An Assay to Identify and Classify Epimutagens

表观诱变剂的识别和分类方法

• 批准号: 7441234
• 负责人: David Ian Kingston Martin
• 金额: $ 24万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7441234
• 关键词: Affect; Azacitidine; Biological Assay; Biological Models; Butyrates; Carcinogens; Cell Line; Cell Separation; Cell physiology; Cells; Chemical Agents; Chemicals; Class; Clone Cells; Cloning; Cultured Cells; DNA; DNA Sequence; Detection; Development; Disease; Disruption; Dose; Elements; Engineering; Ensure; Environmental Health; Environmental Protection; Epigenetic Process; Ethionine; Eukaryota; Eukaryotic Cell; Exhibits; Future; Gene Mutation; Generations; Genome; Genomics; Grant; Green Fluorescent Proteins; Health; Human; Human Development; Learning; Malignant Neoplasms; Mammalian Cell; Mammals; Measurement; Measures; Methods; Monitor; Mutagenesis; Mutagenicity Tests; Mutagens; Mutation; Numbers; Organism; Pathway interactions; Pilot Projects; Play; Population; Public Health; Reading; Regulation; Reporter; Reporter Genes; Reporting; Reproducibility; Research; Role; Screening procedure; Site; System; Techniques; Testing; Transcriptional Regulation; Transfection; Transgenes; Transgenic Organisms; Trichostatin A; base; butyrate; design; environmental agent; environmental chemical; follow-up; response; sodium arsenite; success; tool; transgene expression

DESCRIPTION (provided by applicant): This proposal aims to develop a method to screen for chemical agents that disrupt epigenetic processes in mammalian cells. Epigenetics deals with heritable changes to the function of DNA that does not involve altered DNA sequence. In mammals and other multicellular organisms, most of the genome is kept in a silent transcriptional state by epigenetic mechanisms. Disruption of this silent state can have drastic effects, including developmental anomalies and cancer. Some chemicals are known to disrupt epigenetic silencing, but we have no comprehensive picture of the environmental agents that can act as "epimutagens". We hypothesize that there are many chemical epimutagens. In order to facilitate the discovery and study of these agents, we propose to develop a mammalian cell-based system that can screen for epimutagenic activity in mammalian cells. We will adapt a system that we have used extensively to study epigenetic silencing of transgenes in cultured cells. By selecting for cell clones that are sensitive to the disruption of epigenetic silencing by known epimutagens, we will derive a panel of cell lines that can be used to screen for epimutagenic activity in a manner analogous to the Ames test for mutagenicity. PUBLIC HEALTH RELEVANCE: Human development and disease are pervasively affected by epigenetic processes. There may be many environmental agents that are capable of disrupting epigenetic silencing and causing health effects, but we lack the means to readily identify them. We propose to develop a system that will permit screening of large numbers of chemicals for epigenetic effects. PUBLIC HEALTH RELEVANCE: The protection of humans from harmful environmental chemicals requires the existence of means to identify such compounds from among the millions of dietary and industrial chemicals to which people are exposed. Tests for mutagenic compounds-those that cause errors in the sequence of DNA and are therefore carcinogenic-have existed since the 1970s. Another class of potential carcinogen, however, the class of epimutagenic compounds, is currently undetectable; research into and regulation of such compounds is not a routine part of environmental health monitoring. We propose to develop tools for the detection and measurement of epimutagens, ultimately enabling environmental protections to be put in place.

描述（由申请人提供）：该提案旨在开发一种方法来筛选破坏哺乳动物细胞表观遗传过程的化学剂。 表观遗传学处理不涉及改变DNA序列的DNA功能的可遗传变化。在哺乳动物和其他多细胞生物中，大多数基因组都通过表观遗传机制保持沉默的转录状态。这种沉默状态的破坏可能会产生巨大的影响，包括发育异常和癌症。已知有些化学物质会破坏表观遗传沉默，但我们对可以充当“ Epimutagens”的环境药物没有全面的了解。我们假设有许多化学表皮。为了促进对这些药物的发现和研究，我们建议开发一种基于哺乳动物的细胞系统，该系统可以筛选哺乳动物细胞中的增生性活性。我们将适应一个系统，该系统已广泛用于研究培养细胞中转基因的表观遗传沉默。通过选择对已知表皮沉默的破坏敏感的细胞克隆，我们将得出一系列细胞系，可用于以类似于AMES测试的诱变性来筛选表皮活性活性。公共卫生相关性：人类发展和疾病在表观遗传过程中普遍影响。可能有许多能够破坏表观遗传沉默并引起健康影响的环境药物，但我们缺乏轻松识别它们的方法。我们建议开发一个系统，该系统将允许筛选大量化学物质以表观遗传作用。公共卫生的相关性：保护人免受有害环境化学物质的保护，需要存在从人们暴露于人们的数百万饮食和工业化学物质中识别这种化合物的手段。自1970年代以来，存在诱变化合物的测试 - 导致DNA序列的误差，因此是致癌物质的。然而，目前无法检测到的另一类潜在致癌物，即表增生性化合物类别。对此类化合物的研究和调节并不是环境健康监测的常规部分。我们建议开发用于检测和测量Epimutagens的工具，最终使环境保护得以实现。