Fetal Alcohol Effects on Circadian clocks and POMC

胎儿酒精对生物钟和 POMC 的影响

• 批准号: 7856010
• 负责人: DIPAK KUMAR SARKAR
• 金额: $ 6.39万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7856010
• 关键词: Adolescent; Adult; Affect; Alcohol consumption; Alcohols; Animal Model; Animals; Behavioral; Binding Proteins; Biological; Biological Clocks; Biological Rhythm; Cell Nucleus; Child; Chronic; Circadian Rhythms; Clinical; Cyclic AMP; Data; Development; Elements; Endocrine; Endorphins; Estrogens; Ethanol; Exposure to; Female; Fetal Alcohol Exposure; Fetal Alcohol Syndrome; Fetal Tissues; Fetal alcohol effects; Fetus; Gastrin releasing peptide; Gene Expression; Gene Proteins; Gonadotropins; Health; Hormonal; Human; Hypothalamic structure; Immunohistochemistry; Lasers; Lead; Life; Messenger RNA; Microscopy; Modeling; Molecular; Naltrexone; Neuraxis; Neurons; Neurosecretory Systems; Opioid; Output; Ovariectomy; Pacemakers; Pathology; Pattern; Perinatal Exposure; Periodicity; Phase; Plasma; Pro-Opiomelanocortin; Proteins; Radioimmunoassay; Rattus; Regulation; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sleep; Sleep Disorders; Structure of nucleus infundibularis hypothalami; Techniques; Testing; Therapeutic; Time; Western Blotting; Withdrawal; alcohol exposure; beta-Endorphin; biological systems; circadian pacemaker; depression; drinking; experience; falls; fetal; laser capture microdissection; male; neonate; offspring; problem drinker; protein expression; response; suprachiasmatic nucleus; transmission process; young adult

Exposure of a fetus to ethanol can lead to the development of fetal alcohol syndrome, which is characterized by various morphological and behavioral deficits in fetal alcohol-exposed (FAE) offspring. These offspring often show clinical sleep-wake disturbances and abnormalities in the functions of the neuroendocrine system. Recent studies have identified the possibility that the sleep-wake disturbances and neuroendocrine function abnormalities in the FAE offspring are related to long-term changes in circadian clock mechanisms. Employing the rat animal model, this proposal determines whether fetal exposure to ethanol causes long- lasting changes in the circadian output of beta-endorphin neurons located in the arcuate nucleus of the hypothalamus and their regulation of plasma gonadotropin release. It tests the hypothesis that fetal exposure to ethanol causes an abnormality in the adult expression of the central clock mechanisms in the suprachaismatic nucleus of the hypothalamus leading to alteration in the internal clock mechanisms and the phasic hormonal output of beta-endorphin neurons. It also identifies whether fetal exposure to ethanol alters the molecular mechanism governing the photic responses of the central and internal clocks. The proposed research uses laser-captured microscopy, immunohistochemistry, Western blot, radioimmunoassay, and real-time RT-PCR techniques to identify gene and protein expressions that are critically involved in the regulation of central and internal clock mechanisms and the phasic hormonal outputs from beta-endorphin neurons. The proposed studies should provide a better understanding of the long-term consequences of fetal exposure to ethanol in the circadian clock functions. This information should help to develop therapeutic strategies in managing sleep-wake disturbances and the resultant health consequences in FAE offspring.

胎儿接触乙醇会导致胎儿酒精综合症的发生，其特征是 酒精暴露（FAE）后代的各种形态和行为缺陷。这些后代 经常表现出临床睡眠-觉醒障碍和神经内分泌功能异常 系统。最近的研究发现睡眠-觉醒障碍和神经内分泌可能 FAE后代的功能异常与生物钟机制的长期变化有关。 该提案采用大鼠动物模型来确定胎儿接触乙醇是否会导致长期 位于大脑弓状核的β-内啡肽神经元的昼夜节律输出持续变化 下丘脑及其对血浆促性腺激素释放的调节。它检验了胎儿暴露的假设 乙醇导致成人中枢时钟机制的表达异常 下丘脑的上核导致内部时钟机制和 β-内啡肽神经元的阶段性激素输出。它还确定胎儿接触乙醇是否会改变 控制中央和内部时钟的光反应的分子机制。拟议的 研究使用激光捕获显微镜、免疫组织化学、蛋白质印迹、放射免疫分析和 实时 RT-PCR 技术可识别与细胞表达密切相关的基因和蛋白质表达 调节中枢和内部时钟机制以及β-内啡肽的阶段性激素输出 神经元。拟议的研究应该可以更好地理解长期后果 胎儿接触乙醇会影响生物钟的功能。这些信息应该有助于开发治疗方法 管理睡眠-觉醒障碍的策略及其对 FAE 后代的健康影响。