Respiratory and Ocular Toxicity of Inhaled Nanomaterials

吸入纳米材料的呼吸和眼毒性

• 批准号: 9770859
• 负责人: KENT Ed PINKERTON
• 金额: $ 43.5万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770859
• 关键词: 3-Dimensional; Aerosols; Affect; Air; Autopsy; Biological; Caliber; California; Carbon; Carbon Nanotubes; Cell Line; Cells; Characteristics; Charge; Cornea; Corneal Injury; Coupled; Deposition; Engineering; Epithelium; Exposure to; Extracellular Matrix; Eye; Eye Injuries; Gene Proteins; Goals; Health; Histologic; Human; In Vitro; Inflammation; Inflammatory; Inhalation; Injury; Laboratories; Liquid substance; Lung; Macaca mulatta; Measures; Mediating; Metals; Methods; Microdissection; Microscopic; Modeling; Molecular; Monkeys; Nebulizer; Ophthalmology; Organ; Organism; Pattern; Physicians; Physiological; Population; Positioning Attribute; Powder dose form; Primates; Process; Property; Publications; Rattus; Research; Research Personnel; Resources; Respiratory System; Retina; Risk; Role; Shapes; Signal Transduction; Site; System; Testing; Therapeutic; Tissues; Toxic effect; Wound Healing; aerosolized; base; body system; cell type; cost; cytotoxicity; experience; exposure route; in vivo; in vivo evaluation; injury and repair; innovation; interest; macrophage; metal oxide; nanomaterials; nonhuman primate; novel; novel strategies; ozone exposure; particle; physiologic model; recruit; respiratory; response; retinal imaging; surface coating; wound

SUMMARY We hypothesize differences in composition, size, diameter and surface coating of engineered nanomaterials (ENM) will modulate the in vivo deposition, distribution and biologic effects of aerosolized ENM to the lungs and the eyes. In this project, we will systematically test diverse ENM following aerosolization to identify the key characteristics that influence their toxicity. We have chosen to examine health effects in the respiratory tract and the eye, since both organ systems represent the major route of exposure to aerosolized ENM. Our focus will be to create real and relevant exposure scenarios by inhalation to the major classes of ENMs, a common and expected route of exposure. Further, the lungs and the eyes are both current targets of ENM-based therapeutic delivery. Our goal in this proposal is to systematically and quantitatively compare the health effects of nanomaterials with different physicochemical properties on these organ systems using physiologically relevant models. The health effects will include detailed molecular and pathophysiologic changes that will be targeted to zones of ENM deposition and retention. We are well positioned to contribute to the new NHIR consortium efforts on ENM. We have experience working with many of the materials listed. Because a potentially large number of materials will be systematically tested, a tiered paradigm with clear indications for which ENM need in vivo testing will be used. We have a strong publication record of ENM health effects research in vivo and ex vivo, particularly of novel material aerosols including laboratory generated, dry powder and nebulized liquid aerosols. Our team has expertise in metals, metal oxides, carbon particles, carbon nanotubes and 3-dimensional ENM Coupled with this are the novel methods developed in the Van Winkle, Thomasy and Pinkerton laboratories to study site-specific cellular responses and well-characterized methods in corneal and retinal imaging commonly used in physician-based ophthalmology. These novel approaches include microscopic and histologic approaches to localize ENM in tissues as well as the application of microdissection to study ENM retention and site specific gene, protein and cellular responses. Further, all three investigators have the ability to take advantage of a unique resource, the California National Primate Research Center This enables in vitro studies of ENM effects in a model physiologically relevant to humans, nonhuman primate explants and cells. We know that cell lines give divergent results and so the proposed studies in this application will emphasize primary cells or tissue explants for our organs of interest, coupled with in vivo studies of select ENM aerosols as defined by the consortium. The specific aims of our proposal provide novel and innovative methods to measure cell-based cytotoxicity, inflammation and remodeling in both normal and injury repair models of the complete respiratory tract, as well as the cornea and retina.

概括 我们假设工程纳米材料的成分、尺寸、直径和表面涂层存在差异 (ENM) 将调节雾化 ENM 对肺部的体内沉积、分布和生物效应 和眼睛。在这个项目中，我们将系统地测试雾化后的各种 ENM，以确定关键的 影响其毒性的特征。我们选择检查对呼吸道健康的影响 和眼睛，因为这两个器官系统都是接触雾化 ENM 的主要途径。我们的重点 将通过吸入主要类别的 ENM 来创建真实且相关的暴露场景，这是一种常见的 和预期的暴露途径。此外，肺部和眼睛都是基于 ENM 的当前目标 治疗递送。我们这项提案的目标是系统地、定量地比较健康影响 利用生理学方法将具有不同理化性质的纳米材料应用于这些器官系统 相关型号。健康影响将包括详细的分子和病​​理生理变化 针对 ENM 沉积和保留区域。我们有能力为新的 NHIR 做出贡献 ENM 联盟的努力。我们拥有处理列出的许多材料的经验。因为一个 潜在的大量材料将被系统地测试，这是一种具有明确指示的分层范例 其中ENM需要体内测试才会使用。我们拥有丰富的 ENM 健康影响发表记录 体内和离体研究，特别是新型材料气溶胶，包括实验室产生的干粉 和雾化液体气溶胶。我们的团队拥有金属、金属氧化物、碳颗粒、碳 纳米管和 3 维 ENM 与此相结合的是 Van Winkle 开发的新颖方法， Thomasy 和 Pinkerton 实验室研究位点特异性细胞反应和充分表征的方法 用于医师眼科常用的角膜和视网膜成像。这些新颖的方法 包括在组织中定位 ENM 的显微镜和组织学方法以及应用 显微切割研究 ENM 保留和位点特异性基因、蛋白质和细胞反应。此外，所有三个 研究人员有能力利用独特的资源，即加州国家灵长类动物研究中心 中心 这使得能够在与人类、非人类生理相关的模型中对 ENM 效应进行体外研究 灵长类动物外植体和细胞。我们知道细胞系会产生不同的结果，因此本研究中提出的研究 应用程序将强调我们感兴趣的器官的原代细胞或组织外植体，再加上体内 对联盟定义的选定 ENM 气溶胶的研究。我们提案的具体目标提供了新颖的 以及测量正常和正常细胞中基于细胞的细胞毒性、炎症和重塑的创新方法 完整呼吸道以及角膜和视网膜的损伤修复模型。