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Cytokine receptor γc chain mediated signal transduction and analysis of immunodeficiency by dysfunction of the γc chain

细胞因子受体γc链介导的信号转导和γc链功能障碍引起的免疫缺陷分析

基本信息

批准号：
10470084
负责人：
TAKESHITA Toshokazu
金额：
$ 8.19万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470084/
关键词：
IL-2 receptor the γc chain Jak3 SCID STAM IL-2 STAM2

项目摘要

The interleukin 2 receptor γ chain (IL-2Rγ ), which we previously cloned, is known to be a causative gene for human X-linked severe combined immunodeficiency (X-SCID). X-SCID is a disease that occurs in as many as 50% of patients with primary SCID, and is characterized with profound defect of T and NK cells and impairment of B cell differentiation. The IL-2Rγ is shared among the receptors for several cytokines, and called the common γ(γc) chain. The cytoplasmic domain of the γc chain is associated with Jak3 tyrosine kinase, of which mutantions also cause an autosomal recessive SCID, Jak3-SCID. These observations suggest that the γc/Jak3 signaling pathway is indispensable for development of T, NK and B cells. We thus hypothesized that molecules involved in the γc/Jak3 signaling pathway may include causative gene products for SCID. In this context, we have identified STAM1, which is associated with Jak3 and Jak2, and involved in signaling for cell proliferation and c-myc induction mediated by IL-2 and GM-CSF. STAM1 knockout mice were born and developed normally, but their body weights decreased gradually after 5 weeks of age, and were below 60-70% of those of normal mice. 90% of the mice died before 16 weeks of age. Until 4 weeks of age, STAM1 knockout mice were normal clinically, but histopathologically they showed an abnormality in the CA3 region of the hippocampus. On the other hand, we molecularly cloned a STAM1 homologous molecule named STAM2, and revealed that STAM2 has similar in vitro functions to STAM1, suggesting that STAM1 may be compensated by STAM2 in the STAM1 knockout mice. We have also developed STAM2 knockout mice, which show normal growth and no abnormal features so far. We are now attempting to establish double KO mice for STAM1 and STAM2 to examine their possible functional relationship.

白细胞介素2受体γ链（IL-2 R γ）是X连锁重症联合免疫缺陷（X-SCID）的致病基因。X-SCID是一种在多达50%的原发性SCID患者中发生的疾病，其特征在于T和NK细胞的严重缺陷以及B细胞分化的损害。IL-2 R γ在几种细胞因子的受体之间共享，称为共同γ（γc）链。γc链的胞质结构域与Jak 3酪氨酸激酶相关，其突变也会导致常染色体隐性SCID，Jak 3-SCID。这些观察结果表明，γc/Jak 3信号通路是T、NK和B细胞发育所不可或缺的。因此，我们假设参与γc/Jak 3信号通路的分子可能包括导致SCID的基因产物。在这种情况下，我们已经确定了STAM 1，这是与Jak 3和Jak 2，并参与信号传导细胞增殖和c-myc诱导介导的IL-2和GM-CSF。STAM 1基因敲除小鼠出生和发育正常，但5周龄后体重逐渐下降，低于正常小鼠的60-70%。90%的小鼠在16周龄之前死亡。直到4周龄，STAM 1敲除小鼠在临床上是正常的，但在组织病理学上，它们在海马CA 3区显示出异常。另一方面，我们克隆了一个STAM 1同源分子STAM 2，并揭示了STAM 2与STAM 1在体外具有相似的功能，这表明STAM 1基因敲除小鼠中STAM 1可能被STAM 2所补偿。我们还开发了STAM 2基因敲除小鼠，到目前为止，它们表现出正常的生长，没有异常特征。我们现在正试图建立STAM 1和STAM 2的双KO小鼠，以研究它们可能的功能关系。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prolongation of allograft survival by administration of mAb specific for the three subunis of IL-2 receptor.

通过施用针对 IL-2 受体三个亚基的单克隆抗体可延长同种异体移植物的存活时间。

DOI：
发表时间：
1998
期刊：
Int.Immunol. Vol.10
影响因子：
0
作者：
Yasuda;K.;Nemoto;T.;Ohashi;Y.;Satomi;S.;Mutara;K.;Ishii;N.;Takeshita;T.;Sugamura;K.
通讯作者：
K.

Yasuda,K.: "Prolongation of allograft survival by administration of mAb specific for the three subunits of IL-2 receptor." Int.Immunol.10. 561-567 (1998)

Yasuda,K.：“通过施用针对 IL-2 受体三个亚基的单克隆抗体可延长同种异体移植物的存活时间。”

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Prolongation of allograft survival by administration of mAb specific for the three subunits of IL-2 receptor.

通过施用针对 IL-2 受体三个亚基的单克隆抗体可延长同种异体移植物的存活时间。

DOI：
发表时间：
1998
期刊：
Int.Immunol. 10
影响因子：
0
作者：
Yasuda;K.;et al.
通讯作者：
et al.

Grf40, A novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT.

DOI：
10.1084/jem.189.9.1383
发表时间：
1999-05-03
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Asada H;Ishii N;Sasaki Y;Endo K;Kasai H;Tanaka N;Takeshita T;Tsuchiya S;Konno T;Sugamura K
通讯作者：
Sugamura K

Possible involvement of a novel STAM-associated molecule "AMSH" in intracellular signal transduction mediate by cytokines.

一种新型 STAM 相关分子“AMSH”可能参与细胞因子介导的细胞内信号转导。