Maternal Fetal Metabolic Disruption in Prenatal Alcohol Exposure

项目摘要 尽管公共卫生努力减少产前酒精暴露(PAE)，但在美国，11.7%的孕妇。 饮酒和3.9%的狂饮。PAE可导致生长迟缓、面部畸形和 神经行为障碍是胎儿酒精谱系障碍(FASD)的主要表现。尽管 生长缺陷与认知和行为障碍相关，我们缺乏对 这些增长赤字的基础。胎儿生长缺陷的一个主要驱动因素是母体代谢紊乱，以及 尽管众所周知，酒精会改变新陈代谢，但令人惊讶的是，这一点在PAE中只进行了最少的研究。 我的初步数据解决了这一知识鸿沟，并表明酒精减少了母体-胎儿的葡萄糖池， 伴随着包括尿素在内的胎儿氨基酸分解代谢的相应增加。虽然酒精刺激骨骼 肌肉分解代谢，我没有发现在酒精暴露的水坝中发生这种情况的迹象。相反，我的初步研究 发现暴露在酒精中的水坝未能对胰岛素抵抗状态进行预期的适应。此外，我 研究发现，酒精引起的母亲空腹血糖和胰岛素的变化与酒精介导的 减轻胎儿的体重和大脑重量。从这些数据出发，这项提案使用了一个既定的鼠标 PAE模型，并检验酒精阻止DAM进入胰岛素抵抗的假说 状态，从而限制胎儿葡萄糖的供应，从而增加胎儿对氨基酸的依赖 支持糖异生而不是生长。K99部分的第一阶段量化了母婴 进食/禁食血糖水平、糖异生及其相关代谢物库，以了解酒精如何改变 降低胎儿葡萄糖供应的母婴能量学。K99部分的第二阶段量化 胰岛素信号，以及母体肝脏中葡萄糖的储存和利用，以检验酒精的假设 防止母亲对胰岛素抵抗的适应。最后，R00阶段将确定潜在的 在酒精暴露的水坝中调节这种适应性失败的机制(S)，关注主要候选者 驱动因素包括瘦素抵抗、催乳素和胎盘催乳素活性。未来的研究将检验这些 功能上使用器官靶向转基因和基因敲除小鼠模型的候选人。我将接受培训， 全动物和细胞代谢评估的方法学和深入了解 胰岛素/瘦素在妊娠中的信号转导。我还将接受老鼠行为评估方面的培训，希望 关于这些新陈代谢变化如何影响认知功能的未来研究。这项工作提供了新颖的、 对胎儿生长缺陷基础的机械论洞察，到目前为止，重点放在关键上 忽视了新陈代谢过程。这些数据还可用于开发代谢物指纹或 荷尔蒙测试以确定高危妊娠，他们将提供对基于营养的干预措施的见解 可以改善这些孕妇的妊娠结局。

Project Summary Despite public health efforts to reduce prenatal alcohol exposure (PAE), 11.7% of pregnant women in the U.S. consume alcohol and 3.9% binge drink. PAE can lead to growth retardation, facial dysmorphology and neurobehavioral disabilities, the key manifestations of Fetal Alcohol Spectrum Disorders (FASD). Although the growth deficits correlate with the cognitive and behavioral impairments, we lack mechanistic insight into the basis for these growth deficits. A major driver of fetal growth deficits is maternal metabolic disruption, and although alcohol is well-known to alter metabolism, surprisingly, this has been minimally investigated in PAE. My preliminary data address this knowledge gap, and show that alcohol reduces maternal-fetal glucose pools, with commensurate rise in fetal amino acid catabolites including urea. Although alcohol stimulates skeletal muscle catabolism, I find no sign that this happens in alcohol-exposed dams. Instead, my preliminary studies find that alcohol-exposed dams fail to undergo an expected adaptation to an insulin-resistant state. Moreover, I find that alcohol-driven changes in maternal fasting glucose and insulin correlate with the alcohol-mediated reductions in fetal body and brain weight. Launching from these data, this proposal uses an established mouse model of PAE and tests the hypothesis that alcohol prevents the dam from entering an insulin-resistant state, thus limiting fetal glucose availability, and thereby increasing fetal reliance on amino acids to support gluconeogenesis instead of growth. The first phase of the K99 portion quantifies maternal-fetal fed/fasted glucose levels, gluconeogenesis, and their related metabolite pools to understand how alcohol alters maternal-fetal energetics to reduce fetal glucose availability. The second phase of the K99 portion quantifies insulin signaling, and glucose storage and utilization in maternal liver, to test the hypothesis that alcohol prevents maternal adaptation to insulin resistance. Finally, the R00 phase will identify the underlying mechanism(s) that mediates this adaptive failure in alcohol-exposed dams, focusing on major candidate drivers including leptin-resistance, and prolactin and placental lactogen activity. Future studies will test these candidates functionally using organ-targeted transgenic and knockout mouse models. I will be trained in the methodologies of whole-animal and cellular metabolic assessment and an in-depth understanding of insulin/leptin signaling in pregnancy. I will also be trained in mouse behavioral assessment, looking toward future studies of how these metabolic changes may impact cognitive function. This work provides novel, mechanistic insight into the basis for the fetal growth deficits that typify FASD, focusing on key, heretofore overlooked metabolic processes. These data may also inform the development of a metabolite fingerprint or hormone test to identify at-risk pregnancies, and they will offer insights into nutrient-based interventions that could improve gestational outcomes in those pregnancies.