Environmental Impact on the Embryonic mtDNA Genome

描述(申请者摘要)：长期目标是了解 分子水平上的致畸机制。小眼球是一种低水平的眼球 甲基汞暴露对小鼠胚胎发育的影响 反映暴露在儿童中的临床疾病。基因表达阵列 将被用来识别基本的生物分子参数 导致这种畸形的关键事件。初步研究确定了一个 涉及P53肿瘤抑制因子(TrP53)和外周型的关键反应 苯二氮卓类受体(Bzrp)，导致拟议的重点是代谢和 控制线粒体DNA(MtDNA)基因组表达的调控途径。 在神经形成过程中，胚胎从无氧(糖酵解)转变为有氧。 (氧化)新陈代谢这种双生性转变需要mtDNA基因组的表达 因此，形态发生和新陈代谢之间有着紧密的联系 差异化。研究人员假设通过逆行调节进行控制 由此在线粒体中开始的信号导致适应性反应 细胞核在线粒体DNA生物发生中达到顶峰。四个具体目标将开始 在分子水平上追踪这条途径。特定目标1，畸形病 研究，将确定甲基汞引起的暴露与疾病的关系 小眼症与剂量反应、遗传易感性(Trp53)、 和治疗性干预(BZRP)。特定目标2将使用表达式 基因表达谱微阵列用于跨关键的发育眼 脆弱期(怀孕第8-10天)。《特定目标3》将简介 甲基汞致小眼炎的暴露-疾病途径 对剂量反应、遗传易感性和治疗干预的影响。 特定目标4需要整合途径以确认细胞活动为 它们会随着时间的推移而改变。最后，我们希望建立一个可搜索的转录组 数据库为发展的眼睛和一个平台发现 假想中定义时间序列的细胞通路 甲基汞等环境毒物致畸形。

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.