury. Thus, the lungs of these mice develop pathology that mimics changes found in COPD patients, highlighting the striking effects of airway dehydration. However, these mice are missing all other effects oftobacco smoke, which are likely to be many due to numerous components of tobacco smoke. We are modeling tobacco smoke exposure in humans by exposing Scnn1b-tg mice to prolonged (6 month) tobacco smoke exposure. Our studies to date suggest that this model mimics the human injury more closely than mouse models to date. In particular, gene expression analysis suggests that smoke exposure in Scnnlb-ig mice results in more similarities to human disease in both detoxification pathways and in immune regulatory pathways. Other similarities to date include changes in mucins within the airways and the presence of large numbers of vesicular exosomes. Thus, we propose to test the hypothesis that smoke exposure in Scnn1b-tg mice is an excellent model of human disease and can be used more effectively than either wild type (WT) mice or other mouse models of COPD to study particular components of smoke or to compare tobacco products or substitutes.

烟草烟雾对健康具有毁灭性影响，特别是对肺部健康。这是最常见的原因 慢性阻塞性肺病（COPD）和肺癌。它还对许多其他方面具有协同效应 肺部疾病，包括间质性肺病和肺炎。大多数与烟草相关的小鼠模型 肺部疾病使小鼠品系暴露于烟草烟雾中。该模型通常会导致轻度至中度 肺气肿，但很少或没有慢性支气管炎的证据，而慢性支气管炎是人类慢性阻塞性肺病的重要组成部分。 我们的目标是建立一个模拟人类肺损伤的模型。这 工作将解决 FDA CPT 研究兴趣“不良健康后果”。该项目的目标是 确定可以验证哪些动物模型来建立标准毒性变化以及什么 体内检测中观察到的幅度与人类健康结果的变化相关（第 31 点）。 如项目 1 中所述，烟雾暴露会导致 CFTR 活性降低，从而导致吸收 气道液体中的水分、粘液脱水以及粘液纤毛清除不良。转基因小鼠 过度表达 Scnnib，该基因编码上皮 Na* 通道亚基 (pENaC) 气道上皮细胞模仿烟草烟雾的这一方面，显示粘液细胞化生、粘液 分泌过多和阻塞、中性粒细胞炎症、大泡沫状巨噬细胞和增加 管腔和管壁中的淋巴细胞数量。这些小鼠还显示出 损伤的 MMP-12 依赖性肺气肿成分。因此，这些小鼠的肺部发育 模仿 COPD 患者变化的病理学，强调气道的显着影响 脱水。然而，这些小鼠忽略了烟草烟雾的所有其他影响，这些影响可能是 许多是由于烟草烟雾中的多种成分造成的。我们正在模拟烟草烟雾暴露 通过将 Scnn1b-tg 小鼠长期（6 个月）暴露于烟草烟雾中来进行研究。迄今为止我们的研究 表明该模型比迄今为止的小鼠模型更能模拟人类损伤。特别是基因 表达分析表明，Scnnlb-ig 小鼠暴露于烟雾会导致与人类更加相似 解毒途径和免疫调节途径中的疾病。迄今为止的其他相似之处包括 气道内粘蛋白的变化以及大量囊泡外泌体的存在。因此，我们 提议检验 Scnn1b-tg 小鼠的烟雾暴露是人类的优秀模型的假设 与野生型 (WT) 小鼠或其他 COPD 小鼠模型相比，可以更有效地用于治疗慢性阻塞性肺病 (COPD) 疾病。 研究烟雾的特定成分或比较烟草产品或替代品。