PHOSPHATIDYLCHOLINE METABOLISM & GESTATIONAL ALCOHOL INDUCED FETAL ABNORMALITIES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级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症(FAS)和相关疾病(FASD)的影响。这些儿童的特点是胎儿宫内发育迟缓(IUGR)、头面部异常和神经缺陷，如反射和认知障碍。在选定的动物模型中，孕期酒精暴露导致的IUGR与成熟期发作性肥胖成对。饮酒会抑制肝脏去饱和酶的活性，导致特定的欧米茄-3脂肪酸(二十二碳六酸和二十碳五酸)供应不足。在目前的应用中，我们建议检验中心假设：母亲饮食补充Omega-3将部分缓解酒精暴露引起的IUGR，这是通过调节母亲肝脏Sirt1的激活和协调增加胎儿脂肪的利用来实现的。酒精诱导的胎儿IUGR的缓解被预测为通过使后代下丘脑中含有Omega-3的脂质含量正常化以及伴随着HPA轴功能的正常化来消除以成熟期肥胖症为特征的幼鼠代谢重新编程。此外，海马区和大脑皮层代谢蛋白的表达将受损，这可能是产前酒精暴露导致神经认知和行为异常的基础。 我们特别建议1)研究孕期酒精暴露期间补充Omega-3脂肪酸对Sirt1表达和组织功能蛋白质标记物的影响；2)研究孕期酒精暴露期间补充Omega-3脂肪酸对胎儿营养供应和幼崽代谢状态的影响。如果正确，我们将确认产前饮食中Sirt1信号的调节可以预防Fas相关的分子组织重塑，这种重塑在过去的暴露中持续。我们还将在母体血浆中确定潜在的分子标志物，这些标志物可以指示胎儿发育异常，并可能广泛适用于酒精中毒以外的疾病。

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.