| Project/Area Number |
17K08595
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Kobe University |
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Principal Investigator |
Adachi Naoko 神戸大学, バイオシグナル総合研究センター, 助教 (70604510)
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| Co-Investigator(Kenkyū-buntansha) |
吉野 健一 神戸大学, バイオシグナル総合研究センター, 助教 (90280792)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | ベータ３アドレナリン受容体 / パルミトイル化 / 翻訳後修飾 / ADRB3 / ヒト化マウスモデル / GPCR / S-palmitoylation / lipidation / アドレナリン受容体 / b3AR / 遺伝子多型 / シグナル伝達 / β３アドレナリン受容体 / パルミトイル化修飾 / ヒト化マウス |
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| Outline of Final Research Achievements |
To clarify the functions and effects of beta-3 adrenergic receptor (β3AR) on obesity, type II diabetes and overactive bladder, we focused on S-palmitoylation, a post-translational modification of β3AR. Interestingly, number and sites of palmitoylation modifications of human and mouse β3AR are distinct, and the mechanism of the increase in receptor expression on the plasma membrane by a β3AR specific agonist, mirabegron, is also distinct. Multiple S-palmitoylation of different sites differentially regulates the human β3AR, and differential S-palmitoylation distinguishes human and rodent β3ARs, potentially contributing to species-specific differences in the clinical efficacy of β3AR-directed pharmacological approaches to disease. In addition, we have generated and analyzed humanized β3AR knock-in mice to clarify the pathophysiological relevances of differential S-palmitoylation on β3AR.
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| Academic Significance and Societal Importance of the Research Achievements |
これまで、肥満・Ⅱ型糖尿病・過活動膀胱の病態に重要な役割を持つβ3アドレナリン受容体の解析の多くはマウスやラットなどげっ歯類を用いて行われていたが、本研究によりヒトとげっ歯類のβ3アドレナリン受容体の調節機構には大きな違いがあることが判明した。このことより、ヒトの病態を再現するために、ヒト化β3アドレナリン受容体を持つマウスを作製し解析することの重要性を示した。
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