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ADAM protease activationin the context of IL-6R biology

IL-6R 生物学背景下的 ADAM 蛋白酶激活

基本信息

批准号：
205822039
负责人：
Professor Dr. Jürgen Scheller
金额：
--
依托单位：
Institut für Biochemie und Molekularbiologie II
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/205822039?language=en
关键词：
ADAM protease activationin context IL

项目摘要

Interleukin 6 (IL-6) trans-signaling is mediated via IL-6 and the soluble IL-6 Receptor (slL-6R). lL-6 transsignaling was found to be upregulated under pathophysiological situations. In humans, ADAM17 is the main sheddase of IL-6R. Our recent data show that in mice shedding of the IL-6R is largely me-diated by ADAM10 and only to a minor extend by ADAM17. This unique species-specific difference will be studied to define protease-substrate recognition and regulation patterns of IL-6R shedding. More than 70 substrates of ADAM17 were described including TNFa and EGFR-ligands. Only In ex-ceptional cases, reduced or increased shedding of a single substrate can be studied in ADAM defi-cient or transgenic mice. We developed novel mouse genetic strategies independent on ADAM pro-tease activity to analyze abrogated and enhanced 1L-6R ectodomain shedding in vivo. In sgp130Fc transgenic mice. IL-6-transsignaling but not IL-6 classic signaling is blocked, which mimics ADAM deficiency for 1L-6R. Tissuespecific Cre-recombination of the novel slL-6R-only GFP-reporter condi-tional Knock In mice will lead to mice expressing increased slL-6R but reduced cellular IL-6R level, thereby mimicking ADAM hyperactivation for 1L-6R. Furthermore, the IL-6R was genetically linked to GFP to follow IL-6R ADAM protease activation in the context of tL-6R biology expression in vivo. These mouse lines will comprehensively characterize the role of lL-6 trans-signaling in inflammatory states.

白细胞介素6 （IL-6）反式信号是通过IL-6和可溶性IL-6受体（slL-6R）介导的。在病理生理条件下，发现lL-6转信号上调。在人类中，ADAM17是IL-6R的主要表达基因。我们最近的数据显示，在小鼠中，IL-6R的脱落主要由ADAM10介导，ADAM17只对IL-6R的脱落有少量影响。这种独特的物种特异性差异将被研究以确定蛋白酶底物识别和IL-6R脱落的调节模式。报道了ADAM17的70多种底物，包括TNFa和egfr配体。只有在特殊情况下，可以在ADAM缺陷或转基因小鼠中研究单个底物脱落的减少或增加。我们开发了一种新的不依赖于ADAM前挑逗活性的小鼠遗传策略来分析体内1L-6R外域脱落的消除和增强。在sgp130Fc转基因小鼠中。IL-6转导信号被阻断，但IL-6经典信号不被阻断，这类似于1L-6R的ADAM缺失。对新型的仅含gfp报告基因的slL-6R的条件敲入小鼠进行组织特异性的cre重组，将导致小鼠表达slL-6R增加，但细胞IL-6R水平降低，从而模拟ADAM对1L-6R的过度激活。此外，IL-6R与GFP遗传关联，在体内IL-6R生物学表达的背景下跟随IL-6R ADAM蛋白酶激活。这些小鼠系将全面表征lL-6反式信号在炎症状态中的作用。