The FHCRC/UW Toxicogenomics Consortium

FHCRC/华盛顿大学毒物基因组学联盟

• 批准号: 6655582
• 负责人: HELMUT ZARBL
• 金额: $ 143.1万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655582
• 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） 毒理学的中心宗旨是，除了急性外 细胞坏死，每一次毒性暴露都会改变 基因表达。这种基因表达的模式改变了细胞？ 尝试应对有毒侮辱，并且可以从诱导范围 异生物代谢至细胞自杀或凋亡的极端。尽管 大量研究研究了数量有限的表达变化 被认为在这些适应性反应中发挥作用的基因的力量 阵列技术是获得数千次全面调查的能力 同时的基因。对基因表达的全球分析提供了 研究人员能够辨别特定模式或签名的能力 与特定类别的毒物相关的表达。这些 签名可能包括以前不涉及的基因类别 对特定有毒损伤的反应。因此，数组的应用 毒理学技术无疑将增强我们对 细胞对毒物的反应，应通过推论提供洞察力 进入药物反应，毒性，发育效果和 诱导疾病。本提议的统一主题是 比较由应激源或毒物诱导的基因表达谱的比较 对其效果差异敏感的细胞将特别是 可用于解剖有毒反应的基础的生化途径。 调查人员已经组建了一个团队专家 生物转化，神经发育毒理学和癌变 使用DNA微阵列技术比较基因表达的常见目标 小鼠和大鼠之间的轮廓，以及差异的人类细胞 对各种环境药物敏感。一系列四个项目， 毒理学研究核心项目，所有这些都利用遗传学 定义的大鼠或小鼠，转基因和敲除小鼠以及原发性人，以及 提出了啮齿动物细胞培养物。这些项目将得到 行政核心和基本三个设施核心。 DNA微阵列 设施核心将为项目研究人员提供最先进的访问权限 在弗雷德·哈钦森癌症研究中心建立的设施 Zarbl博士。组织采集核心将使研究人员访问 华盛顿大学的转基因/淘汰小鼠机构提供 研究人员可以使用遗传定义的小鼠及其组织。认可 需要查看包括器官的单个细胞类型，研究人员 还包括在此核心访问细胞富集技术中。这 组织采集核心将为研究人员提供高速细胞的访问 分类和激光捕获显微解剖功能。最终设施 核心将为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，存储和分析大量数据 由项目研究人员生成。每个核心也将相互作用 与其他财团成员和中央承包商通过 毒理学研究核心项目，以执行跨物种和跨平台 比较并制定数据标准化标准。后者 对于生成数据的公共数据库至关重要 财团的所有成员。