Ethanol Teratogenesis and Genomic Imprinting

乙醇致畸和基因组印记

• 批准号: 7291667
• 负责人: Thomas E. Johnson
• 金额: $ 35.91万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291667
• 关键词: Acetylation; Affect; Alcohols; Architecture; Biological Assay; Chromosome Mapping; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 7; Colorado; DNA Methylation; Diet; Distal; Dose; Embryo; Epigenetic Process; Ethanol; Fetal Alcohol Exposure; Fetus; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genomic Imprinting; Growth and Development function; Harvest; Health Sciences; Histone H3; Histones; Hour; Human; Laboratories; Maps; Mediating; Medical; Methylation; Modeling; Modification; Mus; Outcome; Parents; Patient currently pregnant; Perinatal Exposure; Personal Satisfaction; Placenta; Play; Polymerase Chain Reaction; Population; Postdoctoral Fellow; Predisposition; Pregnancy; Public Health; Quantitative Trait Loci; Research; Role; Science; Series; Supplementation; Time; Tissue-Specific Gene Expression; Tissues; Universities; Woman; Work; alcohol effect; alcohol exposure; alcohol measurement; base; cost; day; fetal; human study; imprint; in utero; segregation

DESCRIPTION (provided by applicant): We propose to study the genetic mechanisms mediating differential susceptibility to the teratogenic effects of ethanol. Previous research has identified a maternal effect mediating different teratogenic outcomes following prenatal ethanol exposure. In this proposal, we will examine genomic imprinting as a mechanism for the effect. We first propose to further characterize the genetic architecture underlying ethanol teratogenesis in populations of mice derived from C57BL/6J and DBA/2J mice and perform quantitative trait locus (QTL) mapping for imprinted QTLs mediating teratogenesis. We will examine DMA methylation, histone modifications and changes in gene expression, in embryos and placentae, following prenatal ethanol exposure, of several imprinted genes known to play a role in growth and development. In addition, we will examine global gene expression changes in fetuses exposed to alcohol in utero. We also will examine the effects of providing dams with a methyl-enriched diet on teratogenesis. Given that, in the US, an estimated 130,000 per year women expose their fetuses to high levels of alcohol, and the estimated associated costs are $4-$11 billion, the relevance of our proposal to public health is paramount. If we identify epigenetic modifications and/or gene expression changes in imprinted genes following prenatal alcohol exposure in mice, they become targets for human studies. If we find that methyl-supplementation of dams diets' ameliorates some of the teratogenic effects of ethanol, it suggests an effective strategy that may be applicable to human pregnancy.

描述（由申请人提供）：我们建议研究介导乙醇致畸作用差异易感性的遗传机制。先前的研究已经确定了产前乙醇暴露后介导不同的致畸结局的母体效应。在此提案中，我们将研究基因组烙印作为该作用的一种机制。我们首先建议进一步表征源自C57BL/6J和DBA/2J小鼠的小鼠种群中的遗传结构，并执行定量性状基因座（QTL）映射，以介导terateopenoper的QTLS QTL。我们将在产前乙醇暴露后，在胚胎和胎盘中研究DMA甲基化，组蛋白的修饰和基因表达的变化，这些基因在生长和发育中发挥作用。此外，我们将检查子宫内酒精暴露于酒精的胎儿的全球基因表达变化。我们还将研究提供富含甲基饮食的大坝对致畸作用的影响。鉴于在美国，估计每年有13万名妇女将胎儿暴露于高水平的酒精中，估计相关费用为4-11亿美元，我们的提议与公共卫生的相关性至关重要。如果我们确定小鼠产前酒精暴露后的烙印基因的表观遗传学修饰和/或基因表达变化，它们将成为人类研究的靶标。如果我们发现大坝饮食的甲基支持可以改善乙醇的某些致畸作用，则表明一种有效的策略可能适用于人类妊娠。