EFFECTS OF ETHANOL ON INSULIN SIGNALING IN THE BRAIN

胎儿酒精谱系障碍 (FASD) 是导致智力低下的最常见的可预防原因 美国。乙醇通过两种主要机制损害神经元存活和功能：1）它抑制胰岛素信号传导 活力、新陈代谢、突触形成和乙酰胆碱产生所需； 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。乙醇抑制胰岛素 信号传导由胰岛素受体 (IR) 介导，是由结合受损和随之而来的胰岛素受体减少引起的。 传递生存信号。此外，增加磷酸酶的激活，逆转 IR 酪氨酸激酶 和 PI3 K 活性，加剧乙醇对神经元存活的抑制作用。相比之下，神经毒剂 乙醇的作用会促进 DNA 损伤，并且可能是由生产过程中形成 DNA 加合物引起的 和乙醛（乙醇的主要代谢物）的积累。因此，子宫内慢性乙醇暴露 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 的遗传或化学耗竭导致 FASD 样形态、生化和分子缺陷； 2) 中枢神经系统胰岛素抵抗相关的损伤可以通过胰岛素增敏剂（即 PPAR）治疗来减少 激动剂； 3) FASD 相关的中枢神经系统异常可能持续存在或进展，导致功能缺陷 青少年。在这个竞争性更新应用中，针对 3 个具体目标提出的实验将表征 妊娠期长期接触乙醇的长期后果，重点关注青春期早期和晚期， 并确定 PPAR 激动剂治疗预防或减少长期症状的程度和机制 子宫内长期接触乙醇引起的中枢神经系统异常。目标 1 将描述长期目标 长期子宫内暴露后青春期早期和晚期大鼠大脑胰岛素抵抗的后果 至乙醇。目标 #2 将利用对照产生的原代小脑神经元培养物的体外模型 和暴露于乙醇的大鼠幼仔，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 治疗性挽救与中枢神经系统相关的慢性宫内乙醇暴露的长期不良影响 青春期早期和晚期的神经元存活和功能。子宫内乙醇暴露分级将用于 确定 PPAR 激动剂的治疗效果是否随乙醇剂量变化。另外，实验 将探讨性别与乙醇引起的中枢神经系统异常的性质和严重程度的关系，以及 对 PPAR 激动剂的反应。实验设计是转化性的，因为它利用了治疗方法 实际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.