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ヒトの概日リズム障害を伴う疾患における生体時計関連遺伝子の解析及び治療法の開発

Research Project

Project/Area Number 11233206
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionSaitama Medical University

Principal Investigator

海老澤 尚 (海老沢 尚)  埼玉医科大学, 医学部, 講師 (00201369)

Co-Investigator(Kenkyū-buntansha) 池田 正明  埼玉医科大学, 医学部, 講師 (80232198)
Project Period (FY) 1999 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥48,800,000 (Direct Cost: ¥48,800,000)
Fiscal Year 2002: ¥11,300,000 (Direct Cost: ¥11,300,000)
Fiscal Year 2001: ¥11,300,000 (Direct Cost: ¥11,300,000)
Fiscal Year 2000: ¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 1999: ¥13,500,000 (Direct Cost: ¥13,500,000)
Keywords概日リズム睡眠障害 / 時計遺伝子 / 遺伝子多型 / リン酸化 / メラトニン受容体 / G蛋白 / カゼインキナーゼ / プロモーター / 概日リズム障害 / 季節性感情障害 / Per3遺伝子 / Bmal1遺伝子 / Clock遺伝子 / 生体時計関連遺伝子 / 遺伝子変異 / period遺伝子 / BMAL2遺伝子
Research Abstract

前年度までに睡眠相後退症候群、非24時間睡眠覚醒症候群の発症に関与する時計遺伝子の多型としてPer3遺伝子のH4ハプロタイプ、Clock遺伝子のT3111C多型を報告済だが、今年度はハムスターのリズム変異体tauの原因遺伝子であり、PER蛋白などの時計蛋白をリン酸化するCasein Kinase I epsilon (CK I ε)遺伝子の多型解析を行い、4個の多型を見出した。うち1個がアミノ酸の変化を伴う多型(ミスセンス多型)だった。ミスセンス多型は正常被験者の約20%が保有していたが、概日リズム障害での保有率は約10%と、有意に低頻度だった(P=0.013)。このミスセンス多型を導入したCK I ε cDNA及び野生型のCK I ε cDNAを発現ベクターに挿入し、大腸菌で蛋白を発現させ、精製してcaseinを基質に酵素活性を調べたところ、ミスセンス多型を持つ酵素の方が約1.8倍高い酵素活性を示した。従ってこのミスセンス多型はCK I εの酵素活性を変化させ、概日リズム障害の発症リスクを抑制する働きを持つと考えられた。(CK I εの酵素活性の解析には大阪大学蛋白質研究所の高野・礒島両氏の協力を得た)
また、以前見出したメラトニン1A受容体のR54W変異が受容体と各G蛋白との結合に及ぼす影響を、G蛋白のキメラ遺伝子を用いて調べた。G蛋白のキメラ遺伝子は慶応大学西本教授から提供を受けた。その結果、R54W変異を持つ1A受容体は、持たないものに比べてGi1/2,Gi3との結合は強化され、Gq/11等との結合が減弱しているのが見出された。このG蛋白との結合性の変化がヒトの概日リズムに影響を与える要因と思われた。
また、時計遺伝子の一つBmal1のプロモーター領域にあるROR-RE配列の機能を解析し、RORα、RORβ、RORγにより転写が促進され、REV-ERBでは変化がないことを見出した。

Report

(4 results)
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (38 results)

All Other

All Publications (38 results)

  • [Publications] Kohtoku Satoh, Kazuo Mishima, Yuichi Inoue, Takashi Ebisawa, Tetsuo Shimizu: "Two pedigrees of familial advanced sleep phase syndrome in Japan"Sleep. (印刷中). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 海老澤 尚: "概日リズムと睡眠障害-時計遺伝子からみた睡眠障害"医学のあゆみ. 204(11). 799-802 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 海老澤 尚: "体内時計機構の分子医学"Molecular Medicine. 40(3). 318-325 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 海老澤 尚: "時計遺伝子の発見と時間生物学"精神科. 1(5). 382-387 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 海老澤 尚: "時計遺伝子と睡眠覚醒障害"脳と精神の医学. 13(3). 289-295 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 海老澤 尚: "概日リズム障害の遺伝子解析"内分泌・糖尿病科. 14(4). 408-413 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 海老澤 尚: "生体リズム障害の分子生物学的背景"Prog.Med.. 22. 1385-1389 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 海老澤 尚: "メラトニン受容体および時計遺伝子多型と概日リズム障害"現代医療. 34. 63-67 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 海老澤 尚 (分担執筆): "「KEYWORD」樋口輝彦、神庭重信、染谷俊幸、宮岡等編集"先端医学社. 252 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 池田正明 (分担執筆): "「KEYWORD」樋口輝彦、神庭重信、染谷俊幸、宮岡等編集"先端医学社. 252 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hakuei Yamashita, Tetsushi Kazawa, Yukiko Minatogawa, Takashi Ebisawa, et al.: "Time course of hepatic cytochrome P450 subfamily induction by chronic carbamazepine administration in rats"Int J Neuropsychopharmacol.. (In press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Makoto Uchiyama, Kayo Shibui, Tatsuro Hayakawa, Yuichi Kamei, Takashi Ebisawa, et al.: "Larger phase angle between sleep propensity and melatonin rhythms in sighted humans with non-24-hour sleep-wake syndrome"Sleep. 25. 83-88 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Toshio Iwase, Naofumi Kajimura, Makoto Uchiyama, Takashi Ebisawa, et al.: "Mutation screening of the human Clock gene in circadian rhythm sleep disorders"Psychiatry Research. 109. 121-128 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yu W, Nomura M, Ikeda M: "Interactivating feedback loops within the mammalian CLOCK : BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2"Biochem Biophys Res Commun. 290. 933-941 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takashi Ebisawa, et al.: "Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome"EMBO Reports. 2. 342-346 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Abe H, Honma S, Namihira M, Masubuchi S, Ikeda M, et al.: "Clock gene expressions in the suprachiasmatic mucleus and other areas of the brain during rhythm splitting in CS mice"Mol Brain Res. 87. 92-99 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Namihira M, Honma S, Abe H, Masubuchi S, Ikeda M, et al.: "Circadian pattern, light responsiveness and localization of rPer1 and rPer2 gene expression in the rat retina"NeuroReport. 12. 471-475 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 海老沢尚: "生体リズム障害と睡眠異常の分子医学"現代医療. 33. 126-131 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 海老澤尚: "睡眠覚醒リズム障害の遺伝子解析"神経研究の進歩. 45. 840-846 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 池田正明, 海老澤尚: "概日リズム障害と時計遺伝子"分子精神医学. 1. 31-38 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 池田正明: "PAS因子の構造と機能"神経研究の進歩. 45. 742-754 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ikeda M, et al. (Honma K, Honma S Eds): "Molecular cloning and characterization of the clock gene Bmal1, in Zeitgebers, entrainment and masking of the circadian system"Hokkaido University Press. 105 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takashi Ebisawa et al.: "Association of structural nolymorphisms in the human period3 gene with delayed sleep phase syndrome."EMBO Reports. (In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masaaki Ikeda,Wangjie Yu,Momoki Hirai,Takashi Ebisawa et al.: "cDNA cloning of a novel bHLH-PAS transcription factor superfamily gene, BMAL2 : Its mRNA expression, subcellular distribution, and chromosomal locallzation."Biochem.Biophys.Res.Commun.. 275. 493-502 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 海老澤尚: "睡眠覚醒リズム障害と時計遺伝子"神経研究の進歩. 44・6. 891-897 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 海老沢尚: "生体時計の分子機構-ストレスへの時間生物学的アプローチに向けて-"日本神経精神薬理学雑誌. 20. 107-111 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 海老沢尚: "家族性致死性不眠症"Clinical Neuroscience. 18・10. 94-95 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 海老沢尚: "生体リズム障害の分子生物学"臨床脳波. 42・10. 629-633 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 海老澤尚: "睡眠覚醒リズム障害と遺伝子変異"自律神経. 37・2. 158-162 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 海老澤尚: "概日リズム障害と遺伝子変異"脳と精神の医学. 11・1. 1-7 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 山内俊雄,海老澤尚: "生物学的精神医学研究の限界と将来"精神医学. 42・3. 263-271 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takasi Ebisawa, et al.: "Genetic polymorphisms of human melatonin 1b receptor gene in circadian rhythm sleep disorders and cotrols"Neuroscience Letters. 280. 29-32 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takasi Ebisawa, et al.: "Alletic variants of human melatnin 1a recceptor : Function and prevalence in subjects with circadian rhythm sleep disorders"Biochem. Biophys, Res. Commun.. 262. 832-837 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Wangjie Yu, et al.: "Characterization of three splice variants and genomic organization of the mous BMAL1 gene"Biochem, Biophys. Res. Commn.. 260. 760-767 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 海老沢尚: "メラトニンと生体リズムの遺伝子機構"Molecular Medicine. 36(10). 1150-1159 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 海老沢尚: "概日リズム障害と遺伝子変異"日本時間生物学会会誌. 5(1). 49-51 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 海老沢尚: "サーカディアンリズム異常の分子生物学"医学のあゆみ. 190(4). 281 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 海老沢尚(分担執筆): "生物時計の分子生物学(担当 ; メラトニンの分子機構-メラトニン受容体)"シュプリンガーフェアラーク東京. 201(担当 ; 96-103) (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2018-03-28  

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