EFFECTS OF ETHANOL ON INSULIN SIGNALING IN THE BRAIN

胎儿酒精谱系障碍（FASD）是最常见的可预防的精神发育迟滞的原因， USA.乙醇通过两种主要机制损害神经元的存活和功能：1）抑制胰岛素信号传导 所需的活力，代谢，突触形成和乙酰胆碱的生产;和2）它的功能， 神经毒素，导致氧化应激，DNA损伤和线粒体功能障碍。乙醇抑制胰岛素 信号传导在胰岛素受体（IR）处介导，并且由受损的结合和伴随的胰岛素受体（IR）的减少引起。 传递生存信号。此外，逆转IR酪氨酸激酶的磷酸酶活化增加， 和PI 3 K活性，加剧了乙醇对神经元存活的抑制作用。相反，神经毒素 乙醇的作用促进DNA损伤，并且可能是通过产生DNA加合物形成引起的。 以及乙醇的主要代谢物乙醛的积累。因此，子宫内长期乙醇暴露 产生CNS胰岛素抵抗和氧化应激的双重状态。初步研究表明：（1） CNS IR的遗传或化学缺失导致FASD样形态、生化和分子缺陷; 2)CNS胰岛素抵抗相关损伤可通过胰岛素增敏剂（即PPAR）治疗减轻 激动剂;和3）FASD相关的CNS异常可能持续存在或进展，导致功能缺陷， 青少年。在这个竞争性的更新应用程序中，在3个具体目标中提出的实验将表征 长期妊娠期暴露于乙醇的长期后果，重点是青春期早期和晚期， 并确定PPAR激动剂治疗预防或减少长期 子宫内长期暴露于乙醇引起的CNS异常。目标#1将描述长期 早期和晚期青春期大鼠子宫内慢性暴露后脑胰岛素抵抗的后果 乙醇。目标#2将利用由对照产生的原代小脑神经元培养物的体外模型 和乙醇暴露的幼鼠，以表征PPAR激动剂对神经元存活和功能的影响。 目标#3将利用目标#2中获得的信息来优化PPAR激动剂的体内方法 子宫内慢性乙醇暴露对CNS的长期不良反应的治疗补救 青春期早期和晚期的神经元存活和功能。将使用分级的子宫内乙醇暴露， 确定PPAR激动剂的治疗效果是否随乙醇剂量而变化。此外，实验 将讨论性别在乙醇诱导的CNS异常的性质和严重程度方面的作用， 对PPAR激动剂的反应性。实验设计是平移的，因为它利用了一种治疗方法， 可以实际应用于人类的策略。

Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of mental retardation in the USA. Ethanol impairs neuronal survival and function by two major mechanisms: 1) it inhibits insulin signaling required for viability, metabolism, synapse formation, and acetylcholine production; and 2) it functions as a neurotoxicant, causing oxidative stress, DNA damage and mitochondrial dysfunction. Ethanol inhibition of insulin signaling is mediated at the insulin receptor (IR), and caused by impaired binding and attendant reductions in the transmission of survival signals. In addition, increased activation of phosphatases that reverse IR tyrosine kinase and PI3 K activities, exacerbates ethanol¿s inhibitory effects on neuronal survival. In contrast, the neurotoxicant effects of ethanol promote DNA damage, and are likely caused by DNA adduct formation through production and accumulation of acetaldehyde, a major metabolite of ethanol. Therefore, chronic in utero ethanol exposure produces a dual state of CNS insulin resistance and oxidative stress. Preliminary studies showed that: 1) genetic or chemical depletion of CNS IR causes FASD-like morphologic, biochemical, and molecular defects; 2) CNS insulin resistance-related impairments can be reduced by treatment with insulin-sensitizers i.e. PPAR agonists; and 3) FASD-associated CNS abnormalities may persist or progress leading to functional deficits in adolescents. In this competing renewal application, experiments proposed in 3 specific aims will characterize the long-term consequences of chronic gestational exposure to ethanol, focusing on early and late adolescence, and determine the degrees and mechanisms in which PPAR agonist treatments prevent or reduce long-term CNS abnormalities caused by chronic in utero exposure to ethanol. Aim #1 will characterize the long-term consequences of brain insulin resistance in early and late adolescent rats following chronic in utero exposure to ethanol. Aim #2 will utilize an in vitro model of primary cerebellar neuron cultures generated from control and ethanol-exposed rat pups to characterize the effects of PPAR agonists on neuronal survival and function. Aim #3 will take advantage of information gained in Aim #2 to optimize an in vivo approach for PPAR agonist therapeutic rescue of the long-term adverse effects of chronic in utero ethanol exposure in relation to CNS neuronal survival and function in early and late adolescence. Graded in utero ethanol exposures will be used to determine if the therapeutic effectiveness of PPAR agonists varies with ethanol dose. In addition, experiments will address the role of gender in relation to the nature and severity of ethanol-induced CNS abnormalities and responsiveness to PPAR agonists. The experimental design is translational because it utilizes a therapeutic strategy that realistically could be applied to humans.