Control mechanism of biological clocks in relation to mood, behavior and sleep disorders and Their treatments.

生物钟与情绪、行为和睡眠障碍的控制机制及其治疗。

• 批准号: 14370289
• 负责人: OKAWA Masako
• 金额: $ 8.83万
• 依托单位: Shiga University of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370289/
• 关键词: clock gene; circadian rhythm; mood disorders; prostaglandin; orexin; adenocine; sleep; melatonin; 催眠

1.In our clinical investigations, for pathogenesis of circadian rhythm sleep disorders, Uchiyama and Yamada reported as follows: Concentrations of serum melatonin, cortisol, and thyroid-stimulating hormone (TSH) were assessed every hour for 26h under dim light condition. The hormonal rhythms were significantly delayed in patients with DSPS compared with controls, whereas the 24-h amounts of hormonal secretions and the phase relations between the hormonal rhythms did not differ between the groups. They postulate that sleep-phase delay in patients with DSPS is a consequence of the phase delay of the circadian pacemaker, suggesting that phase delay in the circadian clock is responsible for this disorder.2.In mammals, clock related genes, such as Per 1/2/3, Cry 1/2, Clock, etc. are expressed in suprachi-asmatic nucleus, the site of a master circadian clock, and form transcriptional/translational feed-Back Loops to generate circadian rhythmicity. Ebisawa et al. reported that polymorphism in … More Per3 gene is associated with delayed sleep phase syndrome (DSPS).3.The importance of hypocretin has been reported to play an important role in food intake, energy homeostasis and maintenance of vigilance level, and orexin knock out (KO) mice showed attenuated food intake behavior. Shibata et al. have observed in control animals the peak time of cell numbers containing both orexin and Fos protein neurons appeared during night time.However, their feeding time was restricted in daytime, the phase advance of food intake rhythm was observed. However, in KO mice, did not show phase advance, which indicates orexin is involved in food intake rhythm.4.Prostaglandin (PG) D2 is one of the most Potent sleep promoting substances. Urade et al. reported PGD2-induced sleep can be inhibited by an adenosine A2a receptor (A2AR) antagonist, suggesting that A2AR probably mediates the sleep promoting effect of PGD2. In the present study, they employed the gene-manipulated A2AR knockout (KO) mice to further explore the involvement of adenosine receptor subtypes in the somnogenic effect of PGD2. The results suggested that activation of A2AR was mainly involved in sleep promotion effect of adenosine and further experiment indicates that adenosine A2AR deficiency attenuates the somnogenic effect of PGD2. Less

1.在我们的临床研究中，对于昼夜节律睡眠障碍的发病机制，Uchiyama和Yamada报道如下：在昏暗的光线条件下，每小时测定一次血清褪黑素、皮质醇和促甲状腺激素（TSH）的浓度，持续26小时。与对照组相比，DSPS患者的激素节律显着延迟，而24小时的激素分泌量和激素节律之间的相位关系在两组之间没有差异。他们认为DSPS患者的睡眠时相延迟是昼夜节律起搏器的时相延迟的结果，提示昼夜节律钟的时相延迟是导致这种疾病的原因。2.在哺乳动物中，生物钟相关基因如Per 1/2/3、Cry 1/2、Clock等表达于视交叉上核，视交叉上核是主昼夜节律钟的所在地，并形成转录/翻译反馈环以产生昼夜节律。Ebisawa等人报道， ...更多信息 Per 3基因与睡眠时相延迟综合征（DSPS）相关。3.下丘脑泌素在食物摄取、能量平衡和维持警觉水平中起重要作用，食欲素基因敲除（KO）小鼠的摄食行为减弱。柴田等在对照组动物中观察到含食欲素和Fos蛋白神经元的细胞数高峰出现在夜间，而其摄食时间限制在白天，观察到摄食节律的时相提前。而在KO小鼠中，没有出现相位提前，这表明食欲素参与了食物摄入节律。4.前列腺素（PG）D2是最有效的睡眠促进物质之一。Urade等报道，PGD 2诱导的睡眠可被腺苷A2 a受体（A2 AR）拮抗剂抑制，表明A2 AR可能介导PGD 2的睡眠促进作用。在本研究中，他们使用基因操纵的A2 AR敲除（KO）小鼠进一步探索腺苷受体亚型参与PGD 2的致眠作用。提示腺苷的促眠作用主要与A2 AR的激活有关，进一步的实验表明腺苷A2 AR缺乏可减弱PGD 2的促眠作用。少

项目成果

Shibui K, Uchiyama M,, Kim K, Tagaya H, Kuriyama K, Suzuki H, Kamei Y, Hayakawa T, Okawa M, Takahashi K: "Melatonin, cortisol and thyroid-stimulating hormone rhythms are delayed in patients with delayed sleep phase syndrome"Sleep and Biological Rhythms. 1

Shibui K、Uchiyama M、Kim K、Tagaya H、Kuriyama K、Suzuki H、Kamei Y、Hayakawa T、Okawa M、Takahashi K：“睡眠相位延迟综合征患者的褪黑激素、皮质醇和促甲状腺激素节律延迟

田ヶ谷浩邦, 内山真: "不眠症とその対策"成人病と生活習慣病. 33. 1184-1188 (2003)

Hirokuni Tagaya，Makoto Uchiyama：“失眠及其对策”成人和生活方式疾病。33。1184-1188（2003）。

亀井雄一, 田ヶ谷浩邦, 金圭子, 栗山健一, 尾崎章子, 渋井佳代, 有竹清夏, 内山真: "エビデンスの使い方:睡眠障害"臨床精神薬理. 6. 1035-1047 (2003)

Yuichi Kamei、Hirokuni Tagaya、Keiko Kane、Kenichi Kuriyama、Akiko Ozaki、Kayo Shibui、Kiyoka Aritake、Makoto Uchiyama：“如何使用证据：睡眠障碍”临床精神药理学。6. 1035-1047 (2003)。

Urade Y, Hayaishi o: "Prostaglandin D synthase : Structure and Function"Vitamins and Hormones. 58. 89-120 (2000)

Urade Y，Hayaisho：“前列腺素 D 合酶：结构和功能”维生素和激素。

Aida R., Moriya T., Araki M., Akiyama M., Wada K., Wada E., Shibata S.: "Gastrin-releasing peptide mediates photic entrainable signals to the dorsal subsets of the suprachiasmatic nucleus via Induction of Period gene in mice"Mol. Pharmacol. 61(1). 26-34 (

Aida R.、Moriya T.、Araki M.、Akiyama M.、Wada K.、Wada E.、Shibata S.：“胃泌素释放肽通过周期基因的诱导将光夹带信号介导至视交叉上核的背侧亚群