The FHCRC/UW Toxicogenomics Consortium

描述（由申请人提供） 毒理学的一个中心原则是， 细胞坏死，每一次有毒接触都会导致细胞坏死模式的改变。 基因表达。这种基因表达模式的改变反映了细胞？S 试图科普有毒的侮辱，可以从诱导 异生物质代谢到细胞自杀或凋亡的极端。而 许多研究都着眼于少数几个基因表达的变化， 在这些适应性反应中发挥作用的基因， 阵列技术是一种能够获得数千个 基因同时这种基因表达的全局分析提供了 研究人员能够辨别特定的模式或签名的能力， 与特定类别的毒物相关的表达。这些 签名可能包括以前没有涉及的基因类别， 对特定毒性的反应。因此，阵列的应用 毒理学技术无疑将增强我们对 细胞对有毒物质的反应，这也应该通过推理提供见解， 药物反应、毒性、发育影响和 诱发疾病。本提案的统一主题是， 应激或毒物诱导的基因表达谱的比较 对它们的作用敏感性不同的细胞将特别 有助于剖析毒性反应背后的生化途径。 调查人员已经组建了一个专家小组， 生物转化、神经发育毒理学和致癌作用， 使用DNA微阵列技术比较基因表达的共同目标 小鼠和大鼠以及人类细胞之间的差异 对各种环境因素敏感。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基因技术， 定义的大鼠或小鼠、转基因和敲除小鼠以及原代人和 提出了啮齿动物细胞培养物。这些项目将得到一个 行政核心和基本的三个设施核心。DNA微阵列 Facility Core将为项目研究人员提供最先进的 在弗雷德哈钦森癌症研究中心建立的设施， 博士扎布尔组织采集核心将项目研究人员访问 华盛顿大学的转基因/敲除小鼠设施，提供 研究人员获得基因定义的小鼠及其组织。认识 研究人员认为，需要观察组成器官的单个细胞类型， 在这一核心中还包括获得细胞富集技术。的 Tissue Acquisition Core将为研究人员提供高速细胞 分类和激光捕获显微切割能力。最后设施 核心将为该项目提供生物信息学和生物统计学支持 研究人员后者将需要协调收购， 处理，存储和分析大量的数据， 由项目研究人员提供。每一个核心也将相互作用 与其他联合体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 比较和制定数据标准化标准。后者 将是必不可少的，以生成一个公共数据库， 由财团的所有成员。

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.