2001 Fiscal Year Final Research Report Summary
Elucidation of molecular mechanism of utrophin expression in dystrophic skeletal muscle and its application to molecular therapy
| Project/Area Number |
11470153
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | National Institute of Neuroscience, NCNP |
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Principal Investigator |
TAKEDA Shin'ichi National Institute of Neuroscience, NCNP, Department of Molecular Therapy, 神経研究所・遺伝子疾患治療研究部, 部長 (90171644)
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| Project Period (FY) |
1999 – 2001
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| Keywords | utrophin / dystrophin / mdx mice / DMD / adenovirus vector / stabilization of mRNA / cytokines / IL-6 |
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| Research Abstract |
Duchenne muscular dystrophy (DMD) is an X-linked lethal disorder caused by a defect in the DMD gene, which encodes the cytoskeletal protein dystrophin. Utrophin is an autosomal homologue of the DMD gene product dystrophin, and augmented expression of endogenous utrophin is expected to provide an alternative therapeutic approach for DMD. We previously reported that immune response against a (β-galactosidase-expressing adenovirus vector, AxCALacZ, resulted in accumulation of endogenous utrophin expression on the extrasynaptic sarcolemma in dystrophin-deficient mdx mice (Hum Gene Ther 11 : 669-680, 2000). In order to determine which cytokine is involved in the regulation of utrophin expression, we directly injected several cytokines separately into neonatal mdx muscles and tested whether the expression of utrophin is increased on the sarcolemma or not. Importantly, among the cytokines tested, solely IL-6 successfully increased expression of utrophin. Moreover, increase of utrophin mRNA was detected from rIL-6-injected mdx muscles by the quantitative real-time RT-PCR study. Further, IL-6 expression was elevated in AxCALacZ-infected mdx muscle in the early stage, and anti-IL-6R antibody treatment blocked enhanced utrophin expression in AxCALacZinfected mdx muscle. We should point out, however, that over-expression of utrophin due to recombinant IL-6 treatment lasted only a week. In addition, expression of utrophin was not evident in normal C57BL/10 neonatal muscles injected with IL-6 (Hum Gene Ther 13 : 509-518, 2002). Taken together, these results suggest that IL6 can induce over-expression of utrophin on the extrasynaptic sarcolemma but requires pre-existing factors in neonatal mdx muscle to fully regulate utrophin expression.
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Research Products
(12 results)
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[Publications] Ishii A, Hagiwara Y, Saito Y, Yamamoto K, Yuasa Y, Sato Y, Arahata K, Shoji S, Nonaka I, Saito I, Nabeshima Y and Takeda S: "Effective adenovirus-mediaed gene expression in adult murine skeletal muscle"Muscle Nerve. 22. 592-599 (1999)
Description
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