Investigating Toxicity of Airborne Metal Nanoparticles: Mechanisms and Characterization

基于纳米粒子的技术正在电子、替代能源、化妆品和生物医药等不同领域得到应用，并有望成为新的治疗和诊断工具以及有效的药物输送装置。与此同时，对人类接触NPs可能导致重大不良毒性效应的日益关注需要作为紧急事项进行调查。空气中的金属基NPs特别令人担忧，因为它们很容易悬浮在环境空气中，因此在其生产和使用过程中可能偶然或意外地被吸入。吸入的NPs在肺区有非常高的沉积效率，并且很容易穿透上皮，到达间质部位和循环系统。因此，NP暴露可能会造成心肺损伤的风险，但这种类型的研究需要基于系统的方法。到目前为止，缺乏适当的细胞np暴露系统阻碍了对吸入暴露于金属np的心肺毒性的研究。******我的研究计划的长期目标是更好地了解空气中的金属基NP如何与生物系统相互作用，通过阐明使用创新的毒理学方法潜在的NP毒性的细胞和分子机制。该计划有两个总体目标：1)推进体外毒性测试系统，以更确定地筛选、排序和预测NP的毒性作用；2)使用毒性基因组学方法识别和表征NP毒性的因果因素。在接下来的五年里，我的短期目标是评估吸入性金属NPs的毒性，并通过提供更多关于其病因和机制的信息，对NPs进行更深入的动物研究。我特别建议：1)阐明NP增强肺部细菌感染的潜在原因和机制；2)评估肺部NP暴露对心血管系统的影响。******随着这项研究的成功完成，将有许多好处提供(1)HQP独特的培训机会，为一个新的科学分支（纳米毒理学）；(2)关于NP毒性等级和NP优先级的有价值信息，作为一种具有成本效益的筛选方法进行体内试验；(3)了解NP暴露产生生物反应的机制，因为这将使我们在制定安全NP设计策略方面处于有利地位。

Nanoparticle (NP, -based technologies are finding applications in fields as diverse as electronics, alternative energy, cosmetics and biomedicine, and hold great promise as new therapeutic and diagnostic tools and as effective drug delivery devices. At the same time, rising concerns that human exposure to NPs may lead to significant adverse toxic effects need to be investigated as a matter of urgency. Airborne metal-based NPs are of particular concern because they are readily suspended in ambient air and so can be inhaled incidentally or accidentally throughout their production and use. Inhaled NPs have a very high deposition efficiency in the pulmonary region, and a high propensity to penetrate the epithelium and reach interstitial sites and the circulatory system. It then follows that NP exposure could pose a risk of cardiopulmonary injury, but this type of study requires a systems-based approach. Until now, the lack of an appropriate cell-NP exposure system has hampered the study of the cardiopulmonary toxicity of inhalation exposure to metal NPs. ******The long-term goal of my research program is to better understand how airborne metal-based NPs interact with biological systems by elucidating the cellular and molecular mechanisms underlying NP toxicity using an innovative toxicology approach. This program has two overarching objectives: to i) advance an in vitro toxicity testing system to screen, rank and predict with greater certainty the toxic effects of NPs and ii) identify and characterize the causal factors and NP toxicity using a toxicogenomic approach. Over the next five years, my short-term objectives will assess the toxicity of inhaled metal NPs and prioritize NPs for more in depth in animal studies by providing more information on its causal factors and mechanisms. I specifically propose to: 1) elucidate the underlying causes and mechanisms by which NPs enhance lung bacterial infection and 2) assess the effects of pulmonary NP exposure on the cardiovascular system.******With successful completion of this research, there will be many benefits providing (1) HQP with unique training opportunities for a new branch of science (nanotoxicology); (2) valuable information on the rank of NP toxicity and prioritization of NPs for in vivo testing as a cost-effective screening; (3) understanding of the mechanisms by which NP exposures produce biological responses as this will put us in a strong position to develop strategies to design safe NPs.