Respiratory Effects of Silver and Carbon Nanomaterials (RESAC)

描述（由申请人提供）：工程纳米材料（enm）具有新颖的物理和化学特性，源于其纳米尺度的尺寸，并且在与生物系统相互作用时可以经历动态变化（例如，团聚，聚集和氧化）。因此，这种相互作用对ENM的健康影响具有重要意义。拟议的中心拨款题为“银和碳纳米材料（RESAC）的呼吸效应”，重点研究enm与肺内膜液之间的相互作用，将使用系统的、综合的、多学科的方法来产生机制驱动的毒理学数据，这些数据将用于enm基于机制的风险分析框架。中心的主要研究将通过三个相互关联的项目进行。项目1将使用细胞模型来确定ENM的物理化学性质（例如，大小、形状、纵横比、化学性质），这些性质决定了ENM与肺内膜液相互作用时的分子、细胞和免疫反应。预计这种相互作用也将严重影响ENM的理化性质，这反过来又会影响ENM与巨噬细胞和上皮细胞的反应性。这些早期细胞和分子水平的事件对于预测吸入enm的最终命运和病理后果至关重要，这将在项目2中使用大鼠和小鼠模型进行研究。项目2将研究吸入ENMs是否以及如何影响肺表面活性物质组成和功能，诱导肺部炎症和肺部病理，产生氧化应激，穿透肺细胞，影响巨噬细胞的先天免疫功能。项目1和项目2产生的结果，以及需要收集的其他相关数据，将用于项目3，即通过实施、调整和扩展现有的最先进的暴露-剂量-效应序列多尺度建模系统，来定义、演示和测试enm的原型广义风险分析框架。我们的新模型将在数学上将ENM的特定特性（例如，表面积）与生物效应联系起来，从而允许在预测ENM健康风险时使用最相关的“剂量学”。

DESCRIPTION (provided by applicant): Engineered nanomaterials (ENMs) have novel physical and chemical properties, stemming from their nanometer-scale size, and can undergo dynamic changes (e.g., agglomeration, aggregation, and oxidation) when interacting with biological systems. This interaction, thus, has important implications for ENM health effects. The proposed Center grant, entitled 'Respiratory Effects of Silver and Carbon Nanomaterials (RESAC)', focusing on the interaction between ENMs and the lung lining fluid, will use a systematic, integrated, multidisciplinary approach to produce mechanism-driven toxicological data that will be used in a mechanism-based risk analysis framework for ENMs. Main research of the Center will be carried out through three inter-related projects. Project 1 will use cell models to determine ENM physicochemical properties (e.g., size, shape, aspect ratio, chemistry) that dictate the molecular, cellular, and immune reactivities in response to ENM interactions with the lung lining fluid. It is expected that such interaction will also critically impact ENM physicochemical properties, which in turn, will impact on the ENM reactivity with macrophages and epithelial cells. These early cellular- and molecular-level events are crucial in predicting the ultimate fate and pathological consequences of inhaled ENMs, which will be studied in Project 2 using rat and mouse models. Project 2 will examine whether and how inhaled ENMs affect lung surfactant composition and function, induce lung inflammation and lung pathology, generate oxidative stress, penetrate lung cells, and affect the innate immune function of macrophages. Results generated from Projects 1 and 2, along with other relevant data to be collected, will be used in Project 3 that is to define, demonstrate, and test a prototype generalized risk analysis framework for ENMs by implementing, adapting, and expanding available state-of-the-art multi-scale modeling systems for the exposure-to-dose-to-effect sequence. Our new models will mathematically link specific ENM properties (e.g., surface area) to biological effects, allowing the use of most relevant 'dosimetry' in predicting ENM health risks.