Objective The regulation of ion concentrations in the cytoplasm and in the lumen of intracellular vesicles provides suitable environments for biochemical reactions, gradients for signal transduction, and generates osmotic gradients for the regulation of the volume of cells and intracellular organelles. Changes in the ion homeostasis and volume of cells and organelles may in turn influence processes like cell division and migration or the budding of vesicles from cellular membranes. Volume changes of cells, and possibly also of intracellular organelles, in turn regulate ion transport across their membranes. Whereas several swelling-activated plasma membrane ion transporters and channels are known, the molecular identity of a key player, the swelling-activated anion channel VRAC, and its impact on cellular functions remain elusive. Only sketchy information is available on ion homeostasis and volume regulation of intracellular organelles like endosomes and lysosomes, in spite of their importance for several diseases.We propose to perform a genome-wide RNAi screen to finally identify the long-sought swelling-activated Cl- channel VRAC at the molecular level. This screen will also identify genes involved in the regulation of VRAC. The network involved in cell volume regulation will be investigated at the structural, biochemical and cellular level as well as with genetically modified mice. In parallel we will examine the ion homeostasis of endosomes and lysosomes. Until recently only the regulation of luminal H+ and Ca++ concentration was studied, but our recent work demonstrated a crucial role of luminal Cl- and hinted at an important role of cations. A combination of proteomics, siRNA screens, candidate approaches, and mouse models will be used to elucidate the ion homeostasis of endosomes/lysosomes and the impact on organellar function and associated pathologies. We expect that our work will break new ground in ion transport physiology, pathology, and cell biology. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsnatural sciencesbiological sciencescell biologymedical and health sciencesbasic medicinepathologymedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS4 - ERC Advanced Grant - Physiology, Pathophysiology and Endocrinology Call for proposal ERC-2011-ADG_20110310 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Coordinator FORSCHUNGSVERBUND BERLIN EV Address Rudower chaussee 17 12489 Berlin Germany See on map Region Berlin Berlin Berlin Activity type Research Organisations Administrative Contact Anne Höner (Dr.) Principal investigator Thomas Jürgen Jentsch (Prof.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all FORSCHUNGSVERBUND BERLIN EV Germany EU contribution € 2 499 600,00 Address Rudower chaussee 17 12489 Berlin See on map Region Berlin Berlin Berlin Activity type Research Organisations Administrative Contact Anne Höner (Dr.) Principal investigator Thomas Jürgen Jentsch (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Other funding No data
