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

基本信息

批准号：
9084564
负责人：
James Christopher Bonner
金额：
$ 33.55万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
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：
2012-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9084564
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 Pulmonary Fibrosis Rattus Regulation Relative Risks Reporting Risk Shapes Signal Transduction Stress Structure Surface Susceptibility Gene TP53 gene Techniques Testing Tissues Toxic effect Tube Vascular Endothelial Growth Factors Work atomic layer deposition chemical property consumer product design exposed human population gene product improved innovation insight lung injury malignant pleura tumor mouse model nanomaterials nanoparticle nanoscale novel novel strategies physical property response surface coating transcription factor

项目摘要

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，在原子水平上进行设计和修饰，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道疾病。一个主要问题是碳纳米管具有一些类似于石棉的特性，石棉是一种与肺纤维化（组织疤痕）和间皮瘤（肺部胸膜表面的罕见癌症）的发展有关的纤维。我们发现，吸入的碳纳米管会迁移到小鼠的胸膜（肺部周围的敏感间皮衬里），导致胸膜损伤和炎症。我们还报道，碳纳米管会增加预先暴露于过敏原或细菌脂多糖的小鼠的肺纤维化。在人类广泛接触碳纳米管之前，了解碳纳米管如何导致小鼠呼吸道疾病，尤其是纤维化和癌症，并确定易感因素以明确评估风险，这一点至关重要。该提案的总体目标是利用对特定呼吸道疾病易感性的基因工程小鼠模型来阐明碳纳米管的毒性；特别是肺纤维化和间皮瘤。我们进一步寻求确定通过原子层沉积（ALD）（一种工程纳米级结构的新技术）实现的选择性表面涂层是否会影响碳纳米管减轻或加剧这些呼吸系统疾病的潜力。该提案要测试的具体假设是，对 CNT 诱导的肺纤维化和间皮瘤的易感性是由于 COX-2、STAT-1 和 p53 之间的表达减少或功能相互作用受损所致。将通过以下具体目标来检验这一假设：在目标 1 中，我们将确定 COX-2 是否介导暴露于 ALD-CNT 后 p53 水平升高，以及 COX-2 缺失是否会降低暴露小鼠肺部的 p53 水平引起纤维化或间皮瘤。在目标 2 中，我们将确定暴露于 ALD-CNT 后 STAT-1 激活是否会诱导和激活 p53，以及 STAT-1 缺失是否会减少暴露小鼠肺部的 p53，从而导致纤维化或间皮瘤。在目标 3 中，我们将确定 p53 缺陷小鼠在接触 CNT 后是否容易患肺纤维化或发展为间皮瘤，以及 CNT 的 ALD 修饰是否会改变疾病结果。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 来诱导 COX-2、STAT-1 或 p53，以及 COX-2、STAT-1 或 p53 的缺失是否会放大 CNT-诱导 MAPK 信号传导。这种新方法将为碳纳米管引起呼吸道疾病的机制提供有价值的信息。此外，我们将确定特定基因，其缺陷将使个体面临碳纳米管暴露带来的更大风险。我们的方法还利用创新的跨学科方法来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。对碳纳米管促进小鼠慢性肺病的分子机制的新见解将提高我们对特定类型肺病易感性的理解。这项工作的广泛影响将通过为更安全的纳米材料的设计提供重要信息，直接影响美国和全世界数百万人的健康和福祉。