An Assay to Identify and Classify Epimutagens

表观诱变剂的识别和分类方法

基本信息

批准号：
7655389
负责人：
David Ian Kingston Martin
金额：
$ 20万
依托单位：
CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7655389
关键词：
Affect Azacitidine Biological Assay Biological Models Butyrates Carcinogens Cell Culture Techniques Cell Line Cell Separation Cell physiology Cells Chemical Agents Chemicals Clone Cells Cloning Cultured Cells DNA DNA Sequence Detection Development Disease Dose Elements Engineering Ensure Environmental Health Environmental Protection Epigenetic Process Ethionine Eukaryota 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 Organism Pathway interactions Pilot Projects Play Population Reading Regulation Reporter Reporter Genes Reporting Reproducibility Research Role Screening procedure Site System Techniques Testing Transcriptional Regulation Transfection Transgenes Transgenic Organisms Trichostatin A base design environmental agent environmental chemical follow-up public health relevance response sodium arsenite success tool transgene expression

项目摘要

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筛选破坏哺乳动物细胞表观遗传过程的化学试剂的方法。表观遗传学研究的是 DNA 功能的遗传性变化，但不涉及 DNA 序列的改变。在哺乳动物和其他多细胞生物中，大部分基因组通过表观遗传机制保持在沉默转录状态。这种沉默状态的破坏可能会产生严重的影响，包括发育异常和癌症。已知一些化学物质会破坏表观遗传沉默，但我们对可以充当“表观诱变剂”的环境因素没有全面的了解。我们假设有许多化学表观诱变剂。为了促进这些药物的发现和研究，我们建议开发一种基于哺乳动物细胞的系统，该系统可以筛选哺乳动物细胞中的表观诱变活性。我们将采用我们广泛用于研究培养细胞中转基因的表观遗传沉默的系统。通过选择对已知表观诱变剂对表观遗传沉默的破坏敏感的细胞克隆，我们将得到一组细胞系，这些细胞系可用于以类似于艾姆斯致突变性测试的方式筛选表观诱变活性。公共卫生相关性：人类发育和疾病普遍受到表观遗传过程的影响。可能有许多环境因素能够破坏表观遗传沉默并造成健康影响，但我们缺乏容易识别它们的方法。我们建议开发一个系统，可以筛选大量化学物质的表观遗传效应。公共卫生相关性：保护人类免受有害环境化学物质的侵害，需要有办法从人们接触的数百万种膳食和工业化学物质中识别出此类化合物。自 20 世纪 70 年代起，人们就开始对诱变化合物（那些会导致 DNA 序列错误并因此致癌的化合物）进行测试。然而，另一类潜在致癌物，即表观突变化合物，目前尚未检测到。对此类化合物的研究和监管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表观诱变剂的工具，最终使环境保护得以落实。