Development of the new therapy for heart failure by the specific splicing variant inhibition

• Project/Area Number: 18H02806
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Osaka University
• Principal Investigator: TANIYAMA YOSHIAKI 大阪大学, 大学院医学系研究科, 特任教授(常勤) (60372611)
• Co-Investigator(Kenkyū-buntansha): 石川 哲也 獨協医科大学, 医学部, 准教授 (80408369)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2022: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2021: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2020: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: ペリオスチン / 心不全 / 腎不全 / スプライシングバリアント / 心筋幹細胞 / splicing variant / heart failure

Outline of Final Research Achievements

There is a periostin splicing variant that exerts a cardioprotective effect on exosome expression in the heart when myocardial stem cells secrete exosomes. As a result, it was confirmed that the cardiomyocyte proliferation effect was observed, and as a result, the deterioration of cardiac function with AMI was suppressed.
In a rhabdomyolytic renal failure model with intramuscular injection of 50% glycerol, we confirmed that inhibition of a specific periostin variant exerts a reno-protective effect.
Injecting the abnormal splicing gene of clinical cardiomyopathy, we confirmed that inhibition of periostin has a cardio-protective effect on a mouse model of cardiomyopathy.

Academic Significance and Societal Importance of the Research Achievements

心臓に存在する心筋幹細胞から分泌されるペリオスチンが心筋細胞増殖効果を持っており心不全も治療てきることから治療薬の候補となることを見出した。臨床の心不全症例に心臓にウイルスベクターを用いて遺伝子発現させることで心機能を改善する可能性が考えられた。一方で、腎不全モデルにおいてはペリオスチンを抑制することが急性腎不全の腎機能低下を抑制することを見出した。急性腎不全症例の急性期に抗体を用いてペリオスチンを抑制することによって腎保護効果を期待することができる。また、心筋症マウスへのペリオスチン抑制が心保護効果につながることがしめされたので、抗体などのよる治療が将来的に応用される可能性が考えられた。

Research Products

• [Int'l Joint Research] Cardiocentro Ticino Institute/University of Zurich/Lausanne University Hospital(スイス)
• [Int'l Joint Research] National Institute of Pathology(ルーマニア)
• [Int'l Joint Research] Imperial College(英国)
• [Int'l Joint Research] Scuola Superiore Sant’Anna/ITB-CNR(イタリア)
• [Journal Article] Therapeutic Angiogenesis Using HGF Plasmid (2020)
  • Author(s): Sanada F., Fujikawa T., Shibata K., Taniyama Y., Rakugi H., Morishita R.
  • Journal Title: Annals of Vascular Diseases Volume: 13 Issue: 2 Pages: 109-115
  • DOI: 10.3400/avd.ra.20-00035
  • NAID: 130007864374
  • ISSN: 1881-641X, 1881-6428
  • Year and Date: 2020-06-25
  • Peer Reviewed / Open Access
• [Presentation] Hepatocyte growth factor (HGF) preclude high-fat diet-induced obesity and improved insulin resistance in mice. (2020)
  • Author(s): Jun Muratsu, Fumihiro Sanada, Yoshiaki Taniyama, Masaaki Iwabayashi, Kana Shibata, Nobutaka Koibuchi, Naruto Katsuragi, Ryoko Nakagawa, Atsuyuki Morishima, Katsuhiko Sakaguchi, Hiromi Rakugi, Ryuichi Morishita
  • Organizer: ERA-EDTA 2020: The 57th Europian Renal Association-European Dialysis and Transplant Association Congress.
  • Int'l Joint Research
• [Presentation] Development of target therapy against chemoresistnat triple-negatve breast cncer (2020)
  • Author(s): 藤川龍弥、眞田文博、谷山義明、柴田佳那、葛城鳴門、鯉渕信孝、中川涼子、楽木宏実、森下竜一
  • Organizer: 第43回日分子生物学会
• [Presentation] Periostin short-fragment including C-terminal exon17 via proteolytic cleavage is required for breast cancer metastasis (2020)
  • Author(s): Yuka Ikeda-Iwabu, Yoshiaki Taniyama, Ryuichi Morishita
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Analysis of the periostin splicing variant function for the triple negative breast (2020)
  • Author(s): Kana Shibata, Yuka Ikeda-Iwabu, Ryuichi Morishita, Yoshiaki Taniyama
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 化学療法抵抗性のトリプルネガティブ乳癌への新規治療法の開発 (2020)
  • Author(s): 谷山義明
  • Organizer: AMED革新的医療技術創出拠点プロジェクト成果報告会(
• [Presentation] Specific inhibition of periostin alternative splicing variant ameriorata cardiacfibrosis after myocardial infarction. (2019)
  • Author(s): 眞田文博
  • Organizer: Cardio Renal Diabetes Conference 2019
• [Remarks] Laboratory of Cellular and Molecular Cardiology
  • URL: https://www.cardiocentro.org/en/research/cellular-molecular-cardiology