2018 Fiscal Year Final Research Report

Molecular and neural mechanisms underlying the robustness of the circadian clock and an approach to jet-lag-related diseases.

Research Project

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Project/Area Number	15H05642
Research Category	Grant-in-Aid for Young Scientists (A)
Allocation Type	Single-year Grants
Research Field	Biological pharmacy
Research Institution	Kyoto University
Principal Investigator	YAMAGUCHI Yoshiaki 京都大学, 薬学研究科, 講師 (30467427)
Research Collaborator	OKAMURA Hitoshi 京都大学, 大学院薬学研究科, 教授
Project Period (FY)	2015-04-01 – 2019-03-31
Keywords	概日リズム / 体内時計 / 時計遺伝子 / 時差 / バソプレッシン / 視交叉上核
Outline of Final Research Achievements	Almost all organisms on Earth have an internal biological clock, the circadian clock. This clock drives stable oscillations in metabolism, physiology, and behavior with a period of approximately 24 h. In mammals, circadian rhythms are generated by a timing system comprised of a master pacemaker located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. We previously reported that arginine vasopressin receptor V1a and V1b regulate the speed of re-entrainment after abrupt light/dark advance. Here, we succeeded in real-time monitoring of Per1 and Per2 transcription separately by detecting the bioluminescence of luciferase reporters using a plastic optical fiber inserted into the SCN of freely moving rats. We also presented a new theoretical concept to understand circadian clock disruption and slow recovery from jet lag based on the mathematical model. Finally, we found that rapidly entrainable V1aV1b double knockout mice showed lower mortality under a chronic jet lag.
Free Research Field	時間生物学
Academic Significance and Societal Importance of the Research Achievements	従来のリズム研究では、例えば「時計遺伝子を欠損させると概日リズムが消失する」という結果より、この時計遺伝子がリズム形成を担うというものであった。ところが、AVP異常のBrattleboroラットは概日リズム異常を示さなかったため、AVPのリズム機能は長らく不明なままであった。私たちは、AVP-V1シグナルは外乱に対する概日リズムの安定化を担うことを見出したが、これは従来のリズム研究では示されなかった極めてユニークな発見である。さらに本研究は、V1aV1bDKOの時差症状を示さないという特質を利用して、これまでに対策なかったシフトワーカーの病態改善に迫るものであり、社会的意義も大きいと言える。