Fetal Alcohol Effects on Circadian clocks and POMC

描述（由申请方提供）：胎儿暴露于乙醇可导致胎儿酒精综合征的发生，其特征为胎儿酒精暴露（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系统功能异常。最近的研究表明，FAE后代的睡眠-觉醒障碍和神经内分泌功能异常可能与生物钟机制的长期变化有关。采用大鼠动物模型，该提议确定胎儿暴露于乙醇是否引起位于下丘脑弓状核中的β-内啡肽神经元的昼夜节律输出及其对血浆促性腺激素释放的调节的持久变化。它测试的假设，胎儿暴露于乙醇导致异常的中枢时钟机制在下丘脑的视神经上核的成人表达，导致改变内部时钟机制和β-内啡肽神经元的相位激素输出。它还确定了胎儿暴露于乙醇是否改变了控制中枢和内部时钟光反应的分子机制。拟议的研究使用激光捕获显微镜，免疫组织化学，Western印迹，放射免疫测定和实时RT-PCR技术来识别关键参与调节中枢和内部时钟机制以及β-内啡肽神经元的阶段性激素输出的基因和蛋白质表达。拟议的研究应该提供一个更好的了解胎儿暴露于乙醇的长期后果的生物钟功能。这些信息应有助于制定治疗策略，在管理睡眠-觉醒障碍和由此产生的健康后果FAE后代。

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.