Collaborative Research: Mechanistic and Predictive Genotoxicity Assessment of Nanomaterials

主要研究者：April Gu / Chad Vecitis提案编号：1437257 / 1437209院校：东北大学/哈佛大学题目：合作研究：碳基纳米材料（CNM）可能是用于不同应用的最有用的工程纳米材料之一，尽管我们对碳基纳米材料对人类和生态系统的毒性和潜在影响的认识仍处于起步阶段。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重要，因为纳米材料的遗传毒性（纳米遗传毒性）可能导致细胞突变并最终导致癌症。本研究将展示一个新的高通量，快速和有效的纳米遗传毒性检测平台和一个新的机制驱动的分层模型框架，将进行测试的应用。研究结果将填补CNMs对环境和健康影响的机械理解方面的迫切知识空白。这项研究对环境和公众健康保护具有重大意义。研究成果将有助于制定与纳米科学和技术有关的战略，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卫生保护之间的差距。在对社区的更广泛的影响方面，教育推广和公共教育计划的协同阵列将在许多层面上向广泛的受众介绍纳米技术的技术，好处以及社会和环境影响。例如，皮谷发起了BEST（生物技术促进环境、展示和培训）计划，作为职业奖的一部分。有了这个建议，她将能够扩大该计划，以及与其他现有的计划（如RET计划，NEU连接等）合作，以促进学生和教师的培训。两所研究所亦会与波士顿科学博物馆合作，制作多媒体，向公众传播研究成果。本项目拟采用新开发的高通量毒理基因组学三维基因/蛋白表达谱分析技术，目的是将纳米材料的理化和结构特性与纳米遗传毒性联系起来，探索原型机制驱动的定量构效关系（QSAR）模型。将使用新开发的分子遗传毒性测定平台，并扩展至不同分类学水平的多个物种（细菌、酵母和人），通过测量NM诱导的基因和蛋白质（指示或对已知DNA损伤和修复途径至关重要）表达变化，评价四种不同CNM（单壁碳纳米管、富勒烯C60、炭黑和石墨烯）及其变体的遗传毒性。将使用我们最近提出的分子效应水平指数（MELI）确定剂量-反应关系和分子遗传毒性终点。为了验证拟定的分子试验并确认检测的CNM的遗传毒性，将平行进行常规表型遗传毒性试验。将采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、聚集体尺寸和状态、zeta电位、亲水性等。一个原型nanogenotoxicity QSAR模型与层次结构，集成当前的QSAR框架与分子生物测定信息，通过CNMs描述符之间的相关联系，DNA损伤机制特异性分子终点和表型遗传毒性endpoints将explored.This奖项反映NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.