2005 Fiscal Year Final Research Report Summary
INVESTIGATION OF PATHOMECHANISM AND TREATMENT OF MYOTONIC DYSTROPHY
| Project/Area Number |
16590825
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | OSAKA UNIVERSITY |
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Principal Investigator |
TAKAHASHI Masanori OSAKA UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, ASSISTANT, 医学系研究科, 助手 (20359847)
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| Co-Investigator(Kenkyū-buntansha) |
SAKODA Saburo OSAKA UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, PROFESSOR, 医学系研究科, 教授 (00178625)
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| Project Period (FY) |
2004 – 2005
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| Keywords | NEUROMUSCULAR DISORDER / RYANODINE RECEPTOR / mRNA / SPLICING / NA CHANNEL / ANTIARRHYTHMIC / CALCIUM / SKELETAL MUSCLE |
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| Research Abstract |
RNA gain of function model has recently been implicated for the pathomechanism of myotonic dystrophy (DM). The RNA with abnormally expanded repeats is suggested to cause altered splicing of several mRNAs, which might relate to clinical features of DM. Viewing the pattern of missplicing reported so far, we hypothesized that the alternative splicing of mRNAs, which are regulated during normal muscle differentiation, might be affected in DM, and we have examined splicing of several candidate mRNAs. In addition to ryanodine receptor, misregulated splicing of sarcoplasmic/endoplasmic reticulum Ca^<2+> -ATPase (Ca^<2+>-pump) has been newly identified in muscles from DM patients and model mice. Since both proteins play major role in regulation of intracellular Ca^<2+> in skeletal muscle, the missplicing might cause impaired Ca^<2+> in DM muscle. Functional studies of the aberrantly spliced ryanodine receptor isoform have consistently showed reduction in channel activity.
In parallel, the effect of a class Ic antiarrhythmic (flecainide) to heterologously expressed Na channels has been investigated in order to develop a new remedy against myotonia. When stimulated comparable to myotonic discharges, flecainide significantly reduced Na current at therapeutic concentration. The data provide basis of simulating the drug effect for myotonia and suggest possible clinical efficacy of flecainide against myotonia.
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