Global Responses to Aflatoxin B1 & Alkylating Agents

全球对黄曲霉毒素 B1 的应对措施

• 批准号: 6932102
• 负责人: LEONA D. SAMSON
• 金额: $ 155.18万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 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/6932102
• 关键词: DNA damage; aflatoxins; alkylating agents; chemical carcinogen; environmental exposure; environmental toxicology

DESCRIPTION (provided by applicant) In response to RFA:ES-01-002, this is an application to become a member of the NIEHS-sponsored Toxicogenomics Research Consortium. The have proposed a highly integrated plan to explore the transcriptional responses of a variety of organisms, including humans, to a broad range of toxic agents found in the environment. Transcriptional profiling is expected to reveal a truly global view of how cells, tissues and animals attempt to recover, not always successfully from environmental insults. The investigators hope to learn what features of environmentally induced transcriptional responses are predictive of success or failure, and in addition to learn what features correlate with specific outcomes of toxic exposures, for instance, cell death, apoptosis, mutagenesis and carcinogenesis. The model environmental agents to be studied are Aflatoxin B1 and its metabolites, plus a range of SNI and SN2 alkylating agents. Together these agents are representative of toxic agents found in the external environment, food supply, the endogenous cellular environment, and the cancer chemotherapy clinic. The model organisms and cell systems whose transcriptional responsiveness will be scrutinized include E. coli, S. cerevisiae, cultured rodent and human cell lines, engineered rat and mouse liver tissues, rats and mice. The investigators have integrated an in vitro tissue engineering Project into this application with the goal of developing an alternative to using animals to test for toxicity and carcinogenicity. It seems to the investigators that appropriate transcriptional responsiveness in this system represents a rigorous test of its similarity to in vivo tissues. Two platforms for mRNA profiling will be employed, namely, Affymetrix GeneChip DNA oligonucleotide microarrays, and cDNA arrays fabricated in the MIT BioMicro Center. The Microarraying and Bioinformatics Core will have its center of gravity in the MIT BioMicro Center, and this Core will serve as the focal point for three Research Projects and the Toxicology Research Core Project (TRCP). The TRCP activities will be closely aligned with the activities of the other 4 or 5 members of the Toxicogenomics Research Consortium. Together the overarching goals will be to establishing good working practices in transcriptional profiling as it relates to the area of toxicogenomics, and to contribute to the development of an extensive relational database as a repository for high quality data emerging from the field of toxicogenomics. The investigators anticipate that this research will uncover a myriad of hitherto unknown ways in which cells respond to environmental agents.

描述（由申请人提供） 响应 RFA:ES-01-002，这是一份成为会员的申请 NIEHS 赞助的毒理学研究联盟。他们提出了一个 高度整合的计划，探索多种转录反应 包括人类在内的生物体对在环境中发现的多种有毒物质的影响 环境。转录分析有望揭示真正的全球性 观察细胞、组织和动物如何尝试恢复，但并不总是如此 成功地摆脱了环境的侵害。调查人员希望了解什么 环境诱导的转录反应的特征具有预测性 成功或失败的关键，此外还要了解哪些特征与此相关 有毒物质暴露的具体结果，例如细胞死亡、细胞凋亡、 诱变和致癌作用。 要研究的模型环境因子是黄曲霉毒素 B1 及其 代谢物，以及一系列 SNI 和 SN2 烷化剂。一起这些 制剂是外部环境中发现的有毒制剂的代表， 食物供应、内源性细胞环境和癌症化疗 诊所。其转录的模式生物和细胞系统 将审查反应性，包括大肠杆菌、酿酒酵母、培养的 啮齿动物和人类细胞系、工程大鼠和小鼠肝组织、大鼠和 老鼠。研究人员整合了体外组织工程 项目到此应用程序中的目的是开发替代方案 使用动物来测试毒性和致癌性。看来对 研究人员认为该系统具有适当的转录反应性 代表了对其与体内组织相似性的严格测试。 将采用两个 mRNA 分析平台，即 Affymetrix GeneChip 麻省理工学院制造的 DNA 寡核苷酸微阵列和 cDNA 阵列 生物微中心。微阵列和生物信息学核心将有其 重心位于麻省理工学院生物微中心，该核心将作为 三个研究项目和毒理学研究核心的焦点 项目（TRCP）。 TRCP 活动将与 毒理学研究的其他 4 或 5 名成员的活动 财团。总体目标将是建立良好的 转录分析的工作实践，因为它涉及以下领域 毒物基因组学，并为广泛的发展做出贡献 关系数据库作为高质量数据的存储库 毒物基因组学领域。研究人员预计这项研究将 揭示细胞响应的无数迄今未知的方式 环保剂。