Cytokine receptor γc chain/Jak3 mediated signal transduction and analysis of immunodeficiecy by dysfunction of the γc chain/Jak3

细胞因子受体γc链/Jak3介导的信号转导和γc链/Jak3功能障碍引起的免疫缺陷分析

• 批准号: 12470075
• 负责人: TAKESHITA Toshikazu
• 金额: $ 9.15万
• 依托单位: Shinshu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470075/
• 关键词: IL-2 receptor; γc chain; Jak3; SCID; STAM1; STAM2; Hgs; Graf40

We identified and have characterized the interleukin 2 receptor γ chain (IL-2Rγ ), of which mutations cause Human X-linked severe combined immunodeficiency disease ( XSCID ), a disease that occurs in as many as 50 % of patients with primary SCID. It was found that mutations of Jak3, which is associated with and mediates the down stream signal transduction from the γ chain, also caused autosomal recessive SCID. Thus, we considered the possibility that there is the novel gene related to SCID down stream of Jak3 and then originally identified novel Jak3 substrates including STAM. In this study, using the gene targeting and transgenic mice we analyzed the in vivo function of the molecules to determine its involvement in the signal transduction pathway from γ chain /Jak3.( 1 ) Double deficient mice, lacking both STAM1 and STAM2, were embryonically lethal. To further elucidate the function of STAM in lymphocytes, we established conditionally targeting mice that will lack of both molecules in lymphocytes( 2 ) Hgs knockout ( KO ) mice showed significantly decreased response to stimulation with transforming growth factor-β ( TGF-β ) family molecules.( 3 ) AMSH-deficient mice exhibited postnatal growth, retardation and died between day 19 and 23. The neurons were defect in the subfield of hippocampus of AMSH-deficient mice.( 4 ) The total number of thymocytes were reduced in the transgenic mice expressing Graf40 mutant, whereas it was significantly increased in the double-negative thymocytes subset.

我们确定并表征了白介素2受体γ链（IL-2Rγ）CY疾病（XSCID），这种疾病发生在多达50％的主要SCID患者中。随着γ链的下降信号转导。从γ链/JAK3（1）双重防御的途径，缺乏stam1和stam2的小鼠是胚胎致死的。 （2）HGS敲除（KO）小鼠在转化的生长因子-β（TGF-β）家族分子的刺激下显着降低。转基因表达GRAF40突变体中的降低，而胸腺细胞的胸膜细胞显着增加。

项目成果

Yamada, M., et al.: "Loss of hippocampal CA3 pyramidal neurons in mice lacking STAM1"Mol. Cell. Biol.. 21. 3807-3819 (2001)

Yamada, M. 等人：“缺乏 STAM1 的小鼠海马 CA3 锥体神经元的丢失”Mol。

Miura,S., et al.: "Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA."Mol.Cell.Biol.. 20. 9346-9355 (2000)

Miura,S., et al.：“Hgs (Hrs) 是一种 FYVE 结构域蛋白，通过与 SARA 合作参与 Smad 信号传导。”Mol.Cell.Biol.. 20. 9346-9355 (2000)

Kikuchi, K., et al.: "Suppression of thymic development by the dominant-negative form of Gads"Int. Immunol. 13. 777-783 (2001)

Kikuchi, K. 等人：“Gad 的显性负性形式对胸腺发育的抑制”Int。

Endo,K., et al.: "STAM2, a new member of the STAM family, binding to the Janus kinases."FEBS Letters. 477. 55-61 (2000)

Endo,K. 等人：“STAM2，STAM 家族的新成员，与 Janus 激酶结合。”FEBS Letters。

Kikuchi, K., et al.: "Suppression of tymic development by the dominant-negative form of Gads"Int. Immunol. 13. 777-783 (2001)

Kikuchi, K. 等人：“Gad 的显性负性形式抑制胸腺发育”Int。