PHOSPHATIDYLCHOLINE METABOLISM & GESTATIONAL ALCOHOL INDUCED FETAL ABNORMALITIES

磷脂酰胆碱代谢

• 批准号: 8360173
• 负责人: Rachel Elizabeth Neal
• 金额: $ 12.96万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360173
• 关键词: Affect; Alcohol consumption; Alcoholic Intoxication; Alcohols; Animal Model; Behavioral; Birth; Cerebral cortex; Child; Craniofacial Abnormalities; Defect; Development; Dietary Supplementation; Disease; Fetal Alcohol Exposure; Fetal Alcohol Syndrome; Fetal Development; Fetal Growth Retardation; Funding; Grant; Hippocampus (Brain); Hypothalamic structure; Impaired cognition; Lecithin; Lipids; Liver; Metabolic; Metabolism; Molecular; Molecular Abnormality; National Center for Research Resources; Neurocognitive; Neurologic; Nutrient; Obesity; Omega-3 Fatty Acids; Plasma; Principal Investigator; Reflex action; Research; Research Infrastructure; Resources; Signal Transduction; Source; Supplementation; Testing; Tissues; United States National Institutes of Health; alcohol exposure; cost; desaturase; eicosapentanoic acid; fetal; molecular marker; offspring; prenatal; protein expression; pup

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Approximately 2% of US births are affected by fetal alcohol syndrome (FAS) and related disorders (FASD). These children are characterized by intrauterine growth retardation (IUGR), craniofacial abnormalities and neurological defects such as reflex and cognitive impairment. In selected animal models, gestational alcohol exposure induced IUGR is paired with maturity onset obesity. Alcohol consumption inhibits liver desaturase activity resulting in deficits in specific Omega-3 fatty acid availability (docosahexanoic and eicosapentanoic acids). In the current application we propose to test the central hypothesis: Maternal dietary supplementation with Omega-3 will partially alleviate alcohol exposure-induced IUGR through modulation of maternal liver Sirt1 activation with coordinately increased fetal lipid availability. The alleviation of alcohol induced fetal IUGR is predicted to eliminate pup metabolic reprogramming characterized by maturity onset obesity through normalization of Omega-3 containing lipid content in the offspring hypothalamus with attendant normalization of HPA-axis function. Further, metabolic protein expression in the hippocampus and cerebral cortex will be compromised which may underlie the prenatal alcohol exposure induced neurocognitive and behavioral abnormalities. We specifically propose to 1) examine the impact of Omega-3 fatty acid supplementation during gestational alcohol exposure on Sirt1 expression and protein markers of tissue function; and 2) examine the impact of Omega-3 fatty acid supplementation during gestational alcohol exposure on fetal nutrient availability and pup metabolic status. If correct, we will have identified prenatal dietary modulation of Sirt1 signaling as preventative for FAS associated molecular tissue remodeling which persists past exposure. We will have also identified potential molecular markers in maternal plasma which are indicative of aberrant fetal development and which may be broadly applicable to diseases other than alcohol intoxication.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 大约2%的美国新生儿受到胎儿酒精综合征（FAS）和相关疾病（FASD）的影响。 这些儿童的特点是宫内发育迟缓（IUGR），颅面畸形和神经缺陷，如反射和认知障碍。在选定的动物模型中，妊娠期酒精暴露诱导的IUGR与成熟期肥胖配对。酒精消耗抑制肝脏去饱和酶活性，导致特定ω-3脂肪酸可用性（二十二碳六烯酸和二十碳五烯酸）不足。在本申请中，我们提出测试中心假设：母体膳食补充Omega-3将通过调节母体肝脏Sirt 1激活与协调增加胎儿脂质可用性来部分缓解酒精摄入诱导的IUGR。预测酒精诱导的胎儿IUGR的缓解通过后代下丘脑中含Omega-3的脂质含量的正常化以及伴随的HPA轴功能的正常化来消除以成熟期肥胖为特征的幼鼠代谢重编程。此外，海马和大脑皮层中的代谢蛋白表达将受到损害，这可能是产前酒精暴露诱导的神经认知和行为异常的基础。 我们特别建议：1）检查妊娠期酒精暴露期间补充Omega-3脂肪酸对Sirt 1表达和组织功能蛋白标志物的影响; 2）检查妊娠期酒精暴露期间补充Omega-3脂肪酸对胎儿营养可用性和幼仔代谢状态的影响。如果正确的话，我们将确定产前饮食调节Sirt 1信号作为预防FAS相关的分子组织重塑，持续过去的曝光。我们还将确定母体血浆中潜在的分子标记物，这些标记物指示异常的胎儿发育，并且可能广泛适用于酒精中毒以外的疾病。