Revealing mechanisms of cardiomyopathy and development of treatments for Duchenne muscular dystrophy patient cardiomyopathy by using iPS cells.

Research Project

Project/Area Number	17K10141
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Pediatrics
Research Institution	Kyoto University
Principal Investigator	Baba Shiro 京都大学, 医学研究科, 助教 (60432382)
Project Period (FY)	2017-04-01 – 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 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords	デュシェンヌ型筋ジストロフィー / iPS細胞 / 細胞死 / オートファジー / 細胞内カルシウム濃度 / mdxマウス / クロロキン / 心筋細胞 / 心不全
Outline of Final Research Achievements	Duchenne muscular dystrophy (DMD), a severe degenerative skeletal and cardiac muscle disease, has a poor prognosis because of progressive dyspnea and heart failure. Recent advances in ventilator support devices have dramatically decreased mortality caused by respiratory distress. Consequently, cardiomyopathy resulting in heart failure is currently the major cause of death among DMD patients. However, mechanisms of developing cardiomyopathy in DMD have not been revealed, yet. Our research results revealed that autophagy, a cell death mechanism, was one of the promising mechanisms which develop cardiomyopathy. In addition, significant elevated Ca2+ concentration in cardiomyocytes derived from DMD patient iPS cells (DMD-iPS CMs) was observed. Moreover, mechanical stretching significantly increased the intracellular Ca2+ concentration in DMD-iPS CMs. These two phenomena possibly relate and cooperate for developing cardiomyopathy in DMD patents.
Academic Significance and Societal Importance of the Research Achievements	本研究成果は、デュシェンヌ型筋ジストロフィー患者の死因の大多数を占める心筋症の発症予防や治療に大きく貢献すると思われる。現在デュシェンヌ型筋ジストロフィー患者の心不全に対する治療は、利尿剤、末梢血管拡張剤、βブロッカーなどの一般的な心不全治療方法しか臨床的には存在しない。心不全発症・進展機序をおさえた治療法の開発が急務である。今回、オートファジーや細胞内カルシウム濃度上昇が心筋症発症に寄与する研究結果を得たことで、オートファジーを抑制するクロロキンや細胞内カルシウムを調整するカルシウムブロッカーやキレート剤が治療に使用できる可能性が示され、臨床応用への道が開かれたと考える。