Project/Area Number |
18K07064
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 49030:Experimental pathology-related
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Research Institution | Shinshu University |
Principal Investigator |
Miyazaki Daigo 信州大学, 医学部附属病院, 講師(特定雇用) (80596370)
|
Co-Investigator(Kenkyū-buntansha) |
中村 昭則 信州大学, 医学部, 特任教授 (10303471)
柴 直子 信州大学, 医学部, 助教 (00639289)
柴 祐司 信州大学, 学術研究院医学系, 教授 (70613503)
|
Project Period (FY) |
2018-04-01 – 2021-03-31
|
Project Status |
Completed (Fiscal Year 2020)
|
Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
Keywords | Duchenne型筋ジストロフィー / 心不全 / IGF2 / デュシェンヌ型筋ジストロフィー / 心筋細胞 / iPS細胞 / ジストロフィン |
Outline of Final Research Achievements |
Heart failure is now becoming the most frequent cause of death in Duchenne muscular dystrophy (DMD); however, the pathomechanisms of cardiomyopathy remain unclear. We generated cardiomyocytes from DMD-specific induced pluripotent stem cells (DMD-iPSC-CMs) donated from a DMD patient, and microarray analysis revealed several proliferation-, regeneration- related genes were down-regulated in DMD-iPSC-CMs. In these genes, IGF2 and TMSB4X gene expressions were recovered along with dystrophin restoration by exon skipping in DMD-iPSC-CMs. Next, we treated iPSC-CMs from healthy person with IGF2 and TMSB4X specific siRNAs. IGF2 knock-down tend to lead decreased size of cardiomyocytes, and led to significant down-regulation of IGF1 in these iPSC-CMs. IGF1 and IGF2 bind IGF1R and activate Erk signal transduction, and are thought to maintain the size of cardiomyocyte and myocardial wall thickness. IGF2 down-regulation might deteriorate the pathology of dilated cardiomyopathy in DMD.
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Academic Significance and Societal Importance of the Research Achievements |
心不全はDMDの主な死亡原因となる重要な障害であるが,心不全に関する研究は心筋の採取が難しく十分に進んでいない.DMD患者由来の心筋細胞の作成と網羅的遺伝子解析の結果, さらに健常者由来の心筋細胞に対するsiRNAによる遺伝子発現抑制実験の結果から,DMD患者由来の心筋細胞におけるIGF2発現の低下は、DMD患者の拡張型心筋症の病態を悪化させる可能性が示唆され,学術的意義のみならず心不全治療開発の基礎として社会的意義のある成果と考える.
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