Abnormal expressions of RasGRPs in autoimmune diseases

RasGRPs在自身免疫性疾病中的异常表达

• 批准号: 20591163
• 负责人: YASUDA Shinsuke
• 金额: $ 2.83万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591163/
• 关键词: 自己免疫疾患; 全身性エリテマトーデス; スプライス異常; RasGRP1; スプライスバリアント; 関節リウマチ; RasGRP4

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.

Ras鸟苷酸释放蛋白（Ras GRP）是Ras的鸟嘌呤交换因子。其中，RasGRP 1优先在T细胞中表达。我们已经调查了系统性红斑狼疮患者中RasGRP 1的异常表达，并且先前报道了RasGRP 1的选择性剪接在狼疮T细胞中丰富，选择性剪接与该信号分子的较低蛋白水平有关。在本研究中，我们首先测试了无义介导的mRNA降解和/或泛素-蛋白酶体途径是否在狼疮T细胞中RasGRP 1蛋白水平降低中发挥作用。抑制无义介导的mRNA衰变也不影响RasGRP 1蛋白的表达水平或模式。然后，我们决定产生Tg小鼠表达RasGRP 1剪接变体A，最常见的选择性剪接RasGRP 1亚型，只在T细胞。我们成功地产生小鼠表达RasGRP 1剪接变体A蛋白在他们的胸腺。尽管胸腺中单阳性/双阴性T细胞的比例没有明显受到这种剪接变体的影响，但我们正在研究抗CD 3/28抗体刺激时Tg T细胞中Ras-Erk通路的激活。

项目成果

Aberrant Splicing of the Transcript of RasGRP4 in the Peripheral Blood Mononuclear Cells of Patients with Rheumatoid Arthritis.

类风湿关节炎患者外周血单核细胞中 RasGRP4 转录本的异常剪接。

• 发表时间: 2010
• 作者: Hashimoto T;Atsumi T;Koike T;et al.
• 通讯作者: et al.

Thrombotic microangiopathy in patients with phosphatidylserine dependent antiprothrombin antibodies and antiphospholipid syndrome.

磷脂酰丝氨酸依赖性抗凝血酶原抗体和抗磷脂综合征患者的血栓性微血管病。

• 发表时间: 2008
• 期刊: Clinical & Experimental Rheumatology 26
• 作者: Kon Y;Atsumi T;Hagiwara H;Furusaki A;Kataoka H;Horita T;Yasuda S;Amengual O;Koike T.
• 通讯作者: Koike T.

セルトリズマブ

赛妥珠单抗

• 发表时间: 2010
• 期刊: Pharma Medica. 28(3)
• 作者: Kamae T;Kashiwagi H;et al.;保田晋助
• 通讯作者: 保田晋助

Antiphospholipid antibodies increase the risk of pregnancy-induced hypertension and adverse pregnancy outcomes.

• DOI: 10.1016/j.jri.2008.11.001
• 发表时间: 2009
• 期刊: Journal of reproductive immunology
• 影响因子: 3.4
• 作者: Hideto Yamada;T. Atsumi;G. Kobashi;Chikako Ota;E. Kato;Noriko Tsuruga;K. Ohta;S. Yasuda;T. Koike;H. Minakami

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• 发表时间: 2008
• 作者: 保田晋助;小池隆夫
• 通讯作者: 小池隆夫