2002 Fiscal Year Final Research Report Summary
Anti-htt single chain antibodies as intrabodies may be useful for gene-therapy in polyglutamine disease
| Project/Area Number |
13680855
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Fujita Health University |
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Principal Investigator |
ISHIGURO Hiroshi Fujita Health University, Education and Research Center of Animal Models for Human Diseases Associate Professor, 疾患モデル教育研究センター, 助教授 (20211039)
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| Co-Investigator(Kenkyū-buntansha) |
SAWADA Hirohide Fujita Health University, Institute for Comprehensive Medical Science Assistant Technologist, 総合医科学研究所, 助手 (30247663)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Huntington disease / huntingtin / neurodegenerative disorder / antibody library / intrabody / gene-therapy |
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| Research Abstract |
Huntington disease (HD) is a neurodegenerative disorder characterized by the expansion of CAG repeats in exon 1 of the HD gene. Expanded pdyglutamine-encoded CAG repeats induce protein-protein interactions related to the pathology of HD, and neuronal cell death may result from the formation of polyglutamine aggregates by huntingtin (htt) or its N-terminal portion. A total of 1056 single-chain Fv (scFv) antibodies were selected from a human phage display library of approximately 1×10^<12>antibodies using recombinant N-terminal huntingtin (htt, 16 residues) fused to maltose-binding protein (MBF) or glutathione S-transferase (GST). Antibodies were tested for binding with the MKAFESLKSF(Q)6 peptide encoded from the second methionine of HD gene exon1. Five scFv antibodies specifically bound to the N-terminal of htt and were tested in a cellular model of HD. Protein expression of htt was used in 293 cells to test binding to the N-terminal portion of htt, with expanded potyglutamine stretches fused to green fluorescent protein (EGFP) and intrabodies. Two anti-htt scFv antibodies were found to inhibit polyglutamine aggregates in cell line, 293 cells. These results suggest that intrabodies will prove useful in genetherapies against neurodegerative disorders such as polyglutamine disease, Alzheimer's disease, Parkinson's disease and prion diseases.
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Research Products
(11 results)
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[Publications] Ishiguro H., Yamada K, Sawada H., Nishii K., Ichino N., Sawada M., Kurosawa Y., Matsushita N., Kobayashi K., Goto J., Hishida H., Masuda N., Kanazawa I. and Nagatsu T.: "Age-dependent and tissue-specific CAG repeat instability occurs in mouse knock-in for a mutant Huntington's disease gene"J.Neurosci.Res.. 65. 289-297 (2001)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Asakura M., Kitakaze M., Takashima S., Liao Y., Ishikura F., Yoshinaka T., Ohmoto H., Node K., Yoshino K., Ishiguro H., Asanuma H., Sanada S., Matsumura Y., Takeda H., Beppu S., Tada M., Hori M. and Higashiyama S.: "Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF : Metalloprotease inhibitors as a potential new therapy for cardiac hypertrophy"Nature Medicine. 8. 35-40 (2002)
Description
「研究成果報告書概要(欧文)」より
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