| Project/Area Number |
15390163
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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 |
Immunology
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| Research Institution | Nihon University |
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Principal Investigator |
RA Chisei Nihon University, School of Medicine, Professor, 医学部, 教授 (60230851)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Yoshihiro Nihon University, School of Medicine, Research Assistant, 医学部, 助手 (80206549)
SHIMOKAWA Toshibumi Nihon University, School of Medicine, Research Assistant, 医学部, 助手 (10339327)
TAKAHASHI Kyoko Nihon University, School of Medicine, Research Assistant, 医学部, 助手 (70366574)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 2004: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2003: ¥7,600,000 (Direct Cost: ¥7,600,000)
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| Keywords | mast cell / FcεRI / Toll like receptors / allergy / innate immunity / reactive oxygen species |
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| Research Abstract |
1.Suppressive signals through the high affinity IgE receptor (FcεRI) β chain
In the FcεRI β chain ITAM mutant cells, activation of ERK, JNK and NF-κ B was significantly enhanced upon FcεRI crosslinking, although recruitment of Lyn, SHIP, and SHP to the β chain was severely impaired. Moreover, we revealed that C terminal region of the β chain positively regulated mast cell activation. β chain ITAM Tg are mated with β chain deficient mouse.
2.Regulation of FcεRI β chain gene expression
The transcription factor MZF-1 suppressed human FcεRI β chain gene expression via an element in the fourth intron. FHL3 was isolated from a human cDNA library as a repressive co-factor of MZF-1 by yeast two hybrid assays. GM-CSF induced translocation of FHL3 to the nucleus in addition to expression of MZF-1,suggesting that GM-CSF downregulated FcεRIβ expression through accumulation of MZF-1/FHL3 complex in the nucleus
3.TLR signaling in mast cells
NF-kappa B activation by LPS was mediated via MyD88 dependent or independent pathways. We also demonstrated that PKR-dependent pathway regulated MyD88-independent NF-κ B activation.
4.FcεRIβ-dependent or independent production of hydrogen peroxide in mast cells
We explored the role of FcεRIβ in the production of H_2O_2 upon FcεRI cross-linking and found that the oxidant is produced through two distinct pathways : dependent or independent of FcεRIβ. The FcεRIβ-dependent production of H_2O_2 was mediated by the physical interaction with Lyn kinase via its immunoreceptor tyrosine-based activation motif, while the FcεRIβ-independent production of H_2O_2 appeared to be a result of intramitochondrial production of superoxide and its dismutation catalyzed by superoxide dismutase. Furthermore, while the FcεRIβ-dependent oxidative burst is required for maximal calcium store emptying, a prerequisite event for the initiation of store-operated calcium entry, the FcεRIβ-independent response seems to be involved in the prolongation of the calcium entry.
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