Environmental Impact on the Embryonic mtDNA Genome

环境对胚胎 mtDNA 基因组的影响

• 批准号: 6518123
• 负责人: Thomas B Knudsen
• 金额: $ 31.8万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6518123
• 关键词: benzodiazepine receptor; developmental genetics; embryo /fetus toxicology; environmental exposure; gene environment interaction; gene expression; genetic susceptibility; genome; laboratory mouse; mammalian embryology; mercury poisoning; microarray technology; microphthalmos; mitochondrial DNA; p53 gene /protein; teratogens

DESCRIPTION (Applicant's Abstract): The long-term goal is to understand teratogenic mechanisms at the molecular level. Microphthalmia is a low level effect of methylmercury exposure and can be induced in early mouse embryos to reflect clinical disorders seen in exposed children. Gene expression arrays will be used to recognize fundamental biomolecular parameters that describe critical events leading to this malformation. Preliminary studies identified a critical response involving p53 tumor suppressor (Trp53) and peripheral-type benzodiazepine receptor (Bzrp), leading to the proposed focus on metabolic and regulatory pathways controlling mitochondrial DNA (mtDNA) genome expression. During neurulation, the embryo shifts from an anaerobic (glycolytic) to aerobic (oxidative) metabolism. This diauxic shift requires mtDNA genome expression and, consequently, a tight link between morphogenetic and metabolic differentiation. The investigators hypothesize control by retrograde regulation whereby a signal started in the mitochondrion leads to an adaptive response in the nucleus to culminate in mtDNA biogenesis. Four specific aims will begin to trace this pathway at the molecular level. Specific Aim 1, a teratological study, will determine exposure-disease relationships for methylmercury-induced microphthalmia with respect to dose response, genetic susceptibility (Trp53), and therapeutic intervention (Bzrp). Specific Aim 2 will use expression microarrays to profile gene expression for developing eye across the critical period of vulnerability (days 8-10 of gestation). Specific Aim 3 will profile exposure-disease pathways for methylmercury-induced microphthalmia with respect to dose-response, genetic susceptibility, and therapeutic intervention. Specific Aim 4 entails pathway integration to confirm cellular activities as they change over time. At ends we expect to build a searchable transcriptome database for the developing eye and a platform with which to discover the cellular pathways that hypothetically define a temporal sequence in dysmorphogenesis induced with methylmercury and other environmental toxicants.

描述（申请人的摘要）：长期目标是了解 分子水平的致化机制。微观恐惧症是低水平的 甲基汞暴露的作用，可以在早期小鼠胚胎中诱导至 反映在暴露儿童中看到的临床障碍。基因表达阵列 将用于识别描述的基本生物分子参数 关键事件导致这种畸形。初步研究确定了 涉及p53肿瘤抑制器（TRP53）和外围型的关键反应 苯二氮卓受体（BZRP），导致提出的专注于代谢和 控制线粒体DNA（mtDNA）基因组表达的调节途径。 在神经化过程中，胚胎从厌氧（糖酵解）转移到有氧运动 （氧化）代谢。这种数字移位需要mtDNA基因组表达 因此，形态发生与代谢之间的紧密联系 分化。研究人员假设通过逆行调节来控制 在线粒体中启动信号会导致自适应反应 核达到MTDNA生物发生。四个具体目标将开始 在分子水平上追踪此途径。特定目的1，一种曲折 研究将确定甲基汞诱导的暴露症关系 微观噬菌体相对于剂量反应，遗传易感性（TRP53）， 和治疗干预（BZRP）。特定的目标2将使用表达 微阵列介绍基因表达，以跨关键的眼睛发育 脆弱性时期（妊娠第8-10天）。特定的目标3将配置 与甲基汞诱导的微观心脏的暴露 - 疾病途径有关 剂量反应，遗传敏感性和治疗性干预。 特定目标4需要途径集成以确认细胞活动为 随着时间的流逝，它们会改变。在末端，我们希望构建可搜索的转录组 发育中的眼睛的数据库和一个可以发现的平台 假设定义时间序列的细胞途径 用甲基压和其他环境有毒物质诱导的畸形发生。