Prediction and Mechanism of Carbon Nanotube-Induced Fibrosis

碳纳米管诱导纤维化的预测及机制

• 批准号: 8268403
• 负责人: Yon Rojanasakul
• 金额: $ 36.63万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268403
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Affect; Alveolar; Alveolar wall; Angiogenic Factor; Animals; Biological; Biological Assay; Biological Markers; Biological Models; Caliber; Carbon Nanotubes; Cell Proliferation; Cells; Characteristics; Chemicals; Chemistry; Collagen; Development; Diagnosis; Diagnostic; Disease; Dose; Drug Delivery Systems; Early Diagnosis; Early treatment; Environmental and Occupational Exposure; Epithelial; Evaluation; Exposure to; Extracellular Matrix; Fibroblasts; Fibrosis; Foundations; Generations; Goals; Growth Factor; Health; Human; In Vitro; Industrial Product; Industry; Inflammation; Investigation; Knowledge; Lung; Lung Inflammation; Lung diseases; Mediating; Mediator of activation protein; Molecular Target; Mus; Nanotechnology; Outcome; Oxidation-Reduction; Pathogenesis; Play; Process; Production; Property; Public Health; Pulmonary Fibrosis; Reactive Oxygen Species; Regulation; Research Design; Risk; Risk Assessment; Role; Science; Screening procedure; Signal Pathway; Signal Transduction; Solutions; Source; Structure of parenchyma of lung; System; Testing; Therapeutic; Toxic effect; Transforming Growth Factors; United States; United States National Institutes of Health; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; angiogenesis; base; cellular targeting; cytokine; fibrogenesis; in vitro Model; in vivo; interstitial; mouse model; nanomaterials; nanoparticle; public health relevance; response; single walled carbon nanotube; trend; 1-Phosphatidylinositol 3-Kinase; Address; Affect; Alveolar; Alveolar wall; Angiogenic Factor; Animals; Biological; Biological Assay; Biological Markers; Biological Models; Caliber; Carbon Nanotubes; Cell Proliferation; Cells; Characteristics; Chemicals; Chemistry; Collagen; Development; Diagnosis; Diagnostic; Disease; Dose; Drug Delivery Systems; Early Diagnosis; Early treatment; Environmental and Occupational Exposure; Epithelial; Evaluation; Exposure to; Extracellular Matrix; Fibroblasts; Fibrosis; Foundations; Generations; Goals; Growth Factor; Health; Human; In Vitro; Industrial Product; Industry; Inflammation; Investigation; Knowledge; Lung; Lung Inflammation; Lung diseases; Mediating; Mediator of activation protein; Molecular Target; Mus; Nanotechnology; Outcome; Oxidation-Reduction; Pathogenesis; Play; Process; Production; Property; Public Health; Pulmonary Fibrosis; Reactive Oxygen Species; Regulation; Research Design; Risk; Risk Assessment; Role; Science; Screening procedure; Signal Pathway; Signal Transduction; Solutions; Source; Structure of parenchyma of lung; System; Testing; Therapeutic; Toxic effect; Transforming Growth Factors; United States; United States National Institutes of Health; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; angiogenesis; base; cellular targeting; cytokine; fibrogenesis; in vitro Model; in vivo; interstitial; mouse model; nanomaterials; nanoparticle; public health relevance; response; single walled carbon nanotube; trend

DESCRIPTION (provided by applicant): Project Summary: Environmental and occupational exposures to manufactured nanomaterials have markedly increased during the past recent years, and in all likelihood this trend will continue as new nanomaterials are being increasingly produced and used by various industries. This trend has been of great concern as the adverse health effects of nanomaterials are relatively unknown and understudied. Recent studies have shown that pulmonary exposure to carbon nanotubes (CNT), one of the most widely used nanomaterials in industry, results in rapid and progressive interstitial lung fibrosis in animals without causing persistent lung inflammation, which is normally associated with other known fibrogenic agents. This unusual fibrogenic effect of CNT raises important health issues since the exposure could result in deadly and incurable lung fibrosis. We hypothesize that CNT, due to their unique properties such as exceptionally small size, large aspect ratio, and chemical composition can rapidly enter the lung, penetrate the alveolar epithelial barrier, and interact with specific lung cells such as interstitial lung fibroblasts to induce fibroproliferation and extracellular matrix accumulation, which are characteristics of lung fibrosis. We also propose that such induction is mediated by signaling cascades that involve phosphatidylinositol-3-kinase(PI3K)/Akt activation and redox regulation of the profibrogenic and angiogenic factors such as TGF-b and VEGF. In Aim 1, we will determine the impact of certain nanoparticle characteristics (e.g., diameter, aspect ratio, dispersion status, and chemistry) on CNT-induced lung fibrosis and develop rapid in vitro screening assays which may be predictive of the in vivo fibrogenic response. Aim 2 will delineate key signaling pathways and fibrogenic factors involved in the induction of fibrosis by CNT in order to identify potential biomarkers and drug targets for diagnosis and treatment of the disease. Aim 3 will investigate the involvement of angiogenesis and angiogenic factors in the development of pulmonary fibrosis induced by CNT. Aim 4 will determine redox regulation of CNT-induced fibrogenesis and angiogenesis and elucidate the underlying mechanisms. Through this application, we expect to define key nanoparticle characteristics and a set of in vitro screening assays for evaluation of the potential fibrogenicity of nanoparticles in vivo. Such information will be important for safe use of nanotechnology. The proposed studies will also identify molecular targets for early detection and treatment of fibrotic lung diseases caused by nanomaterials. PUBLIC HEALTH RELEVANCE: Relevance to Public Health: Nanotechnology presents enormous opportunities to create new and better products for industrial applications and for diagnosis and treatment of diseases. However, the potential adverse health effects of nanomaterials are unclear since information is lacking that would allow prediction of the biological activity of these new materials. This project will address NIH goals and public health needs by 1) determining key physiochemical properties of nanomaterials that contribute to their pulmonary toxicity and fibrogenicity, 2) developing rapid screening assays for prediction of the fibrogenic effects of nanomaterials, and 3) elucidating the underlying mechanisms of pulmonary fibrosis induced by nanomaterials in order to identify specific biomarkers and drug targets for early diagnosis and treatment of the disease.

描述（由申请人提供）： 项目摘要：在过去几年中，环境和职业对制造的纳米材料的暴露量显着增加，并且由于各个行业越来越多地生产和使用新的纳米材料，这种趋势很可能会继续下去。由于纳米材料的不良健康影响相对未知和研究，因此这种趋势引起了人们的关注。最近的研究表明，肺部纳米管（CNT）是行业中使用最广泛的纳米材料之一，导致动物中快速和进行性的间质性肺纤维化，而不会引起持续性肺部炎症，通常与其他已知的纤维蛋白酶相关。 CNT的这种不寻常的纤维化作用引起了重要的健康问题，因为暴露可能会导致致命且无法治愈的肺纤维化。 We hypothesize that CNT, due to their unique properties such as exceptionally small size, large aspect ratio, and chemical composition can rapidly enter the lung, penetrate the alveolar epithelial barrier, and interact with specific lung cells such as interstitial lung fibroblasts to induce fibroproliferation and extracellular matrix accumulation, which are characteristics of lung fibrosis.我们还提出，这种诱导是通过涉及磷脂酰肌醇-3-激酶（PI3K）/Akt激活的信号级联反应介导的，以及对TGF-B和VEGF等能力原性和血管生成因子的氧化还原调节。在AIM 1中，我们将确定某些纳米颗粒特性（例如，直径，纵横比，分散状态和化学）对CNT诱导的肺纤维化并发展快速的体外筛查测定法的影响，这可能可以预测体内纤维纤维响应。 AIM 2将描绘CNT诱导纤维化涉及的关键信号通路和纤维化因素，以确定潜在的生物标志物和药物靶标，以诊断和治疗该疾病。 AIM 3将研究血管生成和血管生成因子参与CNT诱导的肺纤维化的发展。 AIM 4将确定CNT诱导的纤维发生和血管生成的氧化还原调节，并阐明基本机制。通过此应用，我们期望定义关键的纳米颗粒特性和一组体外筛选测定法，以评估体内纳米颗粒的潜在纤维化性。此类信息对于安全使用纳米技术非常重要。拟议的研究还将确定纳米材料引起的纤维化肺疾病的早期检测和治疗的分子靶标。 公共卫生相关性： 与公共卫生的相关性：纳米技术提供了巨大的机会，可以为工业应用以及诊断和治疗疾病创建新的更好的产品。但是，纳米材料的潜在不良健康影响尚不清楚，因为缺乏信息可以预测这些新材料的生物学活性。该项目将通过1）确定有助于其肺毒性和纤维化的纳米材料的关键生理化学特性来满足NIH目标和公共卫生需求用于早期诊断和治疗该疾病。