| Budget Amount *help |
¥49,270,000 (Direct Cost: ¥37,900,000、Indirect Cost: ¥11,370,000)
Fiscal Year 2004: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2003: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2002: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
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| Research Abstract |
Pre-B cell receptor (pre-BCR) signaling induces proliferative expansion of large pre-B cells and the following differentiation into small pre-B cells (pre-B cell transition), and inhibits V_H to DJ_H rearrangement of IgH locus (IgH allelic exclusion), the latter also accounting for counter-selection of pro-B cells expressing Dμ protein (Dμ selection). We have previously shown that a B-cell specific adaptor protein, BASH (or BLNK/SLP-65), which is critical for B-cell antigen receptor(BCR) signaling, is important, but not essential, for pre-B cell transition. In this study we have discovered a buck-up role in the pre-BCR signaling for CD19, a B-cell specific co-receptor for BCR. The pre-B cell transition was completely abolished and accumulation of large non-cycling, pre-BCR-expressing cells was augmented in BASH/CD19 double-mutant mice. However, IgH allelic exclusion was intact even in the double-mutant mice, while Dμ selection was abolished in BASH- and the double-mutant mice. Thus, di
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stinct signals are required for these events. In addition, these mice succumbed to pre-B cell leukemia, indicating BASH (and CD19) contributes to tumor suppression.
We also found that editing of self-binding antigen receptors is significantly dependent on BASH, through examining anti-DNA-antibody knock-in mice deficient for BASH. Thus contribution of the receptor editing in the establishment of self-tolerance is clearly documented. In addition, BASH has turned out to be unnecessary for T-independent secondary and memory response, as well as affinity maturation of antibodies.
BASH interacts with signaling molecules such as Btk, PLCγ, Vav, Grb2, HPK1, and the significance of such interactions in BCR signal transduction has been shown. We have identified novel proteins that bind to a conserved N-terminal domain of BASH, and termed them BNAS1 and BNAS2. They are both presumed to be a 4-times membrane-span protein and localize at endoplasmic reticulum, Golgi apparatus and peri-nuclear region. Functional studies utilizing gene targeting methodology are currently underway. Less
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