EFFECTS OF ETHANOL ON INSULIN SIGNALING IN THE BRAIN

乙醇对大脑胰岛素信号传导的影响

• 批准号: 7754121
• 负责人: SUZANNE M. DE LA MONTE
• 金额: $ 37.22万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7754121
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acetaldehyde; Acetylcholine; Address; Adolescence; Adolescent; Adverse effects; Agonist; Asses; Binding; Biochemical; Brain; Chemicals; Chronic; DNA Adduction; DNA Damage; Data; Defect; Dose; Effectiveness; Ethanol; Experimental Designs; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Gender Role; Genetic; Goals; Human; Impairment; Insulin Receptor; Insulin Resistance; Link; Mediating; Mental Retardation; Metabolism; Molecular; Motor; Nature; Neuronal Injury; Neurons; Neurotoxins; Oxidative Stress; Perinatal Exposure; Peroxisome Proliferator-Activated Receptors; Phosphoric Monoester Hydrolases; Planet Mars; Production; Protein Tyrosine Kinase; Rattus; Severities; Signal Transduction; Therapeutic; Work; alcohol effect; alcohol exposure; functional disability; in vitro Model; in vivo; insulin receptor substrate 1 protein; insulin receptor tyrosine kinase; insulin sensitizing drugs; insulin signaling; mitochondrial dysfunction; neuronal survival; prevent; public health relevance; pup; receptor; research study; synaptogenesis; therapeutic effectiveness; transmission process

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE We have linked fetal alcohol spectrum disorder-associated brain abnormalities to insulin resistance and oxidative stress in neurons. Preliminary data suggest that prenatal alcohol exposure may cause persistent or progressive neuronal injury in adolescent brains, and therefore, we now propose to characterize the degree to which pre-natal alcohol exposure causes long-lasting adverse effects on brain function. Our second goal is to evaluate treatments that target the underlying causes of ethanol-mediated brain abnormalities and assess their effectiveness in preventing structural and functional impairments in adolescent brains following chronic prenatal alcohol exposure.

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）是美国智力低下的最常见原因。乙醇通过两种主要机制损害神经元的生存和功能：1）它抑制生存力，代谢，突触形成和乙酰胆碱产生所需的胰岛素信号传导； 2）它充当神经毒性，导致氧化应激，DNA损伤和线粒体功能障碍。胰岛素信号抑制乙醇在胰岛素受体（IR）上介导，并由生存信号传播的结合和随之而减少的减少引起。此外，增加的磷酸酶的激活增加，逆转IR酪氨酸激酶和PI3 K活性加剧了乙醇对神经元存活的抑制作用。相反，乙醇的神经毒性作用促进了DNA损伤，并且很可能是由DNA加合物通过乙醇的主要代谢产生乙醇的产生和积累而引起的。因此，子宫乙醇暴露中的慢性会产生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的遗传或化学耗竭会导致FASD样形态学，生化和分子缺陷； 2）CNS胰岛素抵抗相关的损伤可以通过用胰岛素敏感剂（即PPAR激动剂）治疗来减少； 3）FASD相关的中枢神经系统异常可能会持续或进展，导致青少年功能不足。在这一竞争性更新应用中，提出的3个特定目标实验将表征长期对乙醇的长期后果，重点关注早期和晚期，并确定PPAR激动剂治疗预防或减少长期CNS异常在UTERO中导致的长期CNS异常的程度和机制。 AIM＃1将表征在子宫内慢性暴露于乙醇后，早期和晚期大鼠脑胰岛素抵抗的长期后果。 AIM＃2将利用由对照和乙醇暴露的大鼠幼崽产生的原发小脑神经元培养物的体外模型，以表征PPAR激动剂对神经元存活和功能的影响。 AIM＃3将利用AIM＃2中获得的信息，以优化一种体内方法，用于对慢性乙醇暴露的长期不良影响PPAR激动剂治疗性挽救相对于CNS神经元的生存和功能，并在青春期早期和晚期。在子宫乙醇暴露中的分级将用于确定PPAR激动剂的治疗有效性是否随乙醇剂量而变化。此外，实验将解决性别在乙醇引起的中枢神经系统异常的性质和严重性方面的作用以及对PPAR激动剂的反应性。实验设计之所以翻译，是因为它利用了现实地应用于人类的治疗策略。 公共卫生相关性我们已将胎儿酒精谱系障碍相关的脑异常与神经元的胰岛素抵抗和氧化应激联系起来。初步数据表明，产前酒精暴露可能会导致青少年大脑中的持续性神经元损伤，因此，我们现在建议表征产前饮酒前的持久性对脑功能的不良影响。我们的第二个目标是 评估针对乙醇介导的脑异常的根本原因的治疗方法，并评估其在慢性产前酒精暴露后预防青少年大脑结构和功能障碍方面的有效性。