Integrative Studies to Define Drivers of Nanomaterial Toxicity

描述（由申请人提供）：纳米毒理学是研究纳米材料暴露可能导致的未知和潜在不可预见的后果，因为纳米材料的独特性质可能导致它们对生命系统产生不利影响。目前，在与纳米材料暴露相关的风险方面存在巨大的毒理学数据缺口，由于缺乏信息，可能预测纳米材料与生物系统相互作用的主要特征尚未确定。因此，快速测试策略是立即必要的，以确定导致毒性的纳米材料的具体特征，以减轻暴露风险，并确定可用于预测纳米材料危害的结构-性质关系，以代替经验数据。该研究利用信息学方法利用纳米材料表征和毒性数据，利用综合方法战略性地定位结构-活性关系。目标是确定控制纳米材料-生物相互作用的主要特征，并定义纳米材料毒性的关键驱动因素。ONES的总体目标是确定尺寸、形状和表面化学对吸收、毒性作用和机制的相对影响。在完成建议的研究后，我们期望：1)通过提供有关纳米材料特性、命运和生物影响的主要数据来填补关键信息空白；ii)提供有效的分析方法，以快速确定纳米材料特性和测试生物影响；iii)确定暴露于环境相关纳米材料浓度的斑马鱼中导致毒性结果的分子事件链；iv)提供一个公正的信息平台，以描述哪些纳米材料的特征；或结合特点，修改毒性潜势。这些信息将产生积极的影响，并通过减少对每一种纳米材料配方进行经验测试的需要，提供可以修改的结构元素的信息以尽量减少固有的纳米材料毒性，增加社区资源来传播关于纳米材料的重要信息，从而推动纳米医学、纳米毒理学和纳米技术领域的发展。最后为风险评估人员提供了新的工具，以保护人类和环境免受潜在的有害暴露。

DESCRIPTION (provided by applicant): Nanotoxicology is the study of the unknown and potentially unforeseen consequences that may result from nanomaterial exposure due to the unique properties that may cause them to adversely impact living systems. Currently, vast toxicological data gaps exist regarding the risks associated with nanomaterial exposure, and the principal characteristics that may be predictive of nanomaterial interactions with biological systems have yet to be identified due of this lack of information. Thus, rapid testing strategies are immediately necessary to identify the specific features of nanomaterial that result in toxicity in order to mitigate risks from exposure and define structure-property relationships that can be used to predict nanomaterial hazard in lieu of empirical data. The proposed research utilizes an integrative approach to strategically target structure-activity relationships by leveraging nanomaterial characterization and toxicity data using informatics. The goal is to identify the principal features that govern nanomaterial- biological interactions and define key drivers for nanomaterial toxicity. The overall objective of the ONES is to determine the relative influence that size, shape and surface chemistry have on uptake, effects and mechanism of toxicity. Upon completion of the proposed studies, we expect to: i) fill critical information gaps by providing primary data on nanomaterial characterization, fate and biological impact, ii) provide validated assays for rapidly determining nanomaterial characteristics and testing for biological impact, iii) identify the chain of molecular events that lead to a toxic outcome in zebrafish exposed to environmentally relevant nanomaterial concentrations, and iv) deliver an unbiased information platform to delineate which nanomaterial features, or combination of features, modify toxic potential. Such information will have a positive impact and advance the fields of nanomedicine, nanotoxicology, and nanotechnology by reducing the need to empirically test every nanomaterial formulation, providing information on the structural elements that can be modified to minimize inherent nanomaterial toxicity, enhancing community resources for dissemination of important information on nanomaterial, and finally providing new tools for risk assessors to protect humans and the environment from potentially harmful exposures.