Evaluation of the Genetic Contribution of the Neuroinflammatory Response Following Neonatal Alcohol Exposure

项目总结/摘要 尽管胎儿酒精综合征在四十多年前就被发现了，而且是完全可以预防的， 胎儿酒精谱系障碍（FASD）的发病率并未降低。酒精中毒的类型和严重程度 产前酒精暴露后的改变受到遗传学的强烈影响。克里斯汀·哈姆雷博士 在对FASD具有不同易感性的BXD重组近交系小鼠品系中证明，遗传学是一个重要的因素。 定义胎儿海马中酒精诱导的神经元死亡的易感性的主要因素， FASD认知缺陷的核心区域。然而，遗传贡献背后的机制还没有 被识别。Cynthia Kane博士的研究表明，酒精暴露在发育中的大脑中， C57 BL/6 J（B6）小鼠（BXD系的亲本品系）产生神经炎性应答，其导致 神经元死亡，包括促炎分子的产生和海马体中的神经胶质活化。她 实验室还发现，给药过氧化物酶体增殖物激活受体-γ激动剂，吡格列酮， 减少发育中的中枢神经系统中酒精诱导的神经炎症反应。但 遗传学在发育期酒精暴露的神经炎症反应中的作用尚未确定。 我们假设胎儿对FASD的易感性至少部分是由遗传差异介导的 导致发育中的海马体对酒精的神经炎症反应发生变化。实验 这项提案概述的将：1）确定酒精诱导的神经炎症反应是否有助于 特定目标1中发育中海马对酒精诱导细胞丢失的差异遗传易感性 和2）研究给予抗炎药吡格列酮是否能保护高度敏感的 BXD菌株通过抑制酒精诱导的神经炎症反应而导致海马细胞丢失， Specific Aim 2中的新生小鼠。将通过检测mRNA表达、表达量、细胞周期和细胞周期来确定效果。 新生儿海马中的蛋白质含量、细胞丢失百分比以及小胶质细胞和星形胶质细胞的活化 暴露于发育期酒精中的小鼠。这项研究将导致进一步了解1）遗传 对FASD严重程度的贡献，2）酒精诱导的神经炎症反应的遗传影响， 和3）吡格列酮是否在抑制酒精诱导的细胞损失方面在不同的动物中同样有效。 基因背景

Project Summary/Abstract Although fetal alcohol syndrome was discovered over forty years ago and is entirely preventable, the incidence of fetal alcohol spectrum disorder (FASD) has not diminished. The type and severity of alcohol-induced alterations following prenatal alcohol exposure is strongly impacted by genetics. Dr. Kristin Hamre has demonstrated in BXD recombinant inbred mouse strains with differential vulnerability to FASD that genetics is a principal factor defining susceptibility to alcohol-induced neuron death in the fetal hippocampus, one of the regions central to FASD cognitive deficits. However, the mechanisms behind the genetic contribution has not been identified. Research by Dr. Cynthia Kane has shown that alcohol exposure in the developing brain of C57BL/6J (B6) mice (a parental strain of the BXD lines) produces neuroinflammatory responses that lead to neuron death, including production of pro-inflammatory molecules and glial activation in the hippocampus. Her lab has also found that administration of the peroxisome proliferator-activated receptor-y agonist, pioglitazone, reduces alcohol-induced neuroinflammatory responses in the developing central nervous system. However, the role of genetics in neuroinflammatory responses to developmental alcohol exposure has not been determined. We hypothesize that differential fetal vulnerability to FASD is mediated, at least in part, by genetic differences leading to variation in the neuroinflammatory response to alcohol in the developing hippocampus. Experiments outlined in this proposal will: 1) determine whether alcohol-induced neuroinflammatory responses contribute to the differential genetic vulnerability to alcohol-induced cell loss in the developing hippocampus in Specific Aim 1 and 2) investigate whether administration of the anti-inflammatory drug, pioglitazone, protects highly sensitive BXD strains from hippocampal cell loss by suppressing alcohol-induced neuroinflammatory responses in neonatal mice in Specific Aim 2. The effects will be determined by examining expression of mRNA, expression of protein, percentage of cell loss, and activation of microglia and astrocytes in the hippocampus of neonatal mice exposed to developmental alcohol. This research will result in a further understanding of 1) the genetic contributions to the severity of FASD, 2) the genetic influence of alcohol-induced neuroinflammatory responses, and 3) whether pioglitazone is equally effective at inhibiting alcohol-induced cell loss across animals of differing genetic backgrounds.