Collaborative Research: Mechanistic and Predictive Genotoxicity Assessment of Nanomaterials

建议编号：1437257/1437209机构：东北大学/哈佛大学标题：合作研究：纳米材料的机理和预测遗传毒性评估碳基纳米材料(CNM)可能是最有用的工程纳米材料之一，但我们对碳基纳米材料的毒性和对人类和生态系统的潜在影响的了解仍处于初级阶段。在观察到的各种毒性效应中，遗传毒性(化学品对基因的损害)对人类和其他生命特别令人担忧，因为纳米材料的遗传毒性(纳米遗传毒性)可能导致细胞突变，最终导致癌症。这项研究将展示一个新的高通量、快速和有效的纳米原生生物毒性检测平台和一个新的机制驱动的层次化模型框架的应用。这项研究的结果将填补在对CNM的环境和健康影响的机械性理解方面的紧迫知识空白。这项研究对环境和公众健康保护具有重大意义。这项研究的结果将有助于与纳米科学和技术相关的战略，并阐明纳米材料对环境和健康的影响，这将有助于弥合科学研究、商业产品创造和公共健康保护之间的差距。在对社区的更广泛影响方面，一系列协同的教育推广和公共教育计划将向多个层次的广泛受众展示纳米技术的技术、好处以及社会和环境影响。例如，作为职业奖项的一部分，Pi Gu发起了BEST(环境、展示和培训生物技术)计划。有了这项建议，她将能够扩大该计划，以及与其他现有计划(如RET计划、NU Connections等)合作，以促进对学生和教师的培训。这两个PI还将与波士顿科学博物馆合作创建向公众传播研究的多媒体。该项目建议使用新开发的高通量基于毒素基因组学的三维基因/蛋白质表达谱技术，对各种表征良好的碳基纳米材料(CNM)进行全面和系统的遗传毒性评估，目的是将纳米遗传毒性与CNM的物理化学和结构特性联系起来，并探索原型机制驱动的QSAR(定量结构活性关系)模型。四种不同的碳纳米管(SWCNT、富勒烯C60、碳黑和石墨烯)的遗传毒性及其变化将通过测量NM诱导的基因和蛋白质的表达变化来评估，这些基因和蛋白质是已知DNA损伤和修复途径的指示性或必需的，使用新开发的分子遗传毒性分析平台，并扩展到不同分类水平的多个物种(细菌、酵母和人类)。剂量-反应关系和分子遗传毒性终点将使用我们最近提出的分子效应水平指数(MELI)来确定。为了验证所提出的分子检测方法并确认所测试的CNM的遗传毒性，将同时进行常规的表型遗传毒性检测。将使用一系列现代技术来确定CNM的纯度、元素组成、尺寸、表面化学、聚集体大小和状态、Zeta电位、亲水性等。通过CNMs描述符、DNA损伤机制特定的分子端点和表型遗传毒性端点之间的关联，探索一个具有层级结构的原型纳米遗传毒性QSAR模型，该模型将当前的QSAR框架与分子生物测定信息相结合。

PI: April Gu / Chad VecitisProposal Number: 1437257 / 1437209 Institutions: Northeastern University / Harvard University Title: Collaborative Research: Mechanistic and Predictive Genotoxicity Assessment of Nanomaterials Carbon-based nanomaterials (CNMs) may be among the most useful engineered nanomaterials for different applications, although our understanding of the toxicity and potential impact of carbon-based nanomaterials on human and ecosystems is still in its infancy. Among the various toxicity effects observed, genotoxicity (the damage to genes from chemicals) is of particular concern to human and other lives because genotoxicity from nanomaterial (nanogenotoxicity) can potentially cause cells to mutate and eventually lead to cancer. This study will demonstrate the application of a new high-throughput, rapid and effective nanogenotoxicity assay platform and a new mechanism-driven hierarchical model framework that will be tested. The results of the research will fill in the urgent knowledge gap in mechanistic understanding of the environmental and health impact of CNMs. This research has significant benefits to the environment and public health protection. The outcome from the research will aid strategies related to nanoscience and technology, as well as elucidate the environmental and health implications of nanomaterials, which will help bridge the gap between scientific research, creation of commercial products and public health protection. In terms of broader impact on the community, the synergized arrays of education outreach and public education programs will present the technology, benefits, and societal and environmental impact of nanotechnology to a wide range of audiences at many levels. For example, PI Gu had initiated the BEST (Biotechnology for the Environment, Showcase and Training) program as part of a CAREER award. With this proposal, she will be able to expand that program, as well as collaborate with additional existing programs (e.g. a RET program, NEU CONNECTIONS, etc) to promote training of students and teachers. Both PIs will also work with the Boston Museum of Science to create multimedia that disseminates research to the public.This project proposes to perform a comprehensive and systematic genotoxicity assessment of a variety of well-characterized carbon-based nanomaterials (CNMs), using a newly developed high throughput toxicogenomics-based 3-D gene/protein expression profiling technique, with the aim to relate nanogenotoxicity with CNMs' physicochemical and structural properties and, explore prototype mechanism-driven QSAR (Quantitative Structure Activity Relationships) model. Genotoxicity of four different CNMs (SWCNT, fullerene C60, carbon black and graphene) and their variations will be evaluated by measuring the NM-induced expression alteration in genes and proteins that are indicative or essential for the known DNA damage and repair pathways, using the newly developed molecular genotoxicity assay platform and, with the extension to multiple species across different taxonomic levels (bacteria, yeast and human). Dose-response relationships and molecular genotoxicity endpoints will be determined using the molecular effect level index (MELI) recently proposed by us. To validate the proposed molecular assay and confirm the genotoxicity of CNMs tested, conventional phenotypic genotoxcity assays will be performed in parallel. An array of modern techniques will be employed to determine the purity, elemental composition, dimension, surface chemistry, aggregate size and state, zeta potential, hydrophilicity etc. of the CNMs. A prototype nanogenotoxicity QSAR model with hierarchical structures that integrates current QSAR framework with molecular bioassay information through correlative links among CNMs descriptors, DNA damage mechanism-specific molecular endpoints and phenotypic genotoxicity endpoints will be explored.