Identification and characterization of a potential drug target regulating the pace of the central circadian clock in the brain through orphan G protein-coupled receptors

2021 Fiscal Year Final Research Report

• Project/Area Number: 17H01524
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Kyoto University
• Principal Investigator: Doi Masao 京都大学, 薬学研究科, 教授 (20432578)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Keywords: 体内時計 / G蛋白質共役受容体

Outline of Final Research Achievements

Toward the development of biological rhythm regulators aimed at correcting lifestyle-related diseases, we found that a specific genome DNA sequence located in the non-coding region, which controls the expression of core clock gene, is essential for the maintenance of body's 24-h activity rhythm (Doi et al., Nat Commun 2019); showed that N-linked glycosylation occurs on the orphan G-protein-coupled receptor Gpr176, which is a period regulator of the master clock in the brain (Wang et al., Sci Rep 2020); revealed Gpr19 as an orphan receptor required for proper phase-entrainment of the clock by light (Yamaguchi et al., Sci Rep 2021); identified the G-protein-coupled receptor Calcr as a component required for keeping proper circadian rhythm in body temperature (Goda & Doi et al., Genes Dev 2018); and discovered an approach that restores local circadian enzymatic activity rhythm in the eyes to alleviate age-associated evaporative dry eye disease (Sasaki et al., Nat Aging 2022).

Free Research Field

時間生物学

Academic Significance and Societal Importance of the Research Achievements

体内時計の異常は、現代社会に見られる多くの生活習慣病の根底に潜む共通の病因となることがこれまで示されてきたが、体内時計を是正すると病気が治せるのかという逆向きの問が重要な医療課題として残されている。このような中、私共は、本研究の結果、眼局所での酵素活性リズムすなわち局所生体時計を正常化する方法により、これまで有効な治療法のなかった加齢性ドライアイを治療できること見出したほか、体内時計の中枢を狙った中枢リズム調整薬の標的候補として創薬可能性の高いG蛋白質共役受容体Gpr176, Gpr19, Calcrを見出した。体内時計を活用した病気の治療・臨床応用に向け重要な基礎を構築できたといえる。