Project R-4151

Title

ElecXite: Molecular and Cellular Mechanisms of Electrical Excitability in the Heart and Central Nervous System

Abstract

In Europe, the challenges of an ageing population dominate the health agenda. In numbers of afflicted persons and impact on health, cardiovascular diseases lead the statistics for mortality, while disorders of the central nervous system (CNS) are among the leading causes of disability in the world. To address these challenges, a broader multidisciplinary approach is required, between clinical and more basic research, and across traditional boundaries of topics. The current proposal brings together teams with different expertise and perspective but with a shared focus on electrical signaling and excitability, from basic mechanisms to clinical translation. The overall objective of the project is to gain further understanding of specific mechanisms in electrical excitability in the heart and CNS focusing on complex molecular mechanisms, examining the associated cell physiology, as well as more integrative physiology and pathophysiology in vivo, complemented by in silico modeling. The participating labs have in-depth expertise in specific aspects of excitability, ion channels and ion transporters in normal and diseased tissue: structure-function relations of channels and their complexes (P3, P5), cardiac excitability and remodeling with disease (Karin Sipido, KULeuven), modulation of ion channel activity through specific ligands (Jan Tytgat, KULeuven), physiology and pharmacology of CNS ion channels (Vincent Seuting, ULg), intercellular communication and hemichannels (Luc Leybaert, UGent), inhibitory ionotropic receptors and neuroglia channels (Jean-Michel Rigo, UHasselt), synaptic plasticity and CNS network activity (Serge Schiffmann, ULB), integrative modeling of excitability and cardiac arrhythmias (A. Panfilov, UGent). The inclusion of European labs adds expertise in arrhythmias at a more integrated level (Marc Vos, Universiteit Utrecht), as well as ischemic heart disease (Rainer Schultz, Justus-Liebig Universität Giessen) and synaptic transmission in the CNS (Neil Marrion, Bristol University). At different levels, we initiate translational approaches exploring diagnostic potential and therapeutic targets. Exchange of junior scientists across the network generates a broad training platform while joint activities enhance visibility of the multidisciplinary approach. The network objectives remain centered on joint research programs, exchange of expertise, shared tools, training of junior scientists and enhanced external communication and impact. The overall research objective is translated in 5 work packages. 1. Molecular architecture of ion channels, macrocomplexes and multi-channel interactions 2. Mechanisms of normal and abnormal pacemaking 3. Linking Ca2+ homeostasis and electrical excitability 4. Ligand-gated ion channels (LGC) in plasticity of excitability 5. Exploring novel approaches and tools to gain further insight in the role of ion channels in normal and abnormal excitability

Period of project

01 April 2012 - 31 December 2017