Genetic Susceptibility to Nanoparticle-Induced Respiratory Disease

纳米粒子诱发的呼吸道疾病的遗传易感性

• 批准号: 8686847
• 负责人: James Christopher Bonner
• 金额: $ 33.28万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686847
• 关键词: Affect; Allergens; Asbestos; Asbestosis; Bleomycin; Breathing; Carbon Nanotubes; Characteristics; Chemistry; Chronic; Chronic lung disease; Cicatrix; Development; Disease; Disease Outcome; Disease Progression; Disease susceptibility; Electronics; Engineering; Enzymes; Epidemic; Event; Exposure to; Fiber; Fibrosis; Generations; Genes; Genetic Predisposition to Disease; Genetically Engineered Mouse; Goals; Health; Human; Individual; Industry; Inflammation; Injury; Laboratories; Link; Lipopolysaccharides; Lung; Lung diseases; MAP Kinase Gene; Malignant Neoplasms; Mediating; Medicine; Mesothelioma; Metals; Methods; Mitogen-Activated Protein Kinases; Modification; Molecular; Mus; Nanotechnology; Nanotubes; PTGS2 gene; Pathogenesis; Personal Satisfaction; Pleura; Pleural; Pleural Diseases; Predisposition; Prevention; Production; Property; Protein p53; Proteins; Pulmonary Fibrosis; Rattus; Regulation; Relative Risks; Reporting; Risk; Shapes; Signal Transduction; Stress; Structure; Surface; Susceptibility Gene; Techniques; Testing; Tissues; Toxic effect; Tube; Vascular Endothelial Growth Factors; Work; atomic layer deposition; chemical property; consumer product; design; exposed human population; improved; innovation; insight; lung injury; malignant pleura tumor; mouse model; nanomaterials; nanoparticle; nanoscale; novel; novel strategies; physical property; response; surface coating; transcription factor

DESCRIPTION (provided by applicant): Rapid advances in nanotechnology will be accompanied by the exposure of millions of individuals to products containing nanomaterials. Carbon Nanotubes (CNTs) are a major type of engineered nanomaterial designed and modified at the atomic level for multiple uses (electronics, engineering, medicine). While there are many beneficial uses for CNTs, there is also strong evidence that they cause lung injury and respiratory disease in mice and rats. A major concern is that CNTs have some properties similar to asbestos, a fiber that is linked with the development of pulmonary fibrosis (tissue scarring) and mesothelioma (a rare cancer on the pleural surface of the lung). We discovered that inhaled CNTs migrate to the pleura (the sensitive mesothelial lining surrounding the lungs) in mice to cause pleural injury and inflammation. We have also reported that CNTs increase pulmonary fibrosis in mice pre-exposed to allergens or bacterial lipopolysaccharide. It is paramount to understand how CNTs cause respiratory diseases in mice, especially fibrosis and cancer, before human exposures become widespread and identify susceptibility factors to clearly evaluate risk. The overall goal of this proposal is to elucidate CNT toxicity using genetically engineered mouse models of susceptibility to specific respiratory diseases; specifically pulmonary fibrosis, and mesothelioma. We further seek to determine whether selective surface coatings achieved by atomic layer deposition (ALD), a novel technique of engineering nanoscale structures, affect the potential of CNTs to mitigate or exacerbate these respiratory diseases. The specific hypothesis to be tested in this proposal is that susceptibility to CNT-induced pulmonary fibrosis and mesothelioma is due to reduced expression or impaired functional interaction between COX-2, STAT-1, and p53. The following specific aims will be carried out to test this hypothesis: In Aim 1, we will determine whether COX-2 mediates increased p53 levels after exposure to ALD-CNTs and whether COX-2 deletion reduces p53 levels in the lungs of exposed mice to cause fibrosis or mesothelioma. In Aim 2, we will determine whether STAT-1 activation induces and activates p53 after exposure to ALD-CNTs and whether STAT-1 deletion reduces p53 in the lungs of exposed mice to cause fibrosis or mesothelioma. In Aim 3, we will determine whether p53-deficient mice are susceptible to pulmonary fibrosis or develop mesothelioma after exposure to CNTs and whether ALD modification of CNTs alters disease outcome. In Aim 4, we will determine whether ALD-modified CNTs activate MAPKs via ROS as a proximal signal to induce COX-2, STAT-1, or p53, and whether loss of COX-2, STAT-1, or p53 amplifies CNT-induced MAPK signaling. This novel approach will provide valuable information on mechanisms through which CNTs cause respiratory diseases. Moreover, we will identify specific genes whose deficiency will put individuals at greater risk resulting from CNT exposure. Our approach also takes advantage of an innovative cross-disciplinary approach to specifically modify the surface chemistry of carbon nanotubes to determine whether toxicity and disease susceptibility are increased or decreased. The new insights into the molecular mechanisms through which CNTs promote chronic lung disease in mice will improve our understanding of susceptibility to specific types of lung disease. The broad impact of this work will directly affect the health and well-being of millions of individuals in the U.S. and worldwide by providing essential information for the design of safer nanomaterials.

描述（由申请人提供）：纳米技术的快速发展将伴随着数百万人接触含有纳米材料的产品。碳纳米管（CNT）是一种主要类型的工程纳米材料，在原子水平上设计和修改，用于多种用途（电子，工程，医学）。虽然碳纳米管有许多有益的用途，但也有强有力的证据表明，它们会导致小鼠和大鼠的肺损伤和呼吸系统疾病。一个主要的问题是，碳纳米管具有一些类似于石棉的性质，石棉是一种与肺纤维化（组织瘢痕）和间皮瘤（肺胸膜表面上的一种罕见癌症）的发展有关的纤维。我们发现吸入的CNT迁移到小鼠的胸膜（肺部周围敏感的间皮衬里），导致胸膜损伤和炎症。我们还报道了CNT增加预先暴露于过敏原或细菌脂多糖的小鼠的肺纤维化。在人类暴露变得广泛之前，了解CNT如何导致小鼠呼吸道疾病，特别是纤维化和癌症，并确定易感因素以明确评估风险至关重要。本提案的总体目标是使用对特定呼吸道疾病（特别是肺纤维化和间皮瘤）易感的基因工程小鼠模型阐明CNT毒性。我们进一步寻求确定是否通过原子层沉积（ALD）实现的选择性表面涂层，工程纳米结构的一种新技术，影响碳纳米管的潜力，以减轻或加剧这些呼吸系统疾病。在这个提议中要检验的特定假设是，CNT诱导的肺纤维化和间皮瘤的易感性是由于考克斯-2、STAT-1和p53之间的表达减少或功能相互作用受损。将进行以下具体目标以检验该假设：在目标1中，我们将确定考克斯-2是否介导暴露于ALD-CNT后p53水平的增加，以及考克斯-2缺失是否降低暴露小鼠肺中的p53水平以引起纤维化或间皮瘤。在目标2中，我们将确定STAT-1激活是否在暴露于ALD-CNT后诱导和激活p53，以及STAT-1缺失是否降低暴露小鼠肺中的p53以引起纤维化或间皮瘤。在目标3中，我们将确定p53缺陷小鼠是否易患肺纤维化或暴露于CNT后发生间皮瘤，以及CNT的ALD修饰是否改变疾病结果。在目标4中，我们将确定ALD修饰的CNT是否通过ROS作为近端信号激活MAPK以诱导考克斯-2、STAT-1或p53，以及考克斯-2、STAT-1或p53的缺失是否放大CNT诱导的MAPK信号传导。这种新的方法将提供有价值的信息机制，通过碳纳米管引起呼吸系统疾病。此外，我们将确定特定的基因，其缺陷将使个人在更大的风险造成的CNT暴露。我们的方法还利用了一种创新的跨学科方法，专门修改碳纳米管的表面化学，以确定毒性和疾病易感性是否增加或减少。对CNT促进小鼠慢性肺部疾病的分子机制的新见解将提高我们对特定类型肺部疾病易感性的理解。 这项工作的广泛影响将直接影响美国和全球数百万人的健康和福祉，为设计更安全的纳米材料提供必要的信息。