IUAP - P7/10

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

 

Advances in treatment, improved living conditions, lifestyle and preventive measures, have led to a dramatic increase in life expectancy in affluent countries. In Europe, the challenges of an ageing population thus 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.

 

Electrical signaling through action potentials is the hallmark of excitable tissue, i.e. the central nervous system (CNS), the heart, skeletal muscle and some endocrine organs like the pancreas. Action potentials trigger complex biological signals that include short term responses, such as excitation-contraction coupling in cardiac myocytes and long term responses such as plasticity and memory in the CNS. Action potentials are generated through a concerted activity of ion channels, on a background of a negative membrane potential in the cell at rest. Ion channels form a large and complex superfamily of transmembrane spanning proteins that are shared across tissues. Tissue and cell specificity are obtained by differences in levels of expression, isoform switches and organization in macro-molecular complexes.

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 (P1), modulation of ion channel activity through specific ligands (P2), physiology and pharmacology of CNS ion channels (P3), intercellular communication and hemichannels (P4), inhibitory ionotropic receptors and neuroglia channels (P5), synaptic plasticity and CNS network activity (P6), integrative modeling of excitability and cardiac arrhythmias (A. Panfilov, P4). The inclusion of European labs adds expertise in arrhythmias at a more integrated level (INT1), as well as ischemic heart disease (INT3) and synaptic transmission in the CNS (INT2).

 

At different levels, we initiate translational approaches exploring diagnostic potential and therapeutic targets. The span across CNS and cardiac fields has already shown specific added value: since the start of our network 4 years ago we have initiated joint studies on candidate ion channels across different tissues, such as the connexin hemichannels (P4, P1) and the SK channels (P3, INT2, P5), and partners in the network bring input at a more molecular level spanning across tissues (P2, P4). Exchange of junior scientists across the network generates a broad training platform while joint activities enhance visibility of the multidisciplinary approach. We have expanded the earlier consortium with additional Belgian partners to strengthen the network with transgenic (P6) and modeling expertise (A. Panfilov at P4), as well as additional foreign partners. 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.

 

 

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