Multidimensional in vivo Assessments of Engineered Nanomaterials and Biological Interactions

虽然纳米技术在满足关键社会需求方面具有巨大潜力，但创新者、政策制定者和 公众担心工程纳米材料（ENM）的新特性可能会造成危害。的 产生的新ENM数量超过了我们了解这些材料影响的努力。到 为了提高我们的理解并跟上新的创新步伐，我们越来越需要ENM的进步 合成、表征和生物活性筛选。由于这项挑战的复杂性，高度互动 需要多学科团队。我们将与纳米材料健康影响研究合作 （NHIR）：工程纳米材料资源和协调核心（ERCC）。我们预计，NHIR将 提供精密设计的多功能ENM，以探测表面化学和核心的作用 在功能和性能方面的特点。我们认为，斑马鱼提供了无与伦比的优势， 询问ENM和生物系统之间的相互作用。现在人们普遍认为， 由于遗传和分子保守性，使用斑马鱼模型很容易转化为人类 这些物种之间。更重要的是，这种模式独特的内在优势为研究 在其他系统中不可能或不可行的机会。例如，使用少量的测试材料， 可以确定给定的ENM是否能够与生物靶标相互作用以产生分子生物学效应。 整个动物体内转录组、蛋白质组和代谢组的变化。这些“omic”的敏感性 由于所有细胞类型都是同时评估的， 整条斑马鱼此外，生长、器官发育、心血管功能和复杂的 神经行为很容易以高通量进行评估。在过去的几年里，我们开发了一个 许多新的工具和测定，以评估ENM对成年斑马鱼和微生物组的影响， 进一步提高我们的多维屏幕的灵敏度。在本提案中，我们将快速评估 使用多维、高通量的早期生命阶段和成年人， 斑马鱼的生物检测方法。我们将迅速提供这些全面的反应概况， NHIR财团。我们将完成以下具体目标：1）定义一个全面的生物 使用早期生命阶段的斑马鱼通过暴露于ENM产生的反应曲线; 2）确定持续时间长的 生命早期暴露于ENM的影响; 3）评估摄入ENM对微生物群的影响， 4）整合来自斑马鱼和其他生物系统的ENM反应，以开发 减少危害的原则。我们预期在完成这些建议的研究后， 与NHIR联盟的互动和合作，ENM生物学的扩展知识库 互动将开始，以减少ENM健康风险的不确定性。在这样做的过程中，我们将朝着 长期目标是最大限度地发挥环境营养措施的效益，最大限度地减少其负面影响。

While nanotechnology has significant potential to address critical societal needs, innovators, policy makers and the public have concerns that the novel properties of engineered nanomaterials (ENMs) may cause harm. The number of new ENMs being generated is outpacing our efforts to understand the impacts of these materials. To advance our understanding and to keep pace with new innovations, we increasingly need advances in ENM synthesis, characterization, and bioactivity screening. Due to the complexity of this challenge, highly interactive multi-disciplinary teams are needed. We will collaborate with the Nanomaterials Health Implications Research (NHIR): Engineered Nanomaterials Resource and Coordination Core (ERCC). We expect that the NHIR will provide precision-engineered, multifunction ENMs to probe the roles of surface chemistry and core characteristics in function and properties. We propose that zebrafish offer unparalleled advantages to broadly interrogate the interactions between ENMs and biological systems. It is now widely accepted that data collected using the zebrafish model is readily translated to humans because of the genetic and molecular conservation between these species. More importantly, the unique inherent advantages of this model provides research opportunities not possible or feasible in other systems. For example, with a small quantity of test material, it is possible to determine whether a given ENM is able to interact with biological targets to produce molecular changes in the transcriptome, proteome and metabolome within the entire animal. Sensitivity of these `omic approaches” is very high and uncertainty is reduced since all cell types are assessed simultaneously in the whole zebrafish. Additionally, changes in growth, organ development, cardiovascular function, and complex neurobehavior are easily assessed at a high throughput. Over the past several years, we have developed a number of novel tools and assays to assess the impacts of ENMs on adult zebrafish and the microbiome to further increase the sensitivity of our multi-dimensional screens. In this proposal we will rapidly evaluate the bioimpacts of the provided materials using multi-dimensional, high throughput early life stage and adult zebrafish bioassays that we have pioneered. We will rapidly provide these comprehensive response profiles to the NHIR consortium. We will complete the following specific aims: 1) Define a comprehensive biological response profile produced by exposure to ENM using early life stage zebrafish; 2) Determine the long lasting impacts of early life stage exposure to ENMs; 3) Evaluate the impact of ingestion of ENMs on the microbiota in adult zebrafish; 4) Integrate ENM responses from the zebrafish and other biological systems to develop principles to reduce hazards. We expect that with completion of these proposed studies and through interactions and collaborations with the NHIR consortium, the expanded knowledge base of ENM-biological interactions will begin to reduce the uncertainty around ENM health risks. In so doing, we will progress toward the longer term goal to maximize the benefits and minimize the negative impacts of ENMs.