Elucidation of Stim2 splicing mechanism and development of a novel therapeutic strategy of heart failure

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15277
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: National Cardiovascular Center Research Institute (2022-2023); Osaka Medical and Pharmaceutical University (2021)
• Principal Investigator: Ito Jumpei 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (30897583)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 心不全 / 選択的スプライシング / ストア作動性カルシウム流入 / STIM2 / 核酸医薬 / アンチセンスオリゴ

Outline of Final Research Achievements

In this study, we focused on STIM2, which has two spliced variants with opposing effects on store-operated calcium entry (SOCE) by alternative splicing. We performed transversal aortic constriction in a mouse to uncover the Stim2 alternative splice mechanisms in the pressure-overloaded heart. In pressure-overloaded hearts, the expression of Stim2 splice variants was changed in cardiomyocytes. Next, we identified the splicing factor that modulates this Stim2 alternative splicing by pull-down assay and mass spectrometry. This factor interacts with specific sequences in Stim2 pre-mRNA. Then, we modulated this splicing change by using antisense oligos in vitro and in vivo. Thus, these results might help to develop a novel heart failure treatment that provides fine-tune SOCE activity by adjusting the STIM2.1/STIM2.2 ratio.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

本研究成果はSTIM2のスプライシング制御が心不全治療の標的として有効であることの証明のみならず、核酸医薬としてのアプローチが心不全の治療・予防法に効果的であることを示唆する。核酸医薬はあらゆる遺伝子に有効であることから、他の疾患の治療への応用が期待される。