Respiratory Effects of Silver and Carbon Nanomaterials (RESAC)

描述（由申请人提供）：工程纳米材料（ENM）具有源于其纳米级尺寸的新颖物理和化学性质，并且可以经历动态变化（例如，附聚、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。拟议的中心赠款，题为“呼吸影响的银和碳纳米材料（RESAC）”，重点是之间的相互作用ENM和肺衬里液，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，将用于基于机制的风险分析框架ENM。该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），其决定了响应于ENM与肺衬里液的相互作用的分子、细胞和免疫反应性。预计这种相互作用也将严重影响ENM的物理化学性质，进而影响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ENM是否以及如何影响肺表面活性物质的组成和功能，诱导肺部炎症和肺部病理，产生氧化应激，穿透肺细胞，并影响巨噬细胞的先天免疫功能。项目1和2生成的结果以及沿着收集的其他相关数据将用于项目3，即通过实施、调整和扩展适用于剂量-效应序列的现有最先进多尺度建模系统，定义、证明和测试ENM的原型广义风险分析框架。我们的新模型将在数学上联系特定的ENM属性（例如，表面积）的生物效应，允许使用最相关的“剂量学”在预测ENM的健康风险。

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.