2007 Fiscal Year Final Research Report Summary
Therapy for neurodegeneerative disease using novel screening method for chemical chaperon.
| Project/Area Number |
18590967
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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 | Kanagawa Cancer Center Research Institute |
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Principal Investigator |
OSAKA Hitoshi Kanagawa Cancer Center Research Institute, Kanagawa Center Research Institute, 技幹 (90426320)
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| Co-Investigator(Kenkyū-buntansha) |
INOUE Ken National Institute of Neuroscience, 神経研究所・疾病研究第二部, 室長 (30392418)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Biological neurochemistry / Neurodegeneration / Chaperon / 小胞体ストレス |
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| Research Abstract |
(1)Therapy for Pelizaeus-Merzbacher with chaperon. We failed to establish the gas-chromatographically measurement for a candidate chemical. We switched to search for chemicals to decrease the expression level of proteolipid protein(PLP). Duplication of PLP accounts for the half of the PMD patients. In C6 glioma cell line expressing PLP, we could measure PLP mRNA level by Quantitative RT-PCR. PLP expression was normalized by that of hypoxanthine guanine phosphoribosyl transferase. At first, we found that the more cell differentiate, the more PLP expresses. We optimized screening condition as follows ; chemicals extracted from food were added at final concentration of 10μM at cell density of 2.5×10^5/well(9.2cm^2) for 48hrs with DMEM(low glucose) including 1%fetal bovine serum. We screened the library including more than one hundred of food chemicals. We found 2 chemicals that decrease the PLP mRNA expression more than 50%. 11 chemicals were found to decrease the PLP expression level mor
… More
e than 30%. We have already found that PLP missence mutations cause overload to proteorytic system in the cell leading to cell death. Therefore, food chemicals that lower the level of PLP may be applied to the PMD patients with duplication as well as missence mutations in PLP gene.
(2)Establishment of therapeutic effect in mouse model of PMD. For proper evaluation of drugs for PMD, we need to assess the degree of myelination in mouse model. We tried to quantitatively measure myelination by microscopic examinations. Firstly, we evaluated the degree of myelination using light microscopic examinations after conventional HE, Kluver-Barrera's or immune staining using the antibodies to PLP and myelin basic protein. These methods partially disclosed the dysmyelination of PMD model mouse. Electron microscopic examination revealed the degree of myelination properly. Optical nerve was superior for quantitative examination among central nervous system, as it contained the uniform numbers of neuron and oligodendrocytes. Less
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Author(s)
Osaka, H., Mazaki, E., Okamura, N., Iai, M., Yamada, M., Yamakawa, K., Yamashita, S.
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Journal Title
Progress in Epileptic Disorders
Pages: In print
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Early onset West syndrome with cerebral hypomyelination and reduced cerebral white matter2008
Author(s)
Tohyama, J., Akasaka, N., Osaka, H.Maegaki, Y., Kato, M., Saito, N.Yamashita, S., Ohno, K.
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Journal Title
Brain Development 30
Pages: 349-355.
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] De novo mutations in the gene encoding STXBP1(MUNC18-1)cause early infantile epileptic encephalopathy2008
Author(s)
Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N
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Journal Title
Nature Genetics
Pages: in print
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] De novo mutations in the gene encoding STXBP1(MUNC18-1) cause early infantile epileptic encephalopathy2008
Author(s)
Saitsu H, Kato M, Mizuguchi T, Hamada K, Osaka H, Tohyama J, Uruno K, Kumada S, Nishiyama K, Nishimura A, Okada I, Yoshimura Y, Hirai S, Kumada T, Hayasaka K, Fukuda A, Ogata K & Matsumoto N
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Journal Title
Nature Genetics 40
Pages: 782-788
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Patients with a sodium channel alpha 1 gene mutation show wide phenotypic variation2007
Author(s)
Osaka, H., Ogiwara, I., Mazaki, E., Okamura, N., Yamashita, S., Imai, M., Yamada, M., Kurosawa, K., Iwamoto, H., Yasui-Furukori, N., Kaneko, S., Fujiwara, T., Inoue, Y., Yamakawa, K
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Journal Title
Epilepsy Research 75
Pages: 46-51
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Aberrant trafficking of a proteolipid protein in a mild Pelizaeus-Merzbacher disease.2006
Author(s)
Koizume, S., Takizawa, S., Fujita, K., Aida, N., Yamashita, S., Miyagi, Y., and Osaka, H.
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Journal Title
Neuroscience 141
Pages: 1861-1869
Description
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[Journal Article] Parkin potentiates ATP-indused currents due to activation of P2X receptors in PC12 cells.2006
Author(s)
Sato, A., Arimura, Y., Manago, Y., Nishikawa, K., Aoki, K., Wada, E., Suzuki, Y., Osaka, H., Setsuie, R., et. al.
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Journal Title
J Cell Physiol. 209
Pages: 172-82
Description
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[Journal Article] Overexpression of ubiqitin carboxyl-terminal hydrolase L1 arrests spermatogenesis in transgenic mice.2006
Author(s)
Wang, Y. L., Liu, W., Sun, Y J., Kwon, J., Setsuie, R., Osaka, H., Noda, M., Aoki, S., Yoshikawa, Y., and Wada, K.
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Journal Title
Mol Reprod Dev 73
Pages: 40-49
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Taccination and infection as causative factors in Japanese patients with Rasmussen syndrome : Molecular mimicry and HLA class I2006
Author(s)
Takahashi, Y, Matsuda, K, Kubota Y, Shimomura J, Yamasaki, E, Kudo, T, Fukushima K, Osaka H, Akasaka N, Imamaura A, Yamada S, Kondo, N, Fujiwara
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Journal Title
Clinical & Developmental Immunology 13
Pages: 381-38
Description
「研究成果報告書概要(欧文)」より
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