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: 8208220
• 负责人: SUZANNE M. DE LA MONTE
• 金额: $ 36.06万
• 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/8208220
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acetaldehyde; Acetylcholine; Address; Adolescence; Adolescent; Adverse effects; Affect; Age; Agonist; Binding; Biochemical; Biological Preservation; Brain; Cell Death; Cell Nucleus; Cerebellum; Cessation of life; Chemicals; Chronic; Congenital neurologic anomalies; DNA; DNA Adduction; DNA Damage; Data; Defect; Development; Dose; Effectiveness; Energy Metabolism; Ethanol; Experimental Designs; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Gender Role; Gene Expression; Generations; Genetic; Genetic Transcription; Goals; Growth; Human; Impairment; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Investigation; Link; Lipid Peroxidation; Long-Term Effects; Measures; Mediating; Mental Retardation; Metabolism; Mitochondria; Modeling; Molecular; Motor; Nature; Nervous system structure; Neuraxis; Neuronal Injury; Neurons; Neurotoxins; Oxidative Stress; Pathway interactions; Perinatal Exposure; Peroxisome Proliferator-Activated Receptors; Phosphoric Monoester Hydrolases; Population; Pregnancy; Production; Protein Tyrosine Kinase; Rattus; Reactive Oxygen Species; Relative (related person); Research; Severities; Signal Transduction; Somatomedins; Structure; Therapeutic; Tyrosine; 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; neuron development; neuron loss; neuronal survival; neurotoxicity; postnatal; prevent; protective effect; pup; receptor; receptor binding; research study; response; synaptogenesis; therapeutic effectiveness; transmission process; 1-Phosphatidylinositol 3-Kinase; Acetaldehyde; Acetylcholine; Address; Adolescence; Adolescent; Adverse effects; Affect; Age; Agonist; Binding; Biochemical; Biological Preservation; Brain; Cell Death; Cell Nucleus; Cerebellum; Cessation of life; Chemicals; Chronic; Congenital neurologic anomalies; DNA; DNA Adduction; DNA Damage; Data; Defect; Development; Dose; Effectiveness; Energy Metabolism; Ethanol; Experimental Designs; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Gender Role; Gene Expression; Generations; Genetic; Genetic Transcription; Goals; Growth; Human; Impairment; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Investigation; Link; Lipid Peroxidation; Long-Term Effects; Measures; Mediating; Mental Retardation; Metabolism; Mitochondria; Modeling; Molecular; Motor; Nature; Nervous system structure; Neuraxis; Neuronal Injury; Neurons; Neurotoxins; Oxidative Stress; Pathway interactions; Perinatal Exposure; Peroxisome Proliferator-Activated Receptors; Phosphoric Monoester Hydrolases; Population; Pregnancy; Production; Protein Tyrosine Kinase; Rattus; Reactive Oxygen Species; Relative (related person); Research; Severities; Signal Transduction; Somatomedins; Structure; Therapeutic; Tyrosine; 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; neuron development; neuron loss; neuronal survival; neurotoxicity; postnatal; prevent; protective effect; pup; receptor; receptor binding; research study; response; synaptogenesis; therapeutic effectiveness; transmission process

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.

在 美国。乙醇通过两种主要机制损害神经元的生存和功能：1）它抑制胰岛素信号传导 生存力，代谢，突触形成和乙酰胆碱产生所必需的； 2）它用作 神经毒性，导致氧化应激，DNA损伤和线粒体功能障碍。胰岛素抑制乙醇 信号传导是在胰岛素受体（IR）处介导的，并由结合和随之而来的减少引起 生存信号的传播。此外，增加磷酸酶的激活增加了逆转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，神经毒性 乙醇的作用促进DNA损伤，可能是由DNA添加剂形成引起的 乙醛是乙醇的主要代谢物。因此，子宫乙醇暴露慢性 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） 中枢神经系统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灵敏剂（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会持续或进展，导致功能性不足 青少年。在此竞争性续订应用中，提出的3个特定目的的实验将表征 长期妊娠暴露于乙醇的长期后果，重点是早期和晚期， 并确定PPAR激动剂治疗预防或减少长期治疗的程度和机制 在子宫内暴露于乙醇的慢性引起的中枢神经系统异常。 AIM＃1将以长期来表征 慢性暴露后，早期和晚期大鼠脑胰岛素抵抗的后果 到乙醇。 AIM＃2将利用由控制产生的主要小脑神经元培养的体外模型 和暴露于乙醇的大鼠幼崽，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，以优化用于PPAR的体内方法 慢性乙醇暴露与中枢神经系统有关 早期和最新青少年的神经元生存和功能。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。另外，实验 将解决性别在乙醇引起的中枢神经系统异常和严重程度和严重性方面的作用 对PPAR激动剂的反应。实验设计被翻译，因为它使用了治疗性 现实地可以应用于人类的策略。