Development of new target discovery methods for circadian clock regulating compounds and elucidation of period and phase control mechanisms

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03178
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Nagoya University
• Principal Investigator: Ohkawa Taeko (西脇妙子) 名古屋大学, 生命農学研究科, 准教授 (30432230)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 概日時計 / ケミカルバイオロジー / 標的同定

Outline of Final Research Achievements

For target identification by genetic methods, a genome-wide knockout library was introduced into a human diploid cell line, and the rhythms of approximately 3,000 clones were measured in 384-well plates. As a result, changes in the period and amplitude of the circadian rhythm were observed in about 0.5% of the clones. Using this system, target of the circadian clock-modulating compound can be identified by isolating clones whose response to the compound differs from that of wild-type cells. This screening system can also be used to identify novel circadian clock genes.
By derivatization of picrotoxinin, a compound that shortens the circadian rhythm cycle, we have obtained a compound that shows approximately 1,000-fold higher activity. We are going to perform affinity purification using the new derivative to identify the target.

Free Research Field

時間生物学

Academic Significance and Societal Importance of the Research Achievements

様々な生理活性は内因性の振動体「概日時計」により制御され、約24時間周期の「概日リズム」を刻む。概日リズム異常は、心血管疾患や代謝異常等の生活習慣病、精神疾患、がんなどと密接な関連がある。また動物の繁殖の季節性は概日時計によって制御されている。概日時計調節化合物の標的の同定を通じて、概日時計発振機構の全貌が解明されれば、上記疾患の予防や治療法の開発、産業動物の繁殖効率の向上など様々な波及効果が期待される。