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2021 Fiscal Year Final Research Report

Therapeutic development targeting molecular basis of dilated-phase hypertrophic cardiomyopathy

Research Project

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Project/Area Number 19K08489
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionOsaka University

Principal Investigator

Higo Shuichiro  大阪大学, 医学系研究科, 特任准教授(常勤) (00604034)

Co-Investigator(Kenkyū-buntansha) 彦惣 俊吾  大阪大学, 医学系研究科, 准教授 (30423164)
Project Period (FY) 2019-04-01 – 2022-03-31
Keywords肥大型心筋症 / 疾患iPS細胞 / ゲノム編集
Outline of Final Research Achievements

We identified TNNT2 Δ160E mutation in a patient with familial HCM showing progressive left ventricular systolic dysfunction. We generated a set of isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying the heterozygous Δ160E, homozygously corrected or homozygously introduced Δ160E using genome editing. Hetero-Δ160E-iPSC-CMs exhibited prolonged calcium decay, relaxation impairment, and hypertrophy compared to WT-iPSC-CMs. These phenotypes were further exacerbated in Homo-Δ160E-iPSC-CMs. TNNT2 Δ160E promoted sarcomeric calcium retention, nuclear translocation of NFATc1, and cardiomyocyte hypertrophy in a dose-dependent manner. Increased phosphorylation of CaMKIIδ and phospholamban at Thr17 was observed in Homo- and Hetero-Δ160E-iPSC-CMs. Epigallocatechin-3-gallate, a calcium desensitizing compound, shortened prolonged calcium decay and relaxation duration in Δ160E-iPSC-CMs.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

現在の心筋症診療では、「心筋症」と診断された症例に対して、合併する心不全や不整脈に対する対症的な薬物療法が施されているのが現状です。ゲノム遺伝子解析によるTNNT2(トロポニンT)Δ160E遺伝子変異の同定と、精密に遺伝子を改変したモデル心筋細胞を用いた病態の再現、治療概念の実証は、トロポニン心筋症に対する個別化医療の確立につながりえると考えられます。

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Published: 2023-01-30  

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