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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

基本信息

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

项目摘要

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.

我们鉴定并表征了白细胞介素2受体γ链（IL-2 R γ），其突变导致人类X连锁严重联合免疫缺陷病（XSCID），该疾病发生在多达50%的原发性SCID患者中。研究发现，与γ链下游信号转导相关并介导下游信号转导的Jak 3突变也可导致常染色体隐性SCID。因此，我们认为Jak 3下游存在与SCID相关的新基因的可能性，然后最初鉴定了新的Jak 3底物，包括STAM。本研究利用基因打靶和转基因小鼠分析了这些分子的体内功能，以确定其参与γ链/Jak 3信号转导途径。（1）STAM 1和STAM 2双缺陷小鼠是胚胎致死的。为了进一步阐明STAM在淋巴细胞中的功能，我们建立了条件性靶向小鼠，其将在淋巴细胞中缺乏这两种分子。（2）Hgs敲除（KO）小鼠对转化生长因子-β（TGF-β）家族分子的刺激反应显著降低。（3）AMSH基因缺陷小鼠出生后生长发育迟缓，并于19 ~ 23天死亡。AMSH缺陷小鼠海马亚区神经元缺损。（4）Graf 40突变体转基因小鼠胸腺细胞总数减少，而双阴性小鼠胸腺细胞总数明显增加。