Truncated dystrophin ameliorates the dystrophic phenotype of mdx mice by reducing sarcolipin-mediated SERCA inhibition.
| Project/Area Number |
16K08726
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Jikei University School of Medicine (2017-2018)
National Center of Neurology and Psychiatry (2016) |
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Principal Investigator |
Tanihata Jun 東京慈恵会医科大学, 医学部, 助教 (00508426)
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| Co-Investigator(Kenkyū-buntansha) |
武田 伸一 国立研究開発法人国立精神・神経医療研究センター, その他部局等, 部長 (90171644)
青木 吉嗣 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 遺伝子疾患治療研究部, 室長 (80534172)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | Duchenne型筋ジストロフィー / 筋小胞体 / SERCA / サルコリピン / デュシェンヌ型筋ジストロフィー / ベッカー型筋ジストロフィー / リアノジン受容体 / 細胞内Ca2+ / ニトロシル化 / 筋ジストロフィー / 細胞内Ca2+動態 / ＳＥＲＣＡ |
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| Outline of Final Research Achievements |
Duchenne muscular dystrophy (DMD), the most common and severe form of muscular dystrophy in childhood, is caused by dystrophin deficiency. Absence of dystrophin has been shown to lead to an increased Ca2+ influx and an abnormal cytosolic Ca2+ homeostasis of myofibers, leading to increased necrosis. Several underlying mechanisms have been suggested to cause this abnormal cytosolic Ca2+ regulation in dystrophic muscle. Therefore, the aim of this study is to identify new therapeutic targets based on cytosolic Ca2+ regulation for DMD. We found that sarcolipin, an intrinsic inhibitory sarcoplasmic reticulum protein of SERCA, is abnormally high in the dystrophic muscle. In this study, we determined the physiological relevance in DMD following loss-of function by sarcolipin gene deletion. Knockdown of SLN ameliorated the cytosolic Ca2+ homeostasis and the dystrophic phenotype in DMD mice model. These findings suggest that SLN may be a novel target for DMD therapy.
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| Academic Significance and Societal Importance of the Research Achievements |
明確な治療法が確立されていないDuchenne型筋ジストロフィーに対して、現在推進されていることは欠失しているジストロフィンを補う・代償することを目指しているが、本研究はそれら方向性とは異なり、細胞内のCa2+動態に着目した研究である。ジストロフィンの補填・代償する治療方法と併用することでより効果的な治療効果が得られることが期待できる。
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Report
(4 results)
Research Products
(32 results)
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[Journal Article] Characterization of a novel microRNA, miR-188, elevated in serum of muscular dystrophy dog model.2019
Author(s)
Shibasaki H, Imamura M, Arima S, Tanihata J, Kuraoka M, Matsuzaka Y, Uchiumi F, Tanuma SI, Takeda S.
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Journal Title
PLoS One
Volume: 14(1)
Issue: 1
Pages: e0211597-e0211597
DOI
Related Report
Peer Reviewed / Open Access
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