ETHANOL, RETINOIDS, AND CONGENITAL HEART MALFORMATIONS
乙醇、类维生素A和先天性心脏畸形
基本信息
- 批准号:6629445
- 负责人:
- 金额:$ 7.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-07-01 至 2005-06-30
- 项目状态:已结题
- 来源:
- 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
项目摘要
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(申请人提供):母亲暴露于各种环境毒素后,已有先天性心脏畸形的报道,但这些致畸暴露扰乱正常形态发生的确切机制(S)仍不清楚。孕期暴露于酒精(胎儿酒精综合征)或孕妇维生素A(维甲酸)缺乏或过量会导致圆锥干心脏缺陷。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动的维甲酸水平导致心脏畸形发生的影响。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,此时心脏神经脊细胞正从背侧神经管迁移到心脏。这些细胞群体中发育调节基因网络的变化将通过使用基因微阵列在致畸物质暴露后进行分析。基因表达谱改变所暗示的潜在机制将通过检测在cDNA阵列中确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来进一步评估与观察到的细胞畸形相关的机制。我们的目标将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扰乱这一过程的机制(S)。我们还将进一步研究产前酒精暴露后心脏畸形的可能性,这是由于酒精和视黄醇竞争酒精脱氢酶途径而导致内源性维甲酸合成减少的结果。因此,拟议的研究计划将测试这一假说,即产前酒精暴露通过扰乱正常的维甲酸信号通路而导致先天性心脏畸形,维甲酸信号通路对于决定迁移的心脏神经脊细胞/圆锥细胞的细胞命运至关重要。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JANEE GELINEAU-VAN WAES其他文献
JANEE GELINEAU-VAN WAES的其他文献
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{{ truncateString('JANEE GELINEAU-VAN WAES', 18)}}的其他基金
Mycotoxins and Birth Defects: A Global Health Concern?
霉菌毒素和出生缺陷:全球健康问题?
- 批准号:
8047867 - 财政年份:2010
- 资助金额:
$ 7.35万 - 项目类别:
COBRE: UNE MED CTR: P3: ROLE OF MITF IN DEVELOPMENT OF THE RPE AND INNER EAR
COBRE:UNE MED CTR:P3:MITF 在 RPE 和内耳发育中的作用
- 批准号:
7960541 - 财政年份:2009
- 资助金额:
$ 7.35万 - 项目类别:
Material Fumonisin Exposure and Pregnancy Outcome: Decoding the Sphingolipid Immu
材料伏马菌素暴露和妊娠结果:解码鞘脂免疫
- 批准号:
7532142 - 财政年份:2008
- 资助金额:
$ 7.35万 - 项目类别:
Material Fumonisin Exposure and Pregnancy Outcome: Decoding the Sphingolipid Immu
材料伏马菌素暴露和妊娠结果:解码鞘脂免疫
- 批准号:
7646413 - 财政年份:2008
- 资助金额:
$ 7.35万 - 项目类别:
Material Fumonisin Exposure and Pregnancy Outcome: Decoding the Sphingolipid Immu
材料伏马菌素暴露和妊娠结果:解码鞘脂免疫
- 批准号:
8066154 - 财政年份:2008
- 资助金额:
$ 7.35万 - 项目类别:
COBRE: UNE MED CTR: P3: ROLE OF MITF IN DEVELOPMENT OF THE RPE AND INNER EAR
COBRE:UNE MED CTR:P3:MITF 在 RPE 和内耳发育中的作用
- 批准号:
7610616 - 财政年份:2007
- 资助金额:
$ 7.35万 - 项目类别:
COBRE: UNE MED CTR: P3: ETHANOL-RETINOID INTERATION IN INNER EAR MALFORMATIONS
COBRE:UNE MED CTR:P3:乙醇-维甲酸相互作用在内耳畸形中的作用
- 批准号:
7382085 - 财政年份:2006
- 资助金额:
$ 7.35万 - 项目类别:
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 - 财政年份:2002
- 资助金额:
$ 7.35万 - 项目类别: