| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Research Abstract |
Ras guanyl nucleotide-releasing proteins (RasGRPs) are guanine exchange factors for Ras. Among them, RasGRP1 is preferentially expressed in T cells. We have investigated abnormal expressions of RasGRP1 in patients with systemic lupus erythematosus and previously reported that alternative splicing of RasGRP1 is abundant in lupus T cells that alternative splicing is related to lower protein levels of this signaling molecule. In the present study, we at first tested if nonsense-mediated mRNA decay and/or ubiquitine-proteasome pathway play a role in lower protein levels of RasGRP1 in lupus T cells. Inhibition of nonsense-mediated mRNA decay nor proteasome impact the expression levels or patterns of RasGRP1 protein. Then we decided to generate Tg mice expressing RasGRP1 splice variant A, the most frequent alternatively-spliced RasGRP1 isoform, exclusively in T cells. We successfully generate mice that express RasGRP1 splice variant A protein in their thymus. Although proportion of single positive/double negative T cells in the thymus was not apparently affected by this splice variant, we are investigating activation of Ras-Erk pathway in Tg Tcells when stimulated by anti-CD3/28 antibodies.
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