| Project/Area Number |
19K08996
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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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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Makita Noriko 東京大学, 医学部附属病院, 准教授 (60353455)
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| Co-Investigator(Kenkyū-buntansha) |
佐藤 潤一郎 東京大学, 医学部附属病院, 助教 (50552890)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | GPCR / biased agonism / endocrine disease / Ca感知受容体 / β受容体 / βアドレナリン受容体 / arrestin / V2受容体 |
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| Outline of Research at the Start |
Biased agonismを切り口としたGPCRシグナル異常による疾患メカニズムの解析と疾患制御の可能性を検討する。
①Ca感知受容体に対する機能選択的な自己抗体の作用機構／構造解析と、後天性低Ca尿性高Ca血症に対する特異的治療法の検討
②V2受容体変異体の機能解析と腎性尿崩症の新しい治療戦略の検討
③心不全・肥満症の治療戦略としてのβ1,2,3受容体に対するarrestin-biasの検証とその作用機構の解明
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| Outline of Final Research Achievements |
Analysis of rare endocrine diseases caused by GPCR signaling disorder has revealed how GPCR signaling can be regulated specifically. In a patient diagnosed with acquired hypocalciuric hypercalcemia, we found unique autoantibodies working as biased allosteric modulators against CaSR and disclosed where they act. In vitro analysis, we found that cinacalcet can overcome the effect of the autoantibodies by working as a positive allosteric modulator, and succeeded in treating the patient with cinacalcet. To explore how biased signaling is constituted in this rare disease, we investigated mechanisms of G protein bias and tried cloning of unique monoclonal antibody against CaSR. These investigations may help us to reveal the unique structure of GPCR which activates a specific signaling and to create a novel drug which activates only a desired signaling.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究成果は、われわれのゲノムで最大のファミリーを形成し、創薬ターゲットの中心となってきたGタンパク質共役受容体（GPCR）の特異的な制御機構の解明に寄与することが期待される。そして、生理的な恒常性維持機構にも関与している可能性、さらには新たな創薬の基盤となる可能性を示唆する。
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