Suprachiasmatic Control of Peripheral Circadian Rhythms

周围昼夜节律的视交叉上控制

基本信息

批准号：
7575755
负责人：
ERIC L BITTMAN
金额：
$ 29.21万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-20 至 2011-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The suprachiasmatic nucleus of the hypothalamus (SCN) contains a master pacemaker that controls a wide variety of circadian rhythms of physiology and behavior. Recent work has provided a thorough understanding of molecular mechanisms by which these oscillations are generated. The rhythmic and light-regulated expression of Period, Bmal1, and Cryptochrome genes are essential to pacemaker function. Surprisingly, these genes are also expressed rhythmically in a variety of peripheral organs, but their sustained oscillations in vivo appear to depend upon integrity of the SCN. The present experiments will focus on the nature of the SCN-dependent signals responsible for the persistence of peripheral oscillations. Such signals may be neural, humoral, or behavioral, and various organs may rely on different signals or a combination of signals. The first two specific aims will focus on the extent of neural control of peripheral oscillations. Specific aim 1 will test further the importance of innervation vs. humoral signals in regulation of circadian rhythms in the periphery through use of Syrian hamsters whose circadian rhythms have been induced to split by long-term exposure to constant light. We will determine whether the asymmetrical haPer1-2 and haBmal1 expression in the SCN of such animals is correlated with asynchrony of expression of the same genes on the left and right sides of the body in bilaterally paired and unpaired peripheral organs. Asymmetrical expression of physiologically important genes in these peripheral organs will also be assessed. Specific aim 2 will extend our findings that SCN lesions eliminate peripheral circadian rhythms in hamsters, and establish whether denervation of testis, spleen or muscle replicates the effects of SCN lesions upon rhythmic haPer1-3 and haBmal1 expression. Specific aim 3 will examine the regulation of peripheral oscillations by non-neural signals by taking advantage of a parabiotic mouse model in which the effects of SCN lesions are reversed by linkage of the blood supply to that of an intact animal. We will extend our characterization of peripheral circadian oscillations in SCN-lesioned, parabiotic mice and determine whether social factors or temperature cues can contribute to this effect. Inasmuch as abnormal phase relationships between the pacemaker and peripheral oscillators appear to contribute to jet lag and may be involved in other pathologies including sleep disorders, seasonal depression, and infertility, our findings will have applications to human health and welfare.

描述（由申请人提供）：下丘脑的视交叉上核（SCN）包含一个主起搏器，控制各种生理和行为的昼夜节律。最近的工作提供了对产生这些振荡的分子机制的透彻理解。 period、Bmal1 和 Cryptochrome 基因的节律和光调节表达对于起搏器功能至关重要。令人惊讶的是，这些基因也在多种外周器官中有节律地表达，但它们在体内的持续振荡似乎取决于视交叉上核的完整性。目前的实验将集中于与 SCN 相关的信号的性质，该信号负责外围振荡的持续存在。这些信号可以是神经信号、体液信号或行为信号，并且各种器官可能依赖于不同的信号或信号的组合。前两个具体目标将集中于神经控制外周振荡的程度。具体目标 1 将通过使用叙利亚仓鼠来进一步测试神经支配与体液信号在外周昼夜节律调节中的重要性，叙利亚仓鼠的昼夜节律因长期暴露在恒定光线下而被诱导分裂。我们将确定此类动物 SCN 中 haPer1-2 和 haBmal1 的不对称表达是否与双边配对和未配对外周器官中身体左侧和右侧相同基因表达的异步相关。还将评估这些外周器官中生理学重要基因的不对称表达。具体目标 2 将扩展我们的发现，即 SCN 损伤消除了仓鼠的外周昼夜节律，并确定睾丸、脾脏或肌肉的去神经支配是否复制了 SCN 损伤对节律性 haPer1-3 和 haBmal1 表达的影响。具体目标 3 将利用共生小鼠模型来检查非神经信号对外周振荡的调节，在该模型中，SCN 损伤的影响通过血液供应与完整动物的血液供应的联系而逆转。我们将扩展对 SCN 损伤、共生小鼠的外周昼夜节律振荡的表征，并确定社会因素或温度线索是否会导致这种效应。由于起搏器和外周振荡器之间的异常相位关系似乎会导致时差反应，并可能与其他疾病有关，包括睡眠障碍、季节性抑郁症和不孕不育，因此我们的研究结果将应用于人类健康和福利。