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ADAM protease activationin the context of IL-6R biology

Fachliche Zuordnung Zellbiologie
Förderung Förderung von 2011 bis 2015
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 205822039
 
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.
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