Fetal Alcohol Effects on Circadian clocks and POMC

胎儿酒精对生物钟和 POMC 的影响

• 批准号: 7097781
• 负责人: DIPAK KUMAR SARKAR
• 金额: $ 27.72万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-10 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097781
• 关键词: biological models; circadian rhythms; confocal scanning microscopy; embryo /fetus toxicology; endorphins; ethanol; fetal alcohol syndrome; gene expression; gonadotropins; hormone regulation /control mechanism; hypothalamus; immunocytochemistry; laboratory rat; molecular pathology; neuroendocrine system; neurophysiology; neurotoxicology; polymerase chain reaction; proopiomelanocortin; radioimmunoassay; sleep; sleep regulatory center; wakefulness; western blottings

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：胎儿暴露于乙醇会导致胎儿酒精综合征的发展，胎儿酒精暴露（FAE）后代的各种形态和行为缺陷的特征。这些后代通常在神经内分泌系统的功能中表现出临床睡眠效果障碍和异常。最近的研究已经确定了FAE后代的睡眠效果障碍和神经内分泌功能异常与昼夜节律时钟机制的长期变化有关。该提议采用大鼠动物模型，确定胎儿暴露于乙醇是否会导致位于下丘脑弓形核的β-内啡肽神经元的昼夜节律持续变化，以及对血浆促性腺激素释放的调节。它检验了以下假设：胎儿暴露于下丘脑的上核核中中央时钟机制的成人表达异常，从而导致内部时钟机制的改变和β-内酚神经元的质量激素输出改变。它还可以确定胎儿暴露于乙醇是否会改变控制中心和内部时钟的光学反应的分子机制。拟议的研究使用激光捕获的显微镜，免疫组织化学，Western印迹，放射免疫测定和实时RT-PCR技术来鉴定基因和蛋白质表达式，这些基因和蛋白质表达与中央时钟机制和内部时钟机制的调节以及来自β-肾上腺源性神经元的阶段性激素输出有关。拟议的研究应更好地理解昼夜节律功能中胎儿暴露于乙醇的长期后果。这些信息应有助于制定治疗策略，以管理睡眠疗程障碍以及FAE后代的健康后果。