Nanoparticle Fibrogenicity and Fibroblast Stem-Like Cells

纳米颗粒成纤维性和成纤维细胞样细胞

• 批准号: 9212809
• 负责人: Yon Rojanasakul
• 金额: $ 33.75万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212809
• 关键词: Address; Animal Model; Animals; Asbestos; Biological Assay; Biological Factors; Biological Markers; Biomedical Engineering; Carbon; Carbon Nanotubes; Cells; Characteristics; Chronic; Clinical; Coculture Techniques; Collagen; DNA Damage; Deposition; Development; Disease; Early Diagnosis; Engineering; Enzymes; Exhibits; Experimental Models; Exposure to; Extracellular Matrix; Failure; Fibroblasts; Fibrosis; Goals; Health; Human; Industrial Product; Industry; Lead; Luciferases; Lung; Lung diseases; Malignant Neoplasms; Metals; Modeling; Molecular Target; Myofibroblast; Nanotechnology; Natural graphite; Nitrogen; Nodule; Oxidation-Reduction; Pathologic; Patients; Phenotype; Population; Prevention; Prevention strategy; Process; Production; Property; Public Health; Pulmonary Fibrosis; Reactive Oxygen Species; Regulation; Reporter; Research; Risk Assessment; Role; Safety; Science; Side; Silicon Dioxide; Source; Specimen; Stem Cell Development; Stem cells; System; Testing; Time; Tissues; Toxic effect; United States National Institutes of Health; Work; Xenobiotics; animal data; base; cellular targeting; commercial application; cytotoxicity; design; effective therapy; expectation; exposed human population; fetal; fibrogenesis; high throughput screening; in vitro Model; in vivo; injured; innovation; interstitial; large scale production; lung development; macrophage; migration; nanomaterials; nanoparticle; novel; particle; progenitor; public health relevance; rapid technique; repaired; response; screening; self-renewal; specific biomarkers; stem; stem-like cell; treatment strategy; trend

 DESCRIPTION (provided by applicant): Engineered anomaterials including carbon nanotubes (CNTs) have emerged as one of the most important classes of new materials having enormous potential to create new and better products. Accumulating evidence indicates that pulmonary exposure to CNTs induces lung fibrosis, a fetal and incurable lung disease with no known effective treatments. The long-term objective of this project is to enable safe nanotechnology through the understanding of underlying mechanisms of fibrogenesis and determining key physicochemical factors controlling the fibrogenic effect of nanomaterials. Evolving research indicates that fibroblast stem cells (FSCs) with unlimited proliferative potential are likely a driing force of fibrosis, but the underlying mechanisms and their role in CNT fibrogenesis are not known. We have obtained breakthrough evidence showing the ability of CNTs to induce FSCs with a functional phenotype of activated fibroblasts that are responsible for extracellular matrix accumulation, a hallmark of lung fibrosis. We hypothesize that CNTs induce lung fibrosis through a process that involves FSC induction and that such induction is dependent on specific physicochemical properties of CNT. Three specific aims are proposed to test the hypotheses. In Aim 1, we will characterize FSC acquisition in CNT-treated fibroblasts and animals and determine their role in fibrogenesis. Aim 2 will develop 3D high-throughput fibroblastic nodule models for quantitative assessment of CNT fibrogenicity and document the impact of CNT characteristics on FSC acquisition and fibrogenesis. This Aim will also identify specific FSC biomarkers and validate the in vitro models in animals. Aim 3 will examine redox regulation of FSC development and fibrogenesis, and determine specific oxidative species and key regulatory enzymes involved in the process. Our expectations are that at the conclusion of this project, we will have determined the role of FSCs in CNT fibrogenesis and identified specific biomarkers and key physicochemical properties of CNTs that influence their fibroticity. This work is important because of the overall impact it will have on the development of safe nanomaterials as well as on risk assessment, early detection and prevention of nanomaterial-induced fibrosis. We expect this impact to be broad since the findings from this project are highly applicable to other fibrogenic agents, nanomaterials and xenobiotics. The proposed work is innovative because it is the first to study FSCs and their role in fibrosis. It will also develop novel experimental models and assay methods for rapid assessment of nanomaterial fibrogenicity and for their potential utility in various stem cell applications.

 描述（由申请人提供）：包括碳纳米管（CNT）在内的工程纳米材料已成为最重要的新材料类别之一，具有创造新的和更好的产品的巨大潜力，越来越多的证据表明，肺部暴露于碳纳米管会诱发肺纤维化。该项目的长期目标是通过了解纤维形成的潜在机制并确定控制纤维形成的关键物理化学因素，实现安全的纳米技术。不断发展的研究表明，具有无限增殖潜力的成纤维细胞干细胞（FSC）可能是纤维化的干燥力量，但其在碳纳米管纤维形成中的潜在机制及其作用尚不清楚。碳纳米管诱导具有活化成纤维细胞功能表型的 FSC，其负责细胞外基质积累，这是肺纤维化的标志。我们发现碳纳米管会诱导肺纤维化。通过涉及 FSC 诱导的过程，并且这种诱导取决于 CNT 的特定理化性质，提出了三个具体目标来测试假设。在目标 1 中，我们将描述 CNT 处理的成纤维细胞和动物中 FSC 的获取并确定其作用。目标 2 将开发 3D 高通量成纤维细胞结节模型，用于定量评估 CNT 纤维发生性，并记录 CNT 特性对 FSC 获取和纤维发生的影响。 Aim 还将确定特定的 FSC 生物标志物并验证动物的体外模型。Aim 3 将检查 FSC 发育和纤维形成的氧化还原调节，并确定参与该过程的特定氧化种类和关键调节酶。在这个项目中，我们将确定 FSC 在 CNT 纤维形成中的作用，并确定影响其纤维化的 CNT 的特定生物标志物和关键理化特性。这项工作很重要，因为它将产生总体影响。关于安全纳米材料的开发以及纳米材料引起的纤维化的风险评估、早期检测和预防，我们预计这种影响将是广泛的，因为该项目的研究结果非常适用于其他纤维形成剂、纳米材料和异生物质。这项工作具有创新性，因为它是第一个研究 FSC 及其在纤维化中的作用的研究，它还将开发新的实验模型和测定方法，用于快速评估纳米材料的纤维形成性及其在各种干细胞应用中的潜在用途。