| Project/Area Number |
17390277
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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 |
Hematology
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| Research Institution | Osaka University |
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Principal Investigator |
ORITANI Kenji Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (70324762)
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| Co-Investigator(Kenkyū-buntansha) |
KANAKURA Yuzuru Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (20177489)
MATSUMURA Itaru Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (00294083)
TOMIYAMA Yoshiaki Osaka University, Graduate School of Medicine, Lecture, 医学系研究科, 講師 (80252667)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2006: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2005: ¥8,700,000 (Direct Cost: ¥8,700,000)
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| Keywords | cytokine / interferon / IFN-ζ / Limitin / mutation / Daxx / sumoylation / receptor / 骨髄抑制 / 抗ウイルス作用 |
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| Research Abstract |
Our identified IFN-ζ/Limitin has similar anti-viral and immunomoduratory activities to IFN-a. However, IFN-ζ/Limitin failed to suppress colony formation of CFU-GM, BFU-E, and CFU-Meg. Although less myelo-suppressive property may suggest wide range of clinical utility of IFN-ζ/Limitin, human homologue of IFN-ζ/Limitin has not been identified yet. There are unique amino acid residues in receptor-binding sites of IFN-ζ/Limitin when compared with IFN-α and IFN-β. To identify responsible amino acid residues for the different biological activities between IFN-t/Lmitin and IFN-α, we constructed several mutated IFN-α (ml-m7-IFN-a) whose amino acid residues were substituted by those of IFN-ζ/Limitin, and compared biological activities of the mutated IFN-as with those of original IFN-α. m3-IFN-α carrying three amino acids substitution in the AB loop has revealed less suppressive effects on colony formation of CFU-GM and BFU-E, while it has similar anti-viral activity to IFN-α. Little myelo-suppr
… More
essive property of m3-IFN-α was also confirmed by the injection to mice. On the other hand, ml-IFN-α carrying four amino acids substitution in the herix C has revealed higher anti-viral activity than original IFN-α. The other mutated IFN-αs lost both anti-viral and myelo-suppressive activities. These results are useful to construct a novel human IFN, which has IFN-ζ/Limitin-like characters.
We have analyzed IFN-signals, which mediate myelo-suppressive activities, and have clarified essential roles of Tyk2 and Daxx. Reduction of protein expression of Tyk2 and/or Daxx by antisense oligonucleotides resulted in lack of myelo-suppressive activities of IFN-α. In addition, a sumoylation-defective Daxx KA mutant (Daxx K630/631A) localized in the cytoplasm, whereas wild-type Daxx localized in the nucleus. Murine pro-B cell line Ba/F3 expressing Daxx KA revealed a resistance to IFN-induced growth suppression, indicating the important role of sumoylation of Daxx in IFN-induced myelo-suppression. These results are useful to design a strategy for the IFN-therapy. Less
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