The FHCRC/UW Toxicogenomics Consortium

FHCRC/华盛顿大学毒物基因组学联盟

• 批准号: 7407773
• 负责人: David L Eaton
• 金额: $ 73.24万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407773
• 关键词: cooperative study; functional /structural genomics; genetic susceptibility; microarray technology; toxicology

DESCRIPTION (provided by applicant) A central tenet of toxicology is that with the possible exception of acute cell necrosis, every toxic exposure leads to an alteration in the pattern of gene expression. This altered pattern of gene expression reflects the cell?s attempt to cope with the toxic insult, and can range from induction of xenobiotic metabolism to the extreme of cell suicide or apoptosis. While numerous studies have looked at changes in the expression of a limited number of genes thought to play a role in these adaptive responses, the power of array technology is the ability to obtain a comprehensive survey of thousands of genes simultaneously. This global analysis of gene expression affords researchers the ability to discern specific patterns or signatures of expression that are associated with particular classes of toxicants. These signatures are likely to include classes of genes not previously implicated in response to specific toxic insult. As such the applications of array technologies to toxicology will undoubtedly enhance our understanding of the cellular response to toxicants, which should by inference also provide insight into the mechanism of drug responses, toxicity, development effects and induction of disease. The unifying theme of the present proposal is that the comparison of gene expression profiles induced by stressors or toxicants in cells that are differentially sensitive to their effects will be particularly useful in dissecting the biochemical pathways underlying a toxic response. The investigators have assembled a team experts in the areas of biotransformations, neurodevelopmental toxicology, and carcinogenesis with the common goal of using DNA microarray technologies to compare gene expression profiles among mouse and rat, and human cells that are differentially sensitive to a variety of environmental agents. A series of four projects and a Toxicology Research Core Project, all of which make use of genetically defined rats or mice, transgenic and knockout mice and primary human and rodent cell cultures are proposed. The projects will be supported by an Administrative Core and essential three facility cores. The DNA Microarray Facility Core will provide project researchers access to the state-of-the-art facility established at the Fred Hutchinson Cancer Research Center by Dr. Zarbl. The Tissue Acquisition Core will project researchers access the Transgenic/Knockout Mice facility at the University of Washington, providing researchers access to genetically defined mice and their tissues. Recognizing the need to look at individual cell types comprising organs, the investigators also included within this Core access to cell enrichment technologies. The Tissue Acquisition Core will provide researchers access to high speed cell sorting and laser capture microdissection capabilities. The final facilities core will provide bioinformatic and biostatistics support to the project researchers. These latter will be required for coordinating the acquisition, processing, storing and analyzing the large volumes of data that will be generated by the project researchers. Each of the Cores will also interact with other Consortium members and the central contractor through the Toxicology Research Core Project to perform cross species and cross platform comparisons and to develop standards for data standardization. The latter will be essential for the generation of a public database for data generated by all members of the Consortium.

描述(由申请人提供) 毒理学的一个中心原则是，除了急性 细胞坏死，每一次接触有毒物质都会导致 基因表达。这种基因表达模式的改变反映了细胞？S 试图应对有毒的侮辱，范围从诱导 异种生物的代谢达到了细胞自杀或凋亡的极端。而当 许多研究着眼于有限数量的表达的变化 被认为在这些适应性反应中发挥作用的基因中， 阵列技术是获得数以千计的全面调查的能力 基因的同时存在。这种对基因表达的全球分析提供了 研究人员能够识别特定的模式或签名 与特定毒物类别相关的表达。这些 签名很可能包括以前没有牵涉到的基因类别 对特定的有毒侮辱的反应。因此，数组的应用 毒理学的技术无疑将加深我们对 细胞对毒物的反应，由此推断也应该提供洞察力 探讨药物反应、毒性、发育效应和 诱发疾病。本提案的统一主题是 应激源和毒物诱导的小鼠基因表达谱比较 对其影响具有不同敏感性的细胞将特别 有助于剖析潜在的毒性反应的生化途径。 调查人员已经组建了一个小组，他们在以下领域拥有专家 生物转化、神经发育毒理学和癌症发生 利用DNA微阵列技术比较基因表达的共同目标 小鼠、大鼠和人类细胞之间的差异 对多种环境物质敏感。一系列四个项目和 毒理学研究核心项目，所有这些项目都利用了基因 定义大鼠或小鼠、转基因和基因敲除小鼠以及原代人类和 建议进行啮齿动物细胞培养。这些项目将得到一个 行政核心和必要的三个设施核心。DNA微阵列 设施核心将为项目研究人员提供接触最先进技术的途径 在弗雷德·哈钦森癌症研究中心建立的设施 扎布尔医生。组织获取核心将计划研究人员访问 华盛顿大学转基因/基因敲除小鼠设施，提供 研究人员获得了基因定义的小鼠及其组织。认识 研究人员表示，有必要研究由器官组成的单个细胞类型 还包括在此核心访问细胞浓缩技术。这个 组织获取核心将为研究人员提供访问高速细胞的途径 分选和激光捕获显微解剖能力。最后的设施 CORE将为该项目提供生物信息学和生物统计学支持 研究人员。后者将被要求用于协调收购， 处理、存储和分析将被 由项目研究人员产生。每个核心还将交互 与其他财团成员和中央承包商通过 毒理学研究核心项目执行跨物种和跨平台 进行比较并制定数据标准化标准。后者 将是为所生成的数据生成公共数据库所必需的 由财团所有成员提供。