Screening of drugs for jet lag and day-night reversal using 3-D brain tissue derived from ES/iPS cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K16519
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Kyoto Prefectural University of Medicine (2023); Kyoto University (2020)
• Principal Investigator: Tamiya Hiroyuki 京都府立医科大学, 医学(系)研究科(研究院), 研修員 (70770519)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 視交叉上核 / 多能性幹細胞 / ES/iPS細胞 / 時差ぼけ / 昼夜逆転 / 脳オルガノイド

Outline of Final Research Achievements

The principal investigator has successfully induced and matured functional clock centers (suprachiasmatic nucleus, SCN) from pluripotent stem cells with high efficiency. The induced SCN tissues (SCN organoids) expressed SCN-specific genes and partially replicated the structure, with over 20% of the organoids being SCN tissue, compared to only 0.7% of SCN tissue in the entire adult hypothalamus. Additionally, bioluminescence imaging of clock genes demonstrated the synchronization mechanism of cellular clocks, which exists only in the SCN. Furthermore, transplantation into SCN-destroyed mice restored the behavioral rhythms lost due to SCN destruction. It was confirmed that the SCN organoid technology is also applicable to human iPS cells and is considered promising for screening drugs for circadian rhythm disorders.

Free Research Field

内科学一般

Academic Significance and Societal Importance of the Research Achievements

体内時計は全身ほぼすべての細胞にあるが, 哺乳類においては視床下部の視交叉上核 (SCN) が時計中枢として機能し, 時刻情報を全身に伝えている. 現代の眠らない社会において, 体内時計は適応できなくなってきている. 近年, SCNの同期機構を弱めると, 時差ぼけになりにくいことが示されつつあり, 創薬ターゲットとして期待されている. 代表者が開発したSCNオルガノイド技術をヒトiPS細胞に応用することで, ヒトSCNを試験管内で作製すれば, 既存薬のスクリーニングすれば, 時差ぼけ治療薬の同定が可能となる. 本治療薬は交替勤務型睡眠障害や高齢者の昼夜逆転などにも応用可能と考えられる.