| Project/Area Number |
13670869
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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 |
Dermatology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
YOKOZEKI Hiroo Tokyo Med. and Dent. Univ., Dermatology, Associate Professor, 大学院・医歯学総合研究科, 助教授 (90210608)
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| Co-Investigator(Kenkyū-buntansha) |
SATOH Takahiro Tokyo Med. and Dent. Univ., Dermatology, Assistant Professor, 医学部附属病院, 講師 (30235361)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2003: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | contact dermatitis / atopic dermatitis / Th2 cytokines / Gene Therapy / STAT6 / IgE / 接触アレルギー / Th2 / サイトカイン / ハプテン / ランゲルハンス細胞 / 遅発型反応 |
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| Research Abstract |
Signal Transducers and Activators of Transcription 6 (STAT6) play a crucial role in the transactivation of IL-4 and IL-13 which might be involved in the pathogenesis of contact dermatitis (CD) and atopic dermatitis (AD). We herein reported that the contact hypersensitivity and IgE mediated late phase reaction significantly decreased in STAT6 deficient (STAT6~) mice in AD model mice induced by intravenous injection of monoclonal anti-DNP-IgE antibody and subsequent skin testing with dinitrofluorobenzene (DNFB). We therefore hypothesized that synthetic double-stranded DNA with a high affinity for STATE could be introduced in vivo as decoy cis elements to bind the transcriptional factor and to block the gene activation of contributing the onset and progression of CD or AD, thus providing effective therapy for CD and AD. Treatment by the transfection of STAT6 decoy oligodeoxynucleotides (ODN), but not scramble decoy ODN after the sensitization by anti-DNP-IgE antibody, had a significantly inhibitory effect on not only STATE binding to nuclei but also on the conact hypersensitivity and late phase response. A histological analysis revealed that both edema and the infiltration of neutrophils and eosinophils significantly decreased in STAT6 decoy ODN transfected mice. To examine the mechanism of the in viva effect of STATE decoy ODN, we employed an in vitro mast cells culture system. After IgE receptor engagement, mast cells transfected by STAT6 decoy ODN exhibited normal histamine release, but their cytokine release (TNF-a, IL-6) markedly decreased. We herein report the first successful in viva transfer of STATE decoy ODN to reduce the late phase reaction thereby providing a new therapeutic strategy for CD and atopic dermatitis.
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