| Project/Area Number |
09670154
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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 |
Pathological medical chemistry
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| Research Institution | Osaka University |
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Principal Investigator |
TSUKADA Satoshi Osaka University Medical School, Assistant Professor, 医学部, 助手 (60273637)
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| Co-Investigator(Kenkyū-buntansha) |
HASHIMOTO Shoji Osaka University Hospital, Medical staff, 医学部・付属病院, 医員
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | agammaglobulinemia / Bruton's tyrosine kinase / Sab / immunodeficiency / 免症不全症 / ブルトン型チロシンキナーゼ / WASP |
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| Research Abstract |
X-linked agammaglobulinemia (XLA), one of the most popular hereditary immunodeficiencies, exhibits the typical B-limphocyte deficiency characterized by a complete absence of humoral immunity.The dificient gene product in XLA is known as Btuon's tyrosine kinase (Btk).We have been investigating the pathogenisis of XLA from both clinical and molecular aspects.
1. We analized the function of the Btk-binding protein Sab (SH3-domain binding protein which preferentially associates with Btk), which we previously reported as a newly-identified SH3 domain-binding protein.Sab was shown to inhibit the auto- and transphosphorylahion activity of Btk, which prompted us to propose that Sab functions as a transregulator of Btk.Forced overexpression of Sab in B cells led to the reduction of BCR-induced tyrosine phosphorylation of Btk and significantly reduced the B cell antigen receptor-mediated early and late events including calcium mobilization, inositol 1, 4, 5-triphosphate production as well as apoptotic cell death in which the involvment of Btk activity has been previously shown.These results indicate the negative regulatory role of Sab in the B cell cytoplasmic tyrosine kinase pathway.
2. To understand the Btk signaling pathway, we have further searched the molecules which interact with Btk.We identified that one of the major Btk-SH2 domain binding proteins in B cells is BLNK (B cell linker protein) and present evidences that the interaction of BLNK and the SH2 domain of Btk contributes to the complete-tyrosine phosphorylation of phospholipase Cgamma, which leads the B cell antigen receptor-coupled clacium signaling to open.
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