Gfi1 in innate immunity: a downstream effector of Toll like receptor signaling and a novel regulator of endotoxin tolerance

先天免疫中的 Gfi1：Toll 样受体信号传导的下游效应器和内毒素耐受的新型调节剂

• 批准号: 5356844
• 负责人: Professor Dr. Tarik Möröy
• 金额: --
• 依托单位: Institut für Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5356844?language=en
• 关键词: Gfi1; innate; immunity; downstream; effector

Gfi-1 is a 55kD nuclear zinc finger protein which until now has been considered to act solely as a T-cell specific transcriptional repressor. However, we have recently discovered that this protein is also expressed in granulocytes and LPS treated macrophages which implicated a role of this protein in the innate immune system. The phenotype of Gfi-1 deficient mice supported such a role since these animals die prematurely with symptoms similar to septic shock within 3 months of age. Moreover Gfi-1 null mice have a severe neutropenia and produce highly elevated levels of inflammatory cytokines as TNF and IL-10. Using combinatorial mutant mice we plan to determine how Gfi-1 modulates the systemic response to endotoxins or an infection with P. aeruginosa, which is one of the clinically most relevant opportunistic bacteria. In addition, we wish to explore the signal transduction pathways that are responsible for the activation of Gfi-1 expression in primary murine macrophages upon LPS treatment or P. aeruginosa infection. Finally, we aim to determine the effector genes and signaling pathways that are regulated by Gfi-1 in bacterially infected macrophages.

GFI-1是一种55KD的核锌指蛋白，到目前为止，它被认为仅充当T细胞特异性转录阻遏物。但是，我们最近发现，该蛋白在粒细胞和LPS处理的巨噬细胞中也表达，这暗示了该蛋白在先天免疫系统中的作用。 GFI-1缺乏小鼠的表型支持了这样的作用，因为这些动物在3个月内与类似于败血性休克的症状过早死亡。此外，GFI-1 NULL小鼠具有严重的中性粒细胞减少症，并产生高度升高的炎性细胞因子，如TNF和IL-10。使用组合突变小鼠，我们计划确定GFI-1如何调节对内毒素的全身反应或铜绿假单胞菌感染，铜绿假单胞菌是临床上最相关的机会细菌之一。此外，我们希望探索负责在LPS处理或铜绿假单胞菌感染后原代鼠巨噬细胞激活GFI-1表达的信号转导途径。最后，我们旨在确定在细菌感染的巨噬细胞中受GFI-1调节的效应基因和信号通路。