Environmental Impact on the Embryonic mtDNA Genome

环境对胚胎 mtDNA 基因组的影响

• 批准号: 6751933
• 负责人: Thomas B Knudsen
• 金额: $ 33.06万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751933
• 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（申请人摘要）：长期目标是了解 分子水平上的致畸机制。小眼症属于低水平 甲基汞暴露的影响，并可诱导早期小鼠胚胎， 反映了在接触过的儿童中观察到的临床病症。基因表达阵列 将用于识别基本的生物分子参数， 导致这种畸形的关键事件。初步研究发现， 关键反应涉及p53肿瘤抑制因子（Trp 53）和外周型 苯并二氮卓受体（Bzrp），导致拟议的重点代谢和 控制线粒体DNA（mtDNA）基因组表达的调控途径。 在神经形成期间，胚胎从厌氧（糖酵解）转变为有氧 （氧化）代谢。这种二倍体转换需要mtDNA基因组表达 因此，形态发生和代谢之间的紧密联系 分化研究人员假设通过逆向调节控制 由此在所述反馈器中开始的信号导致自适应响应， 细胞核在mtDNA生物合成中达到顶峰。四个具体目标将开始， 在分子水平上追踪这一途径。具体目标1，畸形学 这项研究将确定甲基汞引起的疾病与疾病之间的关系， 小眼症的剂量反应，遗传易感性（Trp 53）， 治疗干预（BZRP）。具体目标2将使用表达 微阵列可以分析关键时期发育中眼睛的基因表达 脆弱期（妊娠第8-10天）。《Specific Aim 3》预告片 甲基汞致小眼症的发病途径 剂量反应、遗传易感性和治疗干预。 特定目标4需要途径整合以确认细胞活性， 它们会随着时间而改变。最后，我们希望建立一个可搜索的转录组， 数据库为发展中的眼睛和一个平台，以发现 细胞通路，假设定义了一个时间序列， 甲基汞和其他环境毒物引起的畸形。

项目成果

Data input module for Birth Defects Systems Manager.

出生缺陷系统管理器的数据输入模块。

• DOI: 10.1016/j.reprotox.2005.04.002
• 发表时间: 2005
• 期刊: Reproductive toxicology (Elmsford, N.Y.)
• 作者: Knudsen,KennethB;Singh,AmarV;Knudsen,ThomasB
• 通讯作者: Knudsen,ThomasB

Computational systems analysis of developmental toxicity: design, development and implementation of a Birth Defects Systems Manager (BDSM).

发育毒性的计算系统分析：出生缺陷系统管理器 (BDSM) 的设计、开发和实施。

• DOI: 10.1016/j.reprotox.2004.11.008
• 发表时间: 2005
• 期刊: Reproductive toxicology (Elmsford, N.Y.)
• 作者: Singh,AmarV;Knudsen,KennethB;Knudsen,ThomasB
• 通讯作者: Knudsen,ThomasB

Response characteristics of the mitochondrial DNA genome in developmental health and disease.

线粒体 DNA 基因组在发育健康和疾病中的反应特征。

• DOI: 10.1002/bdrc.20028
• 发表时间: 2004
• 期刊: Birth defects research. Part C, Embryo today : reviews
• 作者: Knudsen,ThomasB;Green,MaiaL
• 通讯作者: Green,MaiaL

Integrative analysis of the mouse embryonic transcriptome.

小鼠胚胎转录组的综合分析。

• DOI: 10.6026/97320630001406
• 发表时间: 2007
• 期刊: Bioinformation
• 影响因子: 1.9
• 作者: Singh,AmarV;Knudsen,KennethB;Knudsen,ThomasB
• 通讯作者: Knudsen,ThomasB

Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study.

• DOI: 10.1002/1096-9926(200010)62:4
• 发表时间: 2000-10
• 期刊: Teratology
• 作者: Guy B. Mulder;N. Manley;J. Grant;K. Schmidt;Weiping Zeng;C. Eckhoff;L. Maggio‐Price