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Ion homeostasis and volume regulation of cells and organelles

Ion homeostasis and volume regulation of cells and organelles

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.
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Principal Investigator

Thomas Jürgen Jentsch (Prof.)

Host institution

FORSCHUNGSVERBUND BERLIN EV

Address

Rudower Chaussee 17
12489 Berlin

Germany

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 499 600

Principal Investigator

Thomas Jürgen Jentsch (Prof.)

Administrative Contact

Anne Höner (Dr.)

Beneficiaries (1)

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FORSCHUNGSVERBUND BERLIN EV

Germany

EU Contribution

€ 2 499 600

Project information

Grant agreement ID: 294435

Status

Closed project

  • Start date

    1 April 2012

  • End date

    31 March 2017

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 2 499 600

  • EU contribution

    € 2 499 600

Hosted by:

FORSCHUNGSVERBUND BERLIN EV

Germany