New therapeutic strategies of GPCR diseases
| Project/Area Number |
16K09797
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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 |
Endocrinology
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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) |
間中 勝則 東京大学, 医学部附属病院, 助教 (10700495)
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| Project Period (FY) |
2016-04-01 – 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 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | GPCR / biased agonism / protean agonism / endocrine disease / Ca感知受容体 / V2受容体 / 内科 |
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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. In cells expressing V2R mutants causing nephrogenic diabetes insipidus, including a novel one, we found that an agonist pharmacochaperone helps the mutants to be folded correctly and translocated to plasma membrane, and enables sustainable signaling, depending on the residual activity of each mutant (protean agonism). These results 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 |
Gタンパク質共役受容体（GPCR）に対するこれまでの薬剤は、GPCRシグナルを全体として刺激したり抑制することで、望ましくないシグナルを発生させたり、望ましいシグナルも抑えたりする問題があった。本研究成果は、望ましいシグナルのみをオンとできるGPCRのユニークな活性化構造の解明につながり、新たな創薬の基盤となる可能性がある。
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Report
(5 results)
Research Products
(51 results)
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[Journal Article] Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody2019
Author(s)
Noriko Makita, Takao Ando, Junichiro Sato, Katsunori Manaka, Koji Mitani, Yasuko Kikuchi, Takayoshi Niwa, Masanori Ootaki, Yuko Takeba,4 Naoki Matsumoto, Atsushi Kawakami, Toshihisa Ogawa, Masaomi Nangaku, and Taroh Iiri
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Journal Title
JCI Insight
Volume: in press
Issue: 8
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Molecular analysis and literature-based hypothesis of an immunonegative prostate small cell carcinoma causing ectopic ACTH syndrome2019
Author(s)
Takeuchi M, Sato J, Manaka K, Tanaka M, Matsui H, Sato Y, Kume H, Fukayama M, Iiri T, Nangaku M, Makita N
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Journal Title
Endocrine Journal
Volume: 66
Issue: 6
Pages: 547-554
DOI
NAID
ISSN
0918-8959, 1348-4540
Related Report
Peer Reviewed / Open Access
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[Journal Article] Rapid Improvement of thyroid storm-related hemodynamic collapse by aggressive anti-thyroid therapy including steroid pulse: A case report.2017
Author(s)
Kiriyama H, Amiya E, Hatano M, Hosoya Y, Maki H, Nitta D, Saito A, Shiraishi Y, Minatsuki S, Sato T, Murakami H, Uehara M, Manaka K, Makita N, Watanabe M, Komuro I.
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Journal Title
Medicine (Baltimore)
Volume: 96
Issue: 22
Pages: e7053-e7053
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] The Influence of Aldosterone Values in the Tributary Veins of Unresected Adrenal Gland on Primary Aldosteronism Surgical Outcomes.2019
Author(s)
Kazuki Nakai, Yuya Tsurutani, Tomoko Takiguchi, Seishi Matsui, Kouzou Makita, Jun Inoue, Maki Nagata, Noriko Makita, Masaomi Nangaku, Jun Saito, Masao Omura, Tetsuo Nishikawa
Organizer
ENDO 2019, New Orleans, 3/23-26, 2019
Related Report
Int'l Joint Research
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[Presentation] The Influence of Aldosterone Values in the Tributary Veins of Unresected Adrenal Gland on Primary Aldosteronism Surgical Outcomes.2018
Author(s)
Kazuki Nakai, Yuya Tsurutani, Tomoko Takiguchi, Seishi Matsui, Kouzou Makita, Jun Inoue, Maki Nagata, Noriko Makita, Masaomi Nangaku, Jun Saito, Masao Omura, Tetsuo Nishikawa
Organizer
米国内分泌学会（ENDO）2019
Related Report
Int'l Joint Research
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