STUDY OF THE PATHOPHYSIOLOGY OF MYOTOIC DYSTROPHY TOWARD THE FUTURE THERAPY FROM THE UNDERSPAND]NG OF MUSCLE WASTING MECHANISM
Project/Area Number |
18590938
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Neurology
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Research Institution | Osaka University |
Principal Investigator |
TAKAHASHI Masanori Osaka University, GRADUATE SCHOOL OF MEDICINE, ASSISTANT PROFESSOR (20359847)
|
Project Period (FY) |
2006 – 2007
|
Project Status |
Completed (Fiscal Year 2007)
|
Budget Amount *help |
¥3,850,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
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Keywords | MUSCLE DISEASE / mRNA / SPLICING / SKELETAL MUSCLE / CYTOSKELETAL PROTEIN / CALCIUM / 小胞体ストレス / ジストロフィン / ジストロブレビン |
Research Abstract |
Recent research has uncovered a new disease mechanism for myotonic dystrophy (DM), so-called "mRNA gain of function". The mutant RNA transcripts with expanded repeats aberrantly affect the splicing of various mRNA. Disrupted splicing of Cl channel and insulin receptor is believed to contribute to myotonia and insulin resistance observed in DM patients. This project has aimed to elucidate the cause of the most disabling symptom of DM, muscle wasting, by identifying the aberrant splicing of other important transcripts. We have successfully identified several abnormally spliced transcripts, which are essential for skeletal muscle function; cytoskeletal proteins, dystrophin and alpha-dystrobrevin, and sarcoplasmic reticulum proteins, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase type 1 (SERCA1) and ryanodine receptor type1. We have extensively analyzed the splicing abnormalities of dystrobrevin, which is a cytoskeletal protein consisting dystrophin-associated complex. We have shown that alternative splicing of dystrobrevin is dysregulated in DM type 1 (DM1) muscle, resulting in changes in syntrophin binding. These results raise the possibility that effects on dystrobrevin splicing may influence signaling in DM1 muscle cells. It has been suggested mutant mRNA alters the function and localization of alternative splicing regulators, such as CUG-BP and MENL1, which are critical for normal RNA processing. We have analyzed the splicing regulation of SERCA1 by MBNL1 and CUG-BP and demonstrated that MBNL1 acts on an intoronic motif. These results indicate that sequestration of MBNL1 into the expanded repeats of mutant mRNA could cause the exclusion of SERCA1 exon 22, the increase of the abnormal isoform observed in DM1 muscle.
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Report
(3 results)
Research Products
(33 results)
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[Journal Article] Aberrantly spliced alpha-dystrobrevin alters alpha-syntrophin binding in myotonic dystrophy type 12008
Author(s)
Nakamori, M, Kimura, T, Kubota, T, Matsumura, T, Sumi, H, Fujimura, H, Takahashi, MP, Sakoda, S
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Journal Title
Neurology 70
Pages: 677-85
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Endoplasmic reticulum stress in myotonic dystrophy type 1 muscle2007
Author(s)
Ikezoe, K, Nakamori, M, Furuya, H, Arahata, H, Kanemoto, S, Kimura, T, Imaizumi, K, Takahashi, MP, Sakoda, S, Fujii, N, Kira, J-I
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Journal Title
Acta Neuropathologica 114
Pages: 527-35
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Molecular mechanisms responsible for aberrant splicing of SERCAI in myotonic dystrophy type 12007
Author(s)
Hino, SI, Kondo, S, Sekiya, H, Saito, A, Kanemoto, S, Murakami, T, Chihara, K, Aoki, Y, Nakamori, M, Takahashi, MP, Imaizumi, K
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Journal Title
Hum Mol Genet 16
Pages: 2834-43
Description
「研究成果報告書概要(欧文)」より
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