| Project/Area Number |
16043261
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | RIKEN (2006)
National Institute of Infectious Diseases (2004-2005) |
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Principal Investigator |
TAKEMORI Toshitada RIKEN, Lab. For Immunological Memory, Group Director, 免疫記憶研究グループ, グループディレクター (60114295)
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| Co-Investigator(Kenkyū-buntansha) |
KAJI Tomohiro RIKEN, Lab. For Immunological Memory, Researcher, 免疫記憶研究グループ, 研究員 (70370963)
OHARA Osamu RIKEN, Lab. For Immunogenomics, Group Director, 免疫ゲノミク研究グループ, グループディレクター (20370926)
HIKITA Masaki RIKEN, Iab. For Lymphocyte Differentiation, Researcher, 分化制御研究グループ, 研究員 (60228715)
TAKAHASHI Yoshimasa National Institute of Infectious Diseases, Dept. Immunology, Researcher, 免疫部, 主任研究員 (60311403)
橋本 修一 国立感染症研究所, 免疫部, 研究員 (60342896)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥39,600,000 (Direct Cost: ¥39,600,000)
Fiscal Year 2006: ¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2005: ¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2004: ¥13,200,000 (Direct Cost: ¥13,200,000)
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| Keywords | memory B cell / memory B cell genes / survival / secondary response / SMN / AIF / committment / AID / Somatic mutations / 記憶B細胞系列決定 / 抗体産生細胞 / 抗酸化ストレス / 抗アポトーシス活性 / 生存維持 / ミトコンドリア / 呼吸鎖複合体 / 抗アポトーシス / Ras / 抗原受容体 |
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| Research Abstract |
Memory B cells acquire several intrinsic properties that differ from na・e B cells, suggesting that memory B cells may have a unique gene expression that differs quantitatively and/or qualitatively from other stages of B cells. Therefore, to clarify the mechanism responsible for memory B cell commitment, survival and terminal differentiation upon antigen reexposure, we identified changes in gene expression that occur in the transition from a naive B cell to either GC B cells, memory B cells or plasma cells upon antigen stimulation. We have cloned several genes which are highly expressed in memory B cells, including E52 and 4010. E52 was turned out to be a human homologue of the survival of motor neuron gene (SMN)1, which is a causative gene for spinal muscular atrophy (SMA). Over expression of SMN in B cell lymphoma cell lines prolonged cell survival in proapoptotic culture conditions, raising the idea that the gene could be responsible for memory B cell survival. Therefore, we characte
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rized the role of SMN in cell survival by biochemical analysis and concluded that SMN prolonged cell survival upon oxidant stress and enhanced the activity of the mitochondrial respiratory chain complex I.
The 4010 gene encodes an adopter molecule and its overexpression in splenic B cells results in an augmentation of IgG1 response upon stimulation with anti-Igs and anti-CD40 mAbs in vitro. Thus, 4010 could be involved in the signaling cascade responsible for either memory B cell terminal differentiation or antibody secretion. To examine this possibility we are now establishing conditional knock out mice.
To know the regulatory network responsible for memory B cell commitment, we utilized Affymetrix GeneChip analysis and characterize the changes in gene expression in the transition from naive B cells to GC B cells, memory B cells or plasma cells upon antigen stimulation. Q-PCR confirmation revealed that memory B cell population expressed a group of transcripts selectively enriched in this population, with similar time-dependent changes in their expression patterns. To utilize such genetic markers for the memory B cell lineage, we analyzed the early events in antigen-specific B cell response and suggested that activated B cells progress to memory B cells, at least, from day 5 to day 6 after immunization, accompanied by class-switch recombination and efficient proliferation. Less
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