Elucidation of the Pathology of STIM1 Myopathy in Skeletal and Cardiac Muscles and Development of Therapeutic Approaches Using iPSCs

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08253
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Shinshu University
• Principal Investigator: Shiba Naoko 信州大学, 学術研究院医学系, 助教 (00639289)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ミオパチー / STIM1

Outline of Final Research Achievements

Myopathy caused by STIM1 gene mutations is a progressive autosomal dominant hereditary neuromuscular disorder characterized by generalized skeletal muscle atrophy, muscle weakness, and occasionally concomitant myocardial injury. STIM1 is a protein that plays an important role in maintaining the homeostasis of calcium inside and outside cells, and it is believed that the disruption of its function is the underlying cause of abnormal calcium dynamics. However, since it is a new disease concept, many aspects of its pathophysiology and natural history are still unknown, and there is no established treatment. In this study, we generated cardiac and skeletal muscle cells from patient-derived induced pluripotent stem cells (iPSCs) and their isogenic control cells to investigate the pathogenic mechanisms and develop therapeutic drugs.

Free Research Field

神経筋疾患

Academic Significance and Societal Importance of the Research Achievements

STIM1は生体内でCa2+恒常性の維持に重要な働きを担うことが知られているが、STIM遺伝子変異によるミオパチーの病態は不明な点が多く治療法が確立されていない。本研究は、本疾患の骨格筋と心筋の病態について患者由来iPS細胞から、心筋細胞および骨格筋細胞を作成し、両細胞について比較解析を行うことでそれぞれの臓器での病態を明らかにし、原因に基づく治療法を開発することを目的として研究を進めた。骨格筋分化誘導に難渋したが、特定のセーフハーバー領域へのTet-On-MyoD1強制発現システムの導入を行うことで短期間での高純度の骨格筋作成が可能となり、今後の骨格筋病態研究に応用し得る成果である。