| Project/Area Number |
14370110
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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 | Tokyo Medical and Dental University |
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Principal Investigator |
KARASUYAMA Hajime Tokyo Medical and Dental University, Department of Immune Regulation, Professor, 大学院・医歯学総合研究科, 教授 (60195013)
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| Co-Investigator(Kenkyū-buntansha) |
YONEKAWA Hiromichi Tokyo Metropolitan Organization for Medical Research, The Tokyo Metropolitan Institute of Medical Science, Vice-director, 東京都臨床医学総合研究所, 副所長 (30142110)
MORIO Tomohiro Tokyo Medical and Dental University, Hospital Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (30239628)
SORIMACHI Noriko International Medical Center of Japan, Department of Gastroenterology Research Institute, Section head, 消化器疾患研究所, 室長 (30217468)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥11,300,000 (Direct Cost: ¥11,300,000)
Fiscal Year 2003: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2002: ¥5,900,000 (Direct Cost: ¥5,900,000)
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| Keywords | B cell development / pre B cell receptor / μH chain / surrogate light chain / signal transduction / quality check / immunodeficiency / autoimmune deseases / 遺伝子再構成 / 大型プレB細胞 / チロシンリン酸化 / NKκB / Srcファミリーキナーゼ / PKC |
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| Research Abstract |
All the genes so far identified till now, which mutations cause B cell-less primary immunodeficiency encode components of preB cell receptor or molecules involved in preB cell receptor signaling. This clearly indicates that preB cell receptor plays a pivotal role in B cell development. However, it remains to be determined how preB cell receptor regulates early B cell development in bone marrow. In this study, we employed our original system to analyze early B cell development and examined the expression pattern of preB cell receptor in B cell precursors, the signaling pathways of preB cell receptor and the quality check of p11 chain through preB cell receptor. It was clearly demonstrated by using highly sensitive immunofluorescence that the surface expression of preB cell receptor was confined to the large preB cell stage of B cell (levelopment m both humans and mice. This finally settled the confusion regarding the preB cell receptor expression. Two distinct pathways of preB cell receptor signahng were identified. One is dependent on Src family kinases, and the other is dependent on Syk. Activation of NFκ3 was observed only in the former pathway. Novel molecules designated TPP36 and TPP32 were identified as tyrosine-phosphorylated by Abl in preB cells. In order to clarify the mechanism of H chain selection at the early stage of B cell development, we have established a novel system to dlstlngnLsh preB cells with preB cell receptor and those without preB cell receptor ih vivo and found that as much as two-thirds of H chains pro(luced at the preB cell stage are incal)able of associating with surrogate L chain to form preB cell receptor. Our recent data suggest that the malfunction of μH chain quality check results in immunodeficiency and autoimmune diseases.
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