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New therapeutic strategies of GPCR diseases

Research Project

Project/Area Number 16K09797
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Endocrinology
Research InstitutionThe University of Tokyo

Principal Investigator

MAKITA Noriko  東京大学, 医学部附属病院, 准教授 (60353455)

Co-Investigator(Kenkyū-buntansha) 間中 勝則  東京大学, 医学部附属病院, 助教 (10700495)
Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
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)
KeywordsGPCR / biased agonism / protean agonism / endocrine disease / Ca感知受容体 / V2受容体 / 内科
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.

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。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (51 results)

All 2020 2019 2018 2017 2016

All Journal Article (13 results) (of which Peer Reviewed: 12 results,  Open Access: 10 results,  Acknowledgement Compliant: 2 results) Presentation (27 results) (of which Int'l Joint Research: 3 results,  Invited: 13 results) Book (11 results)

  • [Journal Article] V2 vasopressin receptor mutations2020

    • Author(s)
      Makita Noriko、Manaka Katsunori、Sato Junichiro、Iiri Taroh
    • Journal Title

      Vitam Horm.

      Volume: 113 Pages: 79-99

    • DOI

      10.1016/bs.vh.2019.08.012

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comparison between the clinical characteristics of patients with adrenal incidentalomas and those with hypertension-associated adrenal tumors in a single center in Japan2020

    • Author(s)
      Aoe Mari、Okada Akira、Usui Tomoko、Manaka Katsunori、Nangaku Masaomi、Makita Noriko
    • Journal Title

      Endocrine Journal

      Volume: 67 Issue: 6 Pages: 645-654

    • DOI

      10.1507/endocrj.EJ19-0262

    • NAID

      130007866176

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
    • Journal Title

      JCI Insight

      Volume: in press Issue: 8

    • DOI

      10.1172/jci.insight.126449

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society2019

    • Author(s)
      Arima Hiroshi、Iwama Shintaro、Inaba Hidefumi、Ariyasu Hiroyuki、Makita Noriko、Otsuki Michio、Kageyama Kazunori、Imagawa Akihisa、Akamizu Takashi
    • Journal Title

      Endocrine Journal

      Volume: 66 Issue: 7 Pages: 581-586

    • DOI

      10.1507/endocrj.EJ19-0163

    • NAID

      130007684340

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effectiveness and safety of cinacalcet for primary hyperparathyroidism: a single center experience2019

    • Author(s)
      Manaka Katsunori、Sato Junichiro、Kinoshita Yuka、Ito Nobuaki、Fujita Megumi、Iiri Taroh、Nangaku Masaomi、Makita Noriko
    • Journal Title

      Endocrine Journal

      Volume: 66 Issue: 8 Pages: 683-689

    • DOI

      10.1507/endocrj.EJ19-0034

    • NAID

      130007696450

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
    • Journal Title

      Endocrine Journal

      Volume: 66 Issue: 6 Pages: 547-554

    • DOI

      10.1507/endocrj.EJ18-0563

    • NAID

      130007668513

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bexarotene‐induced hypothyroidism: characteristics and therapeutic strategies2019

    • Author(s)
      Makita Noriko、Manaka Katsunori、Sato Junichiro、Mitani Koji、Nangaku Masaomi、Iiri Taroh
    • Journal Title

      Clinical Endocrinology

      Volume: 印刷中 Issue: 1 Pages: 195-200

    • DOI

      10.1111/cen.13975

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical guidelines for endocrine disorders associated with immune checkpoint inhibitors2018

    • Author(s)
      有馬寛、赤水尚史、今川彰久、影山和則、大月道夫、有安宏之、稲葉秀文、槙田紀子、岩間信太郎
    • Journal Title

      Folia Endocrinologica Japonica

      Volume: 94 Issue: S.November Pages: 1-11

    • DOI

      10.1507/endocrine.94.S.November_1

    • NAID

      130007522331

    • ISSN
      0029-0661, 2186-506X
    • Year and Date
      2018-11-20
    • Related Report
      2018 Research-status Report
    • Open Access
  • [Journal Article] Urinary Iodine Concentration and Mortality Among U.S. Adults2018

    • Author(s)
      Inoue Kosuke、Leung Angela M.、Sugiyama Takehiro、Tsujimoto Tetsuro、Makita Noriko、Nangaku Masaomi、Ritz Beate R.
    • Journal Title

      Thyroid

      Volume: 28 Issue: 7 Pages: 913-920

    • DOI

      10.1089/thy.2018.0034

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Changes in bone metabolic parameters following oral calcium supplementation in an adult patient with vitamin D-dependent rickets type 2A2017

    • Author(s)
      Yuka Kinoshita, et al.
    • Journal Title

      Endocrine Journal

      Volume: 64 Issue: 6 Pages: 589-596

    • DOI

      10.1507/endocrj.EJ16-0583

    • NAID

      130007307955

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [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.
    • Journal Title

      Medicine (Baltimore)

      Volume: 96 Issue: 22 Pages: e7053-e7053

    • DOI

      10.1097/md.0000000000007053

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inverse agonism: the classic concept of GPCRs revisited [Review]2016

    • Author(s)
      25.Sato J, Makita N, Iiri T.
    • Journal Title

      Endocrine Journal

      Volume: 63 Issue: 6 Pages: 507-514

    • DOI

      10.1507/endocrj.EJ16-0084

    • NAID

      130005159565

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Analysis of the V2 Vasopressin Receptor (V2R) Mutations Causing Partial Nephrogenic Diabetes Insipidus Highlights a Sustainable Signaling by a Non-peptide V2R Agonist.2016

    • Author(s)
      26.Makita N, Sato T, Yajima-Shoji Y, Sato J, Manaka K, Eda-Hashimoto M, Ootaki M, Matsumoto N, Nangaku M, Iiri T.
    • Journal Title

      J Biol Chem.

      Volume: 291 Pages: 22460-22471

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] まれな疾患からみえてくる新しい世界2019

    • Author(s)
      槙田紀子、間中勝則、佐藤潤一郎、南学正臣、飯利太朗
    • Organizer
      第29回臨床内分泌代謝Update 11/29, 2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 薬剤性甲状腺機能障害2019

    • Author(s)
      槙田紀子、間中勝則、佐藤潤一郎、竹内牧、南学正臣、飯利太朗
    • Organizer
      第62回日本甲状腺学会学術集会 10/11, 2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Ca、P、Mg異常を考える2019

    • Author(s)
      槙田紀子
    • Organizer
      第20回日本内分泌学会関東甲信越支部学術集会 9/14, 2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] これでわかる内分泌臨床の新たな知見:The JCEM 2018-2019から2019

    • Author(s)
      槙田紀子
    • Organizer
      第19回日本内分泌学会九州支部学術集会 9/7, 2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] わたしが何ものでもなかったころのこと2019

    • Author(s)
      槙田紀子
    • Organizer
      第1回九州内分泌・代謝「若手の会」9/6, 2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] まれな内分泌疾患の解析から生まれる新しいコンセプト2019

    • Author(s)
      槙田紀子
    • Organizer
      第37回内分泌代謝学サマーセミナー 7/5, 2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 内科医の考える甲状腺の手術適応2019

    • Author(s)
      槙田紀子、間中勝則、佐藤潤一郎、竹内牧、飯利太朗、南学正臣
    • Organizer
      第31回日本内分泌外科学会総会 6/14, 2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [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
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 後天性低カルシウム尿性高カルシウム血症(AHH)で見出されたカルシウム感知受容体抗体の機能解析2019

    • Author(s)
      槙田紀子、佐藤潤一郎、間中勝則、江田真紀子、安藤隆雄、山崎肇、矢島隆寛、伊藤崇浩、赤羽貴美子、中井一貴、三谷康二、大石篤郎、南学正臣、飯利太朗
    • Organizer
      第92日本内分泌学会学術総会 仙台国際センター 5/9, 2019
    • Related Report
      2019 Annual Research Report
  • [Presentation] 内科からみた原発性副甲状腺機能亢進症2018

    • Author(s)
      槙田紀子
    • Organizer
      第91回日本内分泌学会総会
    • Related Report
      2018 Research-status Report
    • Invited
  • [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
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 新規脂肪分解薬の開発と機能解析2018

    • Author(s)
      佐藤潤一郎、槙田紀子、間中勝則、三谷康二、江田真紀子、大和田智彦、 南学正臣、飯利太朗
    • Organizer
      第91回日本内 分泌学会
    • Related Report
      2018 Research-status Report
  • [Presentation] パ シレオチドLARによるインスリン分泌能低下に対してGLP-1受容体作動 薬が著効した1例2018

    • Author(s)
      佐藤潤一郎、槙田紀子、古家美菜絵、間中勝則、飯利太朗、南学正臣 パ シレオチドLARによるインスリン分泌能低下に対してGLP-1受容体作動 薬が著効した1例
    • Organizer
      第91回日本内分泌学会
    • Related Report
      2018 Research-status Report
  • [Presentation] 非典型的進行性骨化性線維異形成症の一例2018

    • Author(s)
      間中勝則、槙田紀子、佐藤潤一郎、飯利太朗、南学正臣
    • Organizer
      日本人類遺伝学会第63回大会
    • Related Report
      2018 Research-status Report
  • [Presentation] What diseases tell us about GPCRs and G proteins2018

    • Author(s)
      飯利太朗、槙田紀子
    • Organizer
      Cardio Renal Diabetes Conference 2018
    • Related Report
      2017 Research-status Report
  • [Presentation] GPCRと疾患-新しい調節機構への示唆2017

    • Author(s)
      槙田紀子・飯利太朗
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      東北大学川内北キャンパス(宮城県仙台市)
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] Analysis of the V2 Vasopressin receptor (V2R) mutations causing partial nephrogenic diabetes insipidus highlights a sustainable signaling by a non-peptide V2R agonist2017

    • Author(s)
      Noriko Makita, Tomohiko Sato, Yuki Yajima-Shoji, Junichiro Sato, Katsunori Manaka, Makiko Eda-Hashimoto, Masanori Ootaki , Naoki Matsumoto, Masaomi Nangaku, and Taroh Iiri
    • Organizer
      Gordon Research Conference Molecular Pharmacology
    • Place of Presentation
      Barga(Italy)
    • Year and Date
      2017-03-12
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 新規脂肪分解薬の発見と解析2017

    • Author(s)
      槙田紀子、佐藤潤一郎、三谷康二、間中勝則、江田真紀子、大和田智彦、飯利太朗
    • Organizer
      第90回日本内分泌学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 分子標的薬を含めた新規抗腫瘍薬と甲状腺機能異常-メカニズムと対策2017

    • Author(s)
      槙田紀子
    • Organizer
      第90回日本内分泌学会総会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 先天性腎性尿崩症の原因となるV2受容体変異体の解析からみえてきた ユニークなGPCR制御と疾患治療の可能性2017

    • Author(s)
      槙田紀子、佐藤知彦、間中勝則、佐藤潤一郎、南学正臣、飯利太朗
    • Organizer
      第14回GPCR研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] 提言:内分泌学の過去・現在・未来2017

    • Author(s)
      槙田紀子
    • Organizer
      日本内分泌学会創設90周年記念式典
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 三量体Gタンパク質の構造安定性に関わる相 互作用解析2017

    • Author(s)
      大滝正訓、太田有紀、渡辺実、武半優子、槙田紀子、飯利太朗、松本直樹
    • Organizer
      第38回日本臨床薬理学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 部分型腎性尿崩症の新しい変異の機能解析とV2受容体作動薬のユニークな作用2017

    • Author(s)
      槙田紀子、佐藤知彦、矢嶋由紀、三谷康二、間中勝則、大石篤郎、佐藤潤一郎、南学正臣、飯利太朗
    • Organizer
      第27回バゾプレシン研究会
    • Place of Presentation
      TKP有楽町会議室(東京都千代田区)
    • Related Report
      2016 Research-status Report
  • [Presentation] 膀胱がんの発症を契機にピオグリタゾンを一時中止し、脂肪肝に対する有効性が明らかになった2型糖尿病の一例2017

    • Author(s)
      槙田紀子、佐藤潤一郎、間中勝則、南学正臣
    • Organizer
      第630回 日本内科学会関東地方会
    • Place of Presentation
      東京国際フォーラム(東京都千代田区)
    • Related Report
      2016 Research-status Report
  • [Presentation] 部分型腎性尿崩症の原因となるV2受容体変異体の機能解析から得られる新たな治験2016

    • Author(s)
      槙田紀子、石堂雄毅、田中征治、三谷康二、矢嶋由紀、大石篤郎、間中勝則、佐藤潤一郎、南学正臣、飯利太朗
    • Organizer
      第89回日本内分泌学会総会
    • Place of Presentation
      国立京都国際会館(京都市左京区)
    • Year and Date
      2016-04-21
    • Related Report
      2016 Research-status Report
  • [Presentation] カルシウム感知受容体:まれな内分泌疾患からGPCRの新しいパラダイムへ2016

    • Author(s)
      飯利太郎、槙田紀子
    • Organizer
      第89回日本内分泌学会総会
    • Place of Presentation
      国立京都国際会館(京都市左京区)
    • Year and Date
      2016-04-21
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] GPCRと疾患―新しい調節機構への示唆2016

    • Author(s)
      槙田紀子、飯利太朗
    • Organizer
      第1回 日本臨床薬理学会 関東・甲信越地方会
    • Place of Presentation
      横浜市社会福祉センター(神奈川県横浜市)
    • Related Report
      2016 Research-status Report
    • Invited
  • [Book] 低カルシウム血症(今日の診断指針 ポケット判 第8版)2020

    • Author(s)
      槙田紀子(永井 良三 総編集)
    • Total Pages
      4
    • Publisher
      医学書院
    • ISBN
      9784260038096
    • Related Report
      2019 Annual Research Report
  • [Book] CaSRの歴史:GPCR研究の古典的常識への挑戦の歴史(透析療法ネクストXXVI)2019

    • Author(s)
      槙田紀子、飯利太朗(秋葉隆、秋澤忠男 編集)
    • Total Pages
      10
    • Publisher
      医学図書出版
    • ISBN
      9784865173499
    • Related Report
      2019 Annual Research Report
  • [Book] 家族性低カルシウム尿性高カルシウム血症(FHH)と後天性低カルシウム尿性高カルシウム血症(AHH)(副甲状腺・骨代謝疾患診療マニュアル 改訂第2版)2019

    • Author(s)
      槙田紀子、飯利太朗(平田結喜緒 監修)
    • Total Pages
      5
    • Publisher
      診断と治療社
    • ISBN
      9784787823748
    • Related Report
      2019 Annual Research Report
  • [Book] 内分泌Up To Date(臨床雑誌 内科)2019

    • Author(s)
      槙田紀子(企画編集)
    • Total Pages
      146
    • Publisher
      南江堂
    • Related Report
      2019 Annual Research Report
  • [Book] 診断力を上げる症例問題集(第10章代謝・内分泌総論)2019

    • Author(s)
      槙田紀子(分担)
    • Publisher
      南江堂
    • Related Report
      2018 Research-status Report
  • [Book] 最新医学 自己免疫の関与する内分泌代謝疾患の最前線2018

    • Author(s)
      槙田紀子(分担)
    • Publisher
      最新医学社
    • Related Report
      2018 Research-status Report
  • [Book] 内分泌代謝科専門医研修ガイドブック2018

    • Author(s)
      槙田紀子(分担)
    • Publisher
      診断と治療社
    • ISBN
      9784787822925
    • Related Report
      2018 Research-status Report
  • [Book] 糖尿病・内分泌疾患ビジュアルブック第2版2018

    • Author(s)
      槙田紀子(分担)
    • Publisher
      学研メディカル秀潤社
    • ISBN
      9784780911756
    • Related Report
      2017 Research-status Report
  • [Book] 本日の内科外来2018

    • Author(s)
      槙田紀子(分担)
    • Publisher
      南江堂
    • ISBN
      9784524255559
    • Related Report
      2017 Research-status Report
  • [Book] 腎臓・水電解質コンサルタント2017

    • Author(s)
      槙田紀子(分担)
    • Publisher
      金芳堂
    • ISBN
      9784765317283
    • Related Report
      2017 Research-status Report
  • [Book] 甲状腺疾患のすべて2017

    • Author(s)
      槙田紀子(企画)
    • Total Pages
      167
    • Publisher
      医歯薬出版株式会社
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2021-02-19  

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