ETHANOL, RETINOIDS, AND CONGENITAL HEART MALFORMATIONS

乙醇、类维生素A和先天性心脏畸形

• 批准号: 6507309
• 负责人: JANEE GELINEAU-VAN WAES
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6507309
• 关键词: alcohol dehydrogenase; alcoholism /alcohol abuse; biological signal transduction; cell differentiation; congenital heart disorder; embryo /fetus toxicology; ethanol; fetal alcohol syndrome; histogenesis; immunocytochemistry; intermolecular interaction; laboratory mouse; microarray technology; molecular genetics; mother /embryo /fetus nutrition; neural crest; nutrition related tag; polymerase chain reaction; retinoate; terminal nick end labeling; vitamin A deficiency; vitamin biosynthesis

DESCRIPTION (provided by applicant): Congenital malformations of the heart have been reported following maternal exposure to various environmental toxins, but the precise mechanism(s) by which these teratogenic exposures disrupt normal morphogenesis remains unknown. Prenatal exposure to ethanol (Fetal Alcohol Syndrome) or maternal vitamin A (retinoic acid) deficiency or excess during gestation have been shown to cause conotruncal heart defects. In the proposed research program, the complex processes underlying embryological development of the mammalian heart and the impact of prenatal exposure to ethanol and perturbed retinoic acid levels leading to cardiac dysmorphogenesis will be studied using molecular-genetic approaches. The proposed studies will focus on a critical gestational timepoint during murine heart development when the cardiac neural crest cells are migrating from the dorsal neural tube to the heart. Alterations in the network of developmentally regulated genes in this cell population will be analyzed following teratogen exposure through the use of genetic microarrays. Potential mechanisms suggested by altered gene expression profiles will be further evaluated relative to the observed cellular dysmorphology by examining protein expression of critical candidate genes identified in the cDNA arrays, as well as proteins associated with changes in cell proliferation and apoptosis. The goal will be to identify significant gene/protein interactions that take place during normal heart development, and the mechanism(s) by which in utero ethanol exposure disrupts this process. We will also further investigate the possibility that malformations of the heart subsequent to prenatal alcohol exposure are a result of decreased endogenous retinoic acid synthesis due to competition between alcohol and retinol for alcohol dehydrogenase enzymatic pathways. The proposed research program will therefore test the hypothesis that prenatal ethanol exposure leads to congenital heart malformations by disrupting normal retinoid signaling pathways critical for cell fate determination in the migrating cardiac neural crest cells/conotruncus.

描述（由申请方提供）：母体暴露于各种环境毒素后，已报告了先天性心脏畸形，但这些致畸暴露破坏正常形态发生的确切机制尚不清楚。产前暴露于乙醇（胎儿酒精综合征）或母体维生素A（视黄酸）缺乏或妊娠期间过量已被证明会导致圆锥动脉干心脏缺陷。在拟议的研究计划中，将使用分子遗传学方法研究哺乳动物心脏胚胎发育的复杂过程，以及产前暴露于乙醇和扰乱维甲酸水平导致心脏畸形的影响。拟议的研究将集中在小鼠心脏发育过程中的一个关键妊娠时间点，此时心脏神经嵴细胞正从背神经管迁移到心脏。在致畸剂暴露后，将通过使用基因微阵列分析该细胞群中发育调控基因网络的改变。通过检查在cDNA阵列中鉴定的关键候选基因的蛋白质表达，以及与细胞增殖和凋亡变化相关的蛋白质，相对于观察到的细胞畸形，将进一步评价改变基因表达谱所提示的潜在机制。目标是确定在正常心脏发育过程中发生的重要基因/蛋白质相互作用，以及子宫内乙醇暴露破坏这一过程的机制。我们还将进一步研究胎儿期酒精暴露后心脏畸形的可能性，这是由于酒精和视黄醇之间竞争酒精脱氢酶酶途径导致内源性视黄酸合成减少的结果。因此，拟议的研究计划将测试这样的假设：产前乙醇暴露会通过破坏正常的类维生素A信号通路而导致先天性心脏畸形，该信号通路对于迁移的心脏神经嵴细胞/圆锥干中的细胞命运决定至关重要。