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：
8850861
负责人：
James Christopher Bonner
金额：
$ 33.58万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850861
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

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）：纳米技术的快速进步将伴随着数百万个个体接触到含有纳米材料的产品。碳纳米管（CNT）是在原子水平上设计和修饰的主要类型的纳米材料，用于多种用途（电子，工程，药物）。尽管CNT有许多有益用途，但也有强有力的证据表明它们在小鼠和大鼠中引起肺损伤和呼吸道疾病。一个主要问题是，CNT具有类似于石棉的特性，这是一种与肺纤维化发展（组织疤痕）和间皮瘤（肺胸膜表面上的罕见癌症）相关的纤维。我们发现，吸入的CNT迁移到小鼠中的胸膜（肺部周围敏感的间皮衬里），以引起胸膜损伤和炎症。我们还报告说，CNT会增加预先暴露于过敏原或细菌脂多糖的小鼠中的肺纤维化。在人类暴露变得普遍之前，了解CNT如何引起小鼠，尤其是纤维化和癌症的呼吸道疾病至关重要，并确定易感性因素清楚地评估风险。该提案的总体目标是使用对特定呼吸系统疾病的易感性的基因工程小鼠模型来阐明CNT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）实现的选择性表面涂层是一种新型的工程纳米级结构技术，会影响CNT减轻或加剧这些呼吸系统疾病的潜力。在此提案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COX-2，STAT-1和P53之间的表达降低或功能相互作用降低所致。将实现以下特定目的来检验以下假设：在AIM 1中，我们将确定COX-2在暴露于ALD-CNT之后是否介导p53水平增加，以及COX-2缺失是否会降低暴露小鼠肺中的p53水平，从而导致纤维化或间皮瘤。在AIM 2中，我们将确定STAT-1激活在暴露于ALD-CNT之后是否诱导并激活p53，以及STAT-1缺失是否会降低暴露小鼠的肺中的p53引起纤维化或间皮瘤。在AIM 3中，我们将确定p53缺陷的小鼠在暴露于CNTS后易感肺纤维化或发展间皮瘤，以及CNTS的ALD修饰是否会改变疾病的结果。在AIM 4中，我们将确定ALD修饰的CNT是否通过ROS激活MAPK作为近端信号诱导COX-2，STAT-1或P53，以及COX-2，STAT-1或P53的丢失是否会扩大CNT诱导的MAPK信号。这种新颖的方法将提供有关CNT引起呼吸系统疾病的机制的宝贵信息。此外，我们将确定其缺乏症将使个人受到CNT暴露导致的风险更大的特定基因。我们的方法还利用了一种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增加还是降低。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的易感性的理解。这项工作的广泛影响将直接通过为更安全的纳米材料设计提供必不可少的信息，直接影响美国和全球数百万个人的健康和福祉。