SOCS-7 A Regulator of Signal Transduction

SOCS-7 信号转导调节器

• 批准号: 7002570
• 负责人: Paul B Rothman
• 金额: $ 28.79万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002570
• 关键词: biological signal transduction; cytokine; gene deletion mutation; genetically modified animals; histology; immunocytochemistry; immunogenetics; insulin receptor; insulin sensitivity /resistance; laboratory mouse; nuclear proteins; pancreatic islets; phenotype; protein protein interaction; protein structure function; receptor expression; skin disorder; transcription factor

DESCRIPTION (provided by applicant): The mechanisms by which cytokine signaling is regulated in cells are not well understood. Recently, a new family of proteins, termed Suppressors of Cytokines Signaling (SOCS), has been identified. SOCS-1 was identified as a potent inhibitor of JAK-STAT signaling. Analysis of DNA databases led to the identification of six additional SOCS family members (SOCS-2 through SOCS-7). The SOCS family of proteins is defined by the presence of a central SH2 domain and a C-terminal SOCS box. The biologic functions of SOCS-2 through SOCS-7 have just begun to be defined. We have sought to define the function of SOCS-7. Towards this goal, we have generated mice that lack SOCS-7 by gene targeting. Our analyses of SOCS-7-deficient mice demonstrate that the mice have several abnormalities. The mice develop an excoriative skin disease, which is associated with elevated levels of IgE. T cells from the mice produce higher levels of IL-4. When backcrossed unto the C571BL/6 strain, the mice die at six weeks of age. These mice have severe hypoglycemia, and enlarged islets in the pancreas. Biochemical analysis suggests that that SOCS-7 can interact with IRS proteins. IRS activation appears to be increased in cells that lack SOCS-7. Together these data lead us to hypothesize that SOCS-7 is a regulator of IRS activation downstream of several different cytokines. We propose to extend these results and to determine the role of SOCS-7 in IRS function and cytokine signaling. Specifically, we propose to: Determine insulin responses in SOCS-7 deficient mice/cells, Determine the mechanisms responsible for the immune phenotype/skin disease in SOCS-7 deficient mice, Define the mechanism(s) by which SOCS-7 alters IRS signaling and Determine the signaling abnormalities in SOCS-6 and SOCS-6/7 deficient mice.

描述（由申请人提供）：细胞中调节细胞因子信号传导的机制尚不清楚。最近，一个新的蛋白质家族，称为细胞因子信号转导抑制因子（SOCS），已被确定。SOCS-1被鉴定为JAK-STAT信号传导的有效抑制剂。DNA数据库的分析导致识别出另外六个SOCS家族成员（SOCS-2至SOCS-7）。SOCS蛋白家族由中心SH 2结构域和C-末端SOCS盒的存在定义。SOCS-2至SOCS-7的生物学功能刚刚开始被定义。我们已设法界定SOCS-7的职能。为了实现这一目标，我们通过基因靶向产生了缺乏SOCS-7的小鼠。我们对SOCS-7缺陷小鼠的分析表明，小鼠有几个异常。小鼠发展出与IgE水平升高相关的表皮剥脱性皮肤病。来自小鼠的T细胞产生更高水平的IL-4。当与C571 BL/6品系回交时，小鼠在6周龄时死亡。这些小鼠有严重的低血糖症，胰腺中的胰岛增大。生化分析表明，SOCS-7可以与IRS蛋白相互作用。IRS活化似乎在缺乏SOCS-7的细胞中增加。总之，这些数据使我们假设SOCS-7是几种不同细胞因子下游IRS活化的调节剂。我们建议扩展这些结果，并确定SOCS-7在IRS功能和细胞因子信号传导中的作用。具体而言，我们建议：确定SOCS-7缺陷小鼠/细胞中的胰岛素应答，确定SOCS-7缺陷小鼠中免疫表型/皮肤病的机制，定义SOCS-7改变IRS信号传导的机制，并确定SOCS-6和SOCS-6/7缺陷小鼠中的信号传导异常。