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

• Project/Area Number: 15K09132
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: The 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: ¥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.

Research Products

• [Journal Article] Pathophysiology and therapeutic potential of cardiac fibrosis (2017)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Prostaglandin E2 Signaling as a Target of Anti-Cardiac Fibrosis in Heart Failure Treatment (2017)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Periodontitis May Deteriorate Sinus of Valsalva Dilatation in Marfan Syndrome Patients (2016)
  • 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
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes (2016)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Fukutin gene mutations that cause left ventricular noncompaction. (2016)
  • 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: 727-729
  • DOI: 10.1016/j.ijcard.2016.08.011
  • Peer Reviewed
• [Journal Article] Hopx distinguishes hippocampal from lateral ventricle neural stem cells (2015)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A deleterious MYH11 mutation causing familial thoracic aortic dissection (2015)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] A novel mutation of TGFBR2 causing Loeys-Dietz syndrome complicated with pregnancy-related fatal cervical arterial dissections (2015)
  • 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
  • Peer Reviewed
• [Journal Article] A deletion mutation in myosin heavy chain 11 causing familial thoracic aortic dissection in two Japanese pedigrees (2015)
  • 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
  • Peer Reviewed
• [Journal Article] Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: Case Report and review of literature (2015)
  • 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
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Congenital Contractural Arachnodactyly without <i>FBN1</i> or <i>FBN2</i> Gene Mutations Complicated by Dilated Cardiomyopathy (2015)
  • 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
  • Peer Reviewed
• [Presentation] Discovery of a small molecule to increase cardiomyocytes and protect the heart after ischemic injury (2018)
  • 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
• [Presentation] Discovery of a small molecule to increase cardiomyocytes and protect the heart after ischemic injury (2018)
  • Author(s): Hironori Hara, Norifumi Takeda, Tatsuo Saito, Takyuki Fujiwara, Sonoko Maemura, Yutaka Hara, Masanobu Uchiyama, Issei Komuro
  • Organizer: 1st Basic CardioVascular Research (BCVR)
• [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
• [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
• [Presentation] Discovery of a small molecule to increase cardiomyocytes and protect the heart afer ischemic injury (2017)
  • 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
  • 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
• [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）
• [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）
• [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）
  • 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
  • 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）
• [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
• [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
• [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
• [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
• [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
• [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
• [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