Molecular mechanisms of Toll-like receptor 9 activation and the role of TLRs in autoimmunity

Toll样受体9激活的分子机制及TLRs在自身免疫中的作用

• 批准号: 5357927
• 负责人: Professor Dr. Stefan Bauer
• 金额: --
• 依托单位: Institut für Immunologie
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5357927?language=en
• 关键词: Molecular; mechanisms; Toll; like; receptor

The innate immune system has developed germ-line encoded pattern recognition receptors (PRR) that promote rapid responses to microbial pathogens. Toll-like receptors (TLRs) represent a newly recognized family of vertebrate PRR that activate and direct the anti-pathogen response through recognition of conserved pathogen associated molecular patterns (PAMP). TLR2 and TLR4 are the receptors for responses to gram-positive and gram-negative bacterial cell wall components such as lipopolysaccharide (LPS) or peptidoglycan. TLR9 has recently been identified as receptor for bacterial DNA, which acts as PAMP, similar to LPS. In contrast to LPS or peptidoglycan, bacterial DNA has to be taken up by an unknown sequence unspecific DNA receptor and endocytozed to activate the signaling pathway. TLR9 is localized in an endosomal / lysosmal vesicular structure and unpublished data suggest an unknown chaperone being responsible for the transport of newly synthesized TLR9 into this compartment. Aim of this project is to identify associated proteins of TLR9 which allow recognition of CpG-DNA. The identification and functional characterization of those co-receptors including knock-out studies in mice will help to understand the molecular mechanisms which are important for recognition of bacterial DNA and give insight into the anti pathogen response of the innate immune system.

先天免疫系统已经开发出胚系编码的模式识别受体(PRR)，促进对微生物病原体的快速反应。Toll样受体是一个新发现的脊椎动物PRR家族，它通过识别保守的病原体相关分子模式(PAMP)来激活和指导抗病原体反应。TLR2和TLR4是对革兰氏阳性和革兰氏阴性细菌细胞壁成分(如脂多糖或肽聚糖)反应的受体。TLR9最近被确定为细菌DNA的受体，其作用类似于内毒素，起着PAMP的作用。与脂多糖或肽聚糖不同的是，细菌DNA必须被未知序列的非特异性DNA受体摄取并内吞以激活信号通路。TLR9定位于内体/溶酶体泡泡结构，未发表的数据表明，一个未知的伴侣负责将新合成的TLR9运输到这个隔室。本项目的目的是鉴定TLR9的相关蛋白，使其能够识别CpG-DNA。这些共受体的鉴定和功能鉴定，包括小鼠的基因敲除研究，将有助于理解识别细菌DNA的重要分子机制，并有助于深入了解先天免疫系统的抗病原体反应。