Ethanol Teratogenesis and Genomic Imprinting

乙醇致畸和基因组印记

• 批准号: 7475823
• 负责人: Thomas E. Johnson
• 金额: $ 48.34万
• 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/7475823
• 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的不同易感性的遗传机制。先前的研究已经确定了产前乙醇暴露后介导不同致畸结果的母体效应。在本提案中，我们将研究基因组印记作为该效应的机制。我们首先建议进一步表征源自 C57BL/6J 和 DBA/2J 小鼠的小鼠群体中乙醇致畸的遗传结构，并对介导致畸的印记 QTL 进行数量性状基因座 (QTL) 作图。我们将检查产前乙醇暴露后胚胎和胎盘中几个已知在生长和发育中发挥作用的印记基因的 DMA 甲基化、组蛋白修饰和基因表达变化。此外，我们将检查子宫内接触酒精的胎儿的整体基因表达变化。我们还将研究为水坝提供富含甲基的饮食对致畸的影响。鉴于在美国，估计每年有 130,000 名妇女让她们的胎儿接触高浓度的酒精，并且估计相关成本为 4-110 亿美元，因此我们的提案与公共卫生的相关性至关重要。如果我们在小鼠产前酒精暴露后识别出印记基因的表观遗传修饰和/或基因表达变化，它们将成为人类研究的目标。如果我们发现母鼠饮食中添加甲基可以改善乙醇的一些致畸作用，那么这就表明了一种可能适用于人类妊娠的有效策略。