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缓的原因 美国。乙醇通过两个主要机制损害神经元的存活和功能：1)抑制胰岛素信号转导 对于生存、新陈代谢、突触形成和乙酰胆碱的产生是必需的；和2)它的功能是 神经毒物，导致氧化应激、DNA损伤和线粒体功能障碍。乙醇对胰岛素的抑制作用 信号是在胰岛素受体(IR)处介导的，并由胰岛素受体结合受损和随之而来的 传递求生信号。此外，逆转IR酪氨酸激酶的磷酸酶活性增加 而PI3K活性，加剧乙醇对S神经元存活的抑制作用。相比之下，神经毒剂 乙醇的作用促进DNA损伤，可能是通过产生DNA加合物而引起的 乙醇的主要代谢物乙醛的积累。因此，宫内慢性酒精暴露 产生中枢神经系统胰岛素抵抗和氧化应激的双重状态。初步研究表明：1) CNS IR的遗传或化学耗竭会导致FASD样的形态、生化和分子缺陷； 2)中枢神经系统胰岛素抵抗相关损害可通过胰岛素增敏剂即PPAR的治疗而减轻 激动剂；以及3)FASD相关的中枢神经系统异常可能持续或进展，导致功能障碍。 青少年。在这项竞争性的更新申请中，在3个特定目标中提出的实验将表征 长期接触酒精的长期后果，主要集中在青春期的早期和晚期， 并确定PPAR激动剂治疗预防或减少长期 宫内慢性酒精暴露引起的中枢神经系统异常。目标1将描述长期的 宫内慢性暴露对青春期早期和晚期大鼠脑胰岛素抵抗的影响 到乙醇。目标2将利用对照产生的原代小脑神经元培养的体外模型 和乙醇暴露的大鼠幼鼠，以表征PPAR激动剂对神经元存活和功能的影响。 AIM#3将利用在AIM#2中获得的信息来优化PPAR激动剂的体内方法 宫内慢性酒精暴露与中枢神经系统相关的长期不良反应的治疗挽救 青春期早期和晚期神经元的存活和功能。子宫内酒精暴露分级将被用于 确定PPAR激动剂的治疗效果是否因乙醇剂量不同而不同。此外，实验， 将讨论性别在酒精诱导的中枢神经系统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 现实上可以应用于人类的策略。

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.