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Enhancement of the endogeneous cardiac regeneration via activation of Hippo-YAP signaling pathway

Research Project

Project/Area Number 15K09132
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

TAKEDA NORIFUMI  東京大学, 医学部附属病院, 助教 (60436483)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords創薬 / 心筋再生 / 心筋細胞分裂 / Hippo-YAP経路 / 心筋梗塞 / 心不全
Outline of Final Research Achievements

Accumulating data suggest that new cardiomyocytes in adults are generated from existing cardiomyocytes throughout life. To enhance the endogenous cardiac regeneration, we performed chemical screenings to identify compounds that activate pro-proliferative YAP and TEADs activities in cardiomyocytes. We synthesized a novel fluorine-containing TT-10 (C11H10FN3OS2) from the biologically hit compound. TT-10 promoted cardiomyocyte proliferation and simultaneously exerted anti-oxidant and anti-apoptotic effects in vitro. TT-10 treatment in mice ameliorated myocardial infarction-induced cardiac dysfunction at least in part via enhancing clonal expansion of existing cardiomyocytes. Stimulating cardiomyocyte proliferation and/or protection with TT-10 might complement current therapies for myocardial infarction.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (31 results)

All 2018 2017 2016 2015

All Journal Article (13 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 13 results,  Open Access: 6 results,  Acknowledgement Compliant: 1 results) Presentation (14 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Book (3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Pathophysiology and therapeutic potential of cardiac fibrosis2017

    • Author(s)
      Hara Hironori、Takeda Norifumi、Komuro Issei
    • Journal Title

      Inflammation and Regeneration

      Volume: 37 Issue: 1 Pages: 13-13

    • DOI

      10.1186/s41232-017-0046-5

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prostaglandin E2 Signaling as a Target of Anti-Cardiac Fibrosis in Heart Failure Treatment2017

    • Author(s)
      Harada M, Takeda N, Toko H.
    • Journal Title

      International Heart Journal

      Volume: 58 Issue: 1 Pages: 3-4

    • DOI

      10.1536/ihj.16-614

    • NAID

      130005330498

    • ISSN
      1349-2365, 1349-3299
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure.2017

    • Author(s)
      Kamo T, Akazawa H, Suda W, Saga-Kamo A, Shimizu Y, Yagi H, Liu Q, Nomura S, Naito AT, Takeda N, Harada M, Toko H, Kumagai H, Ikeda Y, Takimoto E, Suzuki JI, Honda K, Morita H, Hattori M, Komuro I.
    • Journal Title

      PLoS One.

      Volume: 12 Issue: 3 Pages: 0174099-0174099

    • DOI

      10.1371/journal.pone.0174099

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Periodontitis May Deteriorate Sinus of Valsalva Dilatation in Marfan Syndrome Patients2016

    • Author(s)
      Suzuki J, Imai Y, Aoki M, Fujita D, Takeda N, Aoyama N, Wakayama K, Ikeda Y, Kumagai H, Akazawa H, Izumi Y, Isobe M, Komuro I, Hirata Y
    • Journal Title

      International Heart Journal

      Volume: 57 Issue: 4 Pages: 456-460

    • DOI

      10.1536/ihj.15-395

    • NAID

      130006895913

    • ISSN
      1349-2365, 1349-3299
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes2016

    • Author(s)
      Takeda N, Yagi H, Hara H, Fujiwara T, Fujita D, Nawata K, Inuzuka R, Taniguchi Y, Harada M, Toko H, Akazawa H, Komuro I.
    • Journal Title

      International Heart Journal

      Volume: 57 Issue: 3 Pages: 271-277

    • DOI

      10.1536/ihj.16-094

    • NAID

      130005153709

    • ISSN
      1349-2365, 1349-3299
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fukutin gene mutations that cause left ventricular noncompaction2016

    • Author(s)
      Amiya E, Morita H, Hatano M, Nitta D, Hosoya Y, Maki H, Motozawa Y, Sato N, Ishiura H, Numakura S, Shintani Y, Kinugawa K, Takeda N, Shimizu J, Tsuji S, Komuro I.
    • Journal Title

      International Journal of Cardiology

      Volume: 222 Pages: 727

    • DOI

      10.1016/j.ijcard.2016.08.011

    • URL

      https://pure.teikyo.jp/en/publications/1c4cf5ad-9158-4757-b2fd-716521f62d9f

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hopx distinguishes hippocampal from lateral ventricle neural stem cells2015

    • Author(s)
      Li D, Takeda N, Jain R, Manderfield LJ, Liu F, Li L, Anderson SA, Epstein JA.
    • Journal Title

      Stem Cell Res

      Volume: 15 Issue: 3 Pages: 522-529

    • DOI

      10.1016/j.scr.2015.09.015

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A deleterious MYH11 mutation causing familial thoracic aortic dissection2015

    • Author(s)
      Takeda N, Morita H, Fujita D, Inuzuka R, Taniguchi Y, Nawata K, Komuro I.
    • Journal Title

      Human Genome Variation

      Volume: 2 Issue: 1 Pages: 15028-15028

    • DOI

      10.1038/hgv.2015.28

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel mutation of TGFBR2 causing Loeys-Dietz syndrome complicated with pregnancy-related fatal cervical arterial dissections2015

    • Author(s)
      Takeda N, Fujita N, Morita H, Kato M, Nishimura H, Inuzuka R, Taniguchi Y, Nawata K, Hyodo H, Imai Y, Hirata Y, Komuro I.
    • Journal Title

      Int J Cardiol

      Volume: 201 Pages: 288-290

    • DOI

      10.1016/j.ijcard.2015.07.109

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] A deletion mutation in myosin heavy chain 11 causing familial thoracic aortic dissection in two Japanese pedigrees2015

    • Author(s)
      Takeda N, Imai Y, Morita H, Miya F, Hyodo H, Fujita D, Tajima T, Tsunoda T, Nagai R, Kubo M, Komuor I.
    • Journal Title

      Int J Cardiol

      Volume: 195 Pages: 290-292

    • DOI

      10.1016/j.ijcard.2015.05.178

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: Case Report and review of literature2015

    • Author(s)
      Takeda N, Morita H, Fujita D, Inuzuka R, Taniguchi Y, Imai Y, Hirata Y, Komuro I.
    • Journal Title

      Am J Med Genet A

      Volume: 167 Issue: 10 Pages: 2382-2387

    • DOI

      10.1002/ajmg.a.37162

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung.2015

    • Author(s)
      Jain R, Barkauskas C.E, Takeda N, Bowie E.J, Aghajanian H, Wang Q, Padmanabhan A, Manderfield L.J, Gupta M, Li D, Li L, Trivedi C.M, Hoan L.M, Epstein J.A.
    • Journal Title

      Nat Commun

      Volume: 6 Issue: 1 Pages: 6722-6722

    • DOI

      10.1038/ncomms7727

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Congenital Contractural Arachnodactyly without <i>FBN1</i> or <i>FBN2</i> Gene Mutations Complicated by Dilated Cardiomyopathy2015

    • Author(s)
      Yagi H, Hatano M, Takeda N#, Harada S, Suzuki Y, Taniguchi Y, Shintani Y, Morita H, Kanamori N, Aoyama T, Watanabe M, Manabe I, Akazawa H, Kinugawa K, Komuro I.
    • Journal Title

      Internal Medicine

      Volume: 54 Issue: 10 Pages: 1237-1241

    • DOI

      10.2169/internalmedicine.54.4280

    • NAID

      130005069778

    • ISSN
      0918-2918, 1349-7235
    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Presentation] Discovery of a small molecule to increase cardiomyocytes and protect the heart after ischemic injury2018

    • Author(s)
      Hironori Hara, Norifumi Takeda, Tatsuo Saito, Takyuki Fujiwara, Sonoko Maemura, Yutaka Hara, Masanobu Uchiyama, Issei Komuro
    • Organizer
      第82回日本循環器病学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Discovery of a small molecule to increase cardiomyocytes and protect the heart after ischemic injury2018

    • Author(s)
      Hironori Hara, Norifumi Takeda, Tatsuo Saito, Takyuki Fujiwara, Sonoko Maemura, Yutaka Hara, Masanobu Uchiyama, Issei Komuro
    • Organizer
      1st Basic CardioVascular Research (BCVR)
    • Related Report
      2017 Annual Research Report
  • [Presentation] 組織幹細胞の分化・増殖機構の解明と内因性心筋再生の増殖法開発への応用2017

    • Author(s)
      武田憲文
    • Organizer
      第21心血管内分泌代謝学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Hippo経路を標的とした心筋再生・保護効果を有する新規薬剤の開発2017

    • Author(s)
      原弘典、武田憲文、斉藤竜男、藤原隆行、前村園子、畑裕、内山真伸、小室一成
    • Organizer
      Molecular Cardiovascular Metabolic Conference 2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] Discovery of a small molecule to increase cardiomyocytes and protect the heart afer ischemic injury2017

    • Author(s)
      Hara Hironori, Takeda N, Saito T, Fujiwara T, Maemura S, Hata Y, Uchiyama M, Komuro I
    • Organizer
      American Heart Association Scientific Sessions 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hippo経路を標的として心筋細胞増殖と心筋再生を増幅する薬剤の開発2017

    • Author(s)
      原 弘典, 武田憲文, 小室一成
    • Organizer
      第54回日本臨床分子医学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 心筋細胞増殖・心筋保護作用を有し、心筋再生を促進する薬剤開発の試み2017

    • Author(s)
      原弘典, 武田憲文, 小室一成
    • Organizer
      第8回東京循環器専門医交流会
    • Place of Presentation
      東京大学伊藤国際学術研究センター(東京都文京区)
    • Related Report
      2016 Research-status Report
  • [Presentation] 心筋細胞の分裂機構の解明・制御と医療への応用2017

    • Author(s)
      原弘典, 武田憲文, 小室一成
    • Organizer
      第4回東京未来医療フォーラム
    • Place of Presentation
      東京ガーデンパレスホテル(東京都文京区)
    • Related Report
      2016 Research-status Report
  • [Presentation] マルファン症候群における最新の知見-RA系抑制を含めて2017

    • Author(s)
      武田憲文
    • Organizer
      循環器疾患研究会
    • Place of Presentation
      興和創薬(株)本社会議室(東京都中央区)
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 心臓線維化の病態と制御2016

    • Author(s)
      武田憲文
    • Organizer
      第37回日本炎症・再生医学会
    • Place of Presentation
      京都勧業館みやこめっせ(京都府京都市)
    • Year and Date
      2016-06-16
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] Hippo-YAP/TAZ-TEADs経路を標的とした、心筋細胞増殖と心筋再生を促進する薬剤開発の試み2016

    • Author(s)
      原弘典, 武田憲文, 小室一成
    • Organizer
      第4回Heart Science Club
    • Place of Presentation
      東京大学伊藤国際学術研究センター(東京都文京区)
    • Related Report
      2016 Research-status Report
  • [Presentation] マルファン症候群におけるFBN1遺伝子変異パターンとの関連性の解析2015

    • Author(s)
      谷口優樹, 筑田博隆, 大島寧, 松林嘉考, 武田憲文, 藤田大司, 犬塚亮, 縄田寛, 小野貴司, 田中栄.
    • Organizer
      第49回日本側弯症学会
    • Place of Presentation
      りゅーとぴあ新潟市民芸術文化会館(新潟県新潟市)
    • Year and Date
      2015-11-05
    • Related Report
      2015 Research-status Report
  • [Presentation] マルファン症候群における包括的診療体制の重要性2015

    • Author(s)
      今井靖, 藤田大司, 武田憲文, 西村敬史, 加藤昌義, 鈴木淳一, 小室一成, 平田恭信.
    • Organizer
      第56回日本脈管学会学術集会
    • Place of Presentation
      虎ノ門ヒルズフォーラム(東京都港区)
    • Year and Date
      2015-10-29
    • Related Report
      2015 Research-status Report
  • [Presentation] 当院マルファン外来における各種遺伝子異常の頻度2015

    • Author(s)
      大森紹玄, 犬塚亮, 田中優, 中釜悠, 進藤考洋, 平田陽一郎, 清水信隆, 藤田大司, 武田憲文, 岡明.
    • Organizer
      第51回日本小児循環器学会総会
    • Place of Presentation
      ホテル日航東京(東京都港区)
    • Year and Date
      2015-07-16
    • Related Report
      2015 Research-status Report
  • [Book] 血管医学:血管再生のメカニズム2016

    • Author(s)
      藤原隆行, 武田憲文, 小室一成.
    • Total Pages
      7
    • Publisher
      メディカルビュー社
    • Related Report
      2015 Research-status Report
  • [Book] Annual Review 循環器 2015:生体心筋細胞は分裂するのか?2015

    • Author(s)
      武田憲文, 原弘典, 小室一成.
    • Total Pages
      7
    • Publisher
      中外医学社
    • Related Report
      2015 Research-status Report
  • [Book] 医学書院:マルファン症候群と類縁疾患2015

    • Author(s)
      武田憲文, 藤田大司, 犬塚亮, 谷口優樹, 縄田寛, 山内治雄, 加藤昌義, 西村敬史, 永原幸, 中島淳, 小野稔, 小室一成.
    • Publisher
      呼吸と循環
    • Related Report
      2015 Research-status Report
  • [Patent(Industrial Property Rights)] 新規化合物、並びにそれを有効成分とする心筋細胞増殖誘導剤及び心筋の機能障害を伴う疾患の治療剤2016

    • Inventor(s)
      小室一成、武田憲文、原弘典、内山真伸、斉藤竜男、畑裕
    • Industrial Property Rights Holder
      小室一成、武田憲文、原弘典、内山真伸、斉藤竜男、畑裕
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2016-244870
    • Filing Date
      2016-12-16
    • Related Report
      2016 Research-status Report

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Published: 2015-04-16   Modified: 2019-03-29  

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