Respiratory and Ocular Toxicity of Inhaled Nanomaterials

总结 我们假设工程纳米材料在成分、尺寸、直径和表面涂层方面存在差异 (ENM)将调节雾化ENM在肺中的体内沉积、分布和生物效应 还有眼睛在这个项目中，我们将系统地测试不同的ENM后雾化，以确定关键的 影响其毒性的特征。我们选择研究呼吸道对健康的影响 和眼睛，因为这两个器官系统代表了暴露于雾化ENM的主要途径。我们的重点 将通过吸入主要类别的ENM，创建真实的和相关的暴露情景， 和预期的接触途径此外，肺和眼睛都是基于ENM的化疗的当前靶点。 治疗性递送。我们在这个提案中的目标是系统地、定量地比较 具有不同物理化学性质的纳米材料在这些器官系统上的作用， 相关模型。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。我们有能力为新的NHIR做出贡献 联合体在环境营养学方面的努力。我们有使用所列材料的经验。因为 将系统地测试可能大量的材料，这是一个分层的范例，有明确的指示， 将使用ENM需要的体内试验。我们有一个强大的出版记录ENM的健康影响 体内和体外研究，特别是新材料气溶胶，包括实验室产生的干粉 和雾化液体气雾剂。我们的团队在金属、金属氧化物、碳颗粒、碳 纳米管和三维ENM与此耦合是货车Winkle开发的新方法， Pinkerton实验室研究位点特异性细胞反应和充分表征的方法 在基于医生的眼科学中通常使用的角膜和视网膜成像中。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 显微切割以研究ENM保留和位点特异性基因、蛋白质和细胞应答。此外，三个 调查人员有能力利用一个独特的资源，加州国家灵长类动物研究 这使得在与人类、非人类生理相关的模型中进行ENM效应的体外研究成为可能。 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 本申请将强调用于我们感兴趣的器官的原代细胞或组织外植体， 研究选定的ENM气溶胶定义的财团。我们提案的具体目标提供了新颖的 和创新的方法来测量细胞为基础的细胞毒性，炎症和重塑在正常和 完整呼吸道以及角膜和视网膜的损伤修复模型。

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.