Tying Distinct Nanoparticle Properties to Cellular Interactions, Fate and Respons

描述（由申请人提供）：本申请是根据重大机遇（RC2）：工程纳米材料环境健康与安全而提交的。工程纳米材料在工业和医疗应用中的使用越来越多，预计会增加意外的环境或职业暴露以及预期的医疗或直接消费者暴露，但这种暴露对人类健康的影响尚不清楚。工程纳米材料的潜在毒性或生物相容性取决于细胞相互作用和颗粒的命运，它们决定细胞反应并最终决定对人类健康的影响。细胞的相互作用和细胞的后续反应是由粒子的物理和化学性质决定的，但粒子性质与这些细胞过程之间的关系还远远没有被理解。此外，纳米材料的性质可能会受到环境（如周围空气）的改变，但这些变化也不清楚。本提案的目的是确定空气工程纳米材料的不同特性与它们在空气-液体界面上的细胞相互作用、命运和肺泡上皮细胞反应之间的关系，目的是支持吸入非材料毒性或生物相容性的预测性评估。空气传播的纳米材料进入呼吸道后很可能在肺泡区沉积，肺泡区是肺泡上皮细胞所在的区域。这些细胞为逃避肺泡巨噬细胞第一道防线的颗粒提供了一个脆弱的目标。越来越多的观察表明，纳米材料可能在体内以单个颗粒或小纳米级聚集体的形式呈现给肺泡细胞，它们与细胞相互作用的能力不同于大颗粒。我们将建立实际暴露于环境空气中定义良好的单分散纳米材料的方法，以描述与空气中颗粒相关的不同特性及其对空气-液体界面上肺泡上皮细胞的影响之间的关系。尺寸排除方法将确保暴露于单个纳米颗粒或小纳米级聚集体，因为它们很可能在体内呈现给细胞。基于我们在单分子灵敏度定量荧光成像方面的经验，结合分子生物学技术，我们将一次研究一个纳米颗粒或纳米级聚集体的细胞相互作用和命运，描绘与单个纳米颗粒特性和体内暴露相关的细胞过程。我们建议将重点放在表面改性和未改性的二氧化钛和无定形二氧化硅纳米颗粒上，它们已广泛用于各种应用，并构成潜在的空气暴露的重要来源。利用分析和物理化学方法，在气液界面收集的颗粒的性质将被表征。这些信息将推导出纳米材料在环境空气中发生的变化，并描绘出与空气中的纳米颗粒及其在体内的细胞相互作用和影响相关的特性。总之，我们的研究将获得空气中纳米材料的特性与其细胞相互作用，命运和反应之间的关键新关系，支持吸入纳米材料的毒性或生物相容性的预测性评估。新的信息将通过指导预防方法来产生大规模影响，这些方法将保护人类健康免受工程纳米材料的不利影响，并为新的工业和医疗应用设计安全的纳米材料。

DESCRIPTION (provided by applicant): This application is submitted in response to Grand Opportunities (RC2): Engineered Nanomaterial Environmental Health and Safety. The increasing use of engineered nanomaterials in industrial and medical applications is expected to increase both unintended environmental or occupational exposures and intended medical or direct consumer exposures, but the impact of such exposures on human health is unclear. The potential toxicity or biocompatibility of engineered nanomaterials is governed by the cellular interactions and fate of the particles, which dictate the cellular response and ultimately determine the impact on human health. The cellular interactions and subsequent response of the cells are governed by the physical and chemical properties of the particles, but the relationships between particle properties and these cellular processes are far from being understood. Furthermore, the properties of nanomaterials are likely to be modified by the environment, such as ambient air, but these changes are also unclear. The purpose of this proposal is to identify relationships between distinct properties of airborne engineered nanomaterials and their cellular interactions, fate, and response in alveolar epithelial cells at the air- liquid interface with the goal of supporting predictive evaluation of inhaled nonmaterial's toxicity or biocompatibility. Airborne nanomaterials that enter the respiratory tract are likely to be deposited in the alveolar region, where alveolar epithelial cells are found. These cells provide a vulnerable target for particles that escape the first line of defense by the alveolar macrophages. Accumulating observations indicate that nanomaterials are likely to be presented to alveolar cells in vivo as individual particles or small nanoscale aggregates, which differ from the larger particles in their ability to interact with the cells. We will establish methods for realistic exposures to well-defined monodispersed nanomaterials in ambient air for delineating relationships between distinct properties that are relevant to airborne particles and their impact on alveolar epithelial cells at the air- liquid interface. Size exclusion methods will ensure exposures to individual nanoparticles or small nanoscale aggregates, as they are likely to be presented to the cells in vivo. Building on our experience in quantitative fluorescence imaging with single molecule sensitivity, combined with molecular biology techniques, we will investigate the cellular interactions and fate of one nanoparticle or nanoscale aggregate at a time, delineating cellular processes that are relevant to the properties of the individual nanoparticle and the exposures in vivo. We propose to focus on surface modified and unmodified titania and amorphous silica nanoparticles, which have been widely used in diverse applications and pose a significant source for potential airborne exposures. Using analytical and physical chemistry methods, the properties of the particles, collected at the air-liquid interface, will be characterized. This information will derive changes that occur to nanomaterials in ambient air and delineate properties that are relevant to airborne nanoparticles and their cellular interactions and impact in vivo. Together, our studies will gain critical new relationships between properties of airborne nanomaterials and their cellular interactions, fate and response, supporting predictive evaluation of toxicity or biocompatibility of inhaled nanomaterials. The new information will have a large scale impact by guiding preventative approaches that will protect human health from adverse effects of engineered nanomaterials and the design of safe nanomaterials for new industrial and medical applications. PUBLIC HEALTH RELEVANCE: The increasing use of engineered nanomaterials in industrial and medical applications is expected to increase both unintended environmental or occupational exposures and intended medical or direct consumer exposures, but the impact of such exposures on human health is unclear. The potential toxicity or biocompatibility of engineered nanomaterials is governed by the cellular interactions and fate of the particles, which dictate the cellular response and ultimately determine the impact on human health. These cellular interactions and subsequent response of the cells are governed by the physical and chemical properties of the particles, but the relationships between particle properties and these cellular processes are far from being understood. Our research will address the specific call and public health needs by identifying critical new relationships between properties of airborne nanomaterials and their cellular interactions, fate and response, supporting predictive evaluation of toxicity or biocompatibility of inhaled nanomaterials. The new information will have a large scale impact by guiding preventative approaches that will protect human health from adverse effects of engineered nanomaterials and the design of safe nanomaterials for new industrial and medical applications.