Project Details
Projekt
Mechanisms of activation of the NLRP3 Inflammasome by extracellular calcium ions
Subject Area
Rheumatology
Term
from 2014 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 264002799
Extracellular Ca2+ ions were identified by the group of the lead applicant as potent stimuli of pro-inflammatory cellular effector mechanisms in monocytes, which act through triggering of the G protein coupled receptors CaSR and GPRC6A. For both receptors, the precise ligand binding sites and signal transduction pathways into the cell are not known. Unpublished data of the applicants show that for the exCa2+-induced stimulation, the presence of phosphate ions is an absolut requirement. Under such pro-inflammatory condition of increased Ca2+ and phosphate concentrations, however, calcium phosphate pre-nucleation cluster and calcium phosphate crystals can develop. The aim of the project is to investigate the mechanisms behind the pro-inflammatory Ca2+ and phosphate sensing, as well as the role of ion clusters and calcium phosphate crystals in this process. The required experiments will be performed using a floxed CaSR knockout and a GPRC6A deficient mouse model as well as genetic knockdown experiments of the phosphate sensitive, sodium dependent Pi-Co-transporter PiT-1. The ectodomains and full length protein of the two GPCRs will be expressed in vitro for functional studies of ligand binding and receptor activation as well for structural analysis of both receptors.
DFG Programme
Research Grants
