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Cardiac Connective Tissue: Beat-by-Beat Relevance for Heart Function in Health and Disease

Objective

Cardiac connective tissue is regarded as passive in terms of cardiac electro-mechanics. However, recent evidence confirms that fibroblasts interact directly with cardiac muscle cells in a way that is likely to affect their beat-by-beat activity.

To overcome limitations of traditional approaches to exploring these interactions in native tissue, we will build and explore murine models that express functional reporters (membrane potential, Vm; calcium concentration, [Ca2+]i) in fibroblasts, to identify how they are functionally integrated in native heart (myocyte => fibroblast effects). Next, we will express light-gated ion channels in murine fibroblast, to selectively interfere with their Vm (fibroblast => myocyte effects). Fibroblast-specific observation and interference will be conducted in normal and pathologically remodelled tissue, to characterise fibroblast relevance for heart function in health & disease.

Based on these studies, we will generate 2 transgenic rabbits (fibroblast Vm reporting / interfering). Rabbit cardiac structure-function is more amenable to translational work, e.g. to study fibroblast involvement in normal origin & spread of excitation across the heart, in pathological settings such as arrhythmogenicity of post-infarct scars (a leading causes of sudden death), or as a determinant of therapeutic outcomes such as in healing of atrial ablation lines (interfering with a key interventions to treat atrial fibrillation).

The final ‘blue-skies’ study will assess whether modulation of cardiac activity, from ‘tuning’ of biological pacemaker rates to ‘unpinning’ / termination of re-entrant excitation waves, can be achieved by targeting not myocytes, but fibroblasts.

The study integrates basic-science-driven discovery research into mechanisms and dynamics of biophysical myocyte-fibroblast interactions, generation of novel transgenic models useful for a broad range of studies, and elucidation of conceptually new approaches to heart rhythm management.

Call for proposal

ERC-2012-ADG_20120314
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Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

UNIVERSITAETSKLINIKUM FREIBURG
Address
Hugstetter Strasse 49
79106 Freiburg
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 723 100,65
Principal investigator
Peter Kohl (Prof.)
Administrative Contact
Gerhard Henninger (Mr.)

Beneficiaries (2)

UNIVERSITAETSKLINIKUM FREIBURG
Germany
EU contribution
€ 1 723 100,65
Address
Hugstetter Strasse 49
79106 Freiburg
Activity type
Higher or Secondary Education Establishments
Principal investigator
Peter Kohl (Prof.)
Administrative Contact
Gerhard Henninger (Mr.)
IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE

Participation ended

United Kingdom
EU contribution
€ 775 511,75
Address
South Kensington Campus Exhibition Road
SW7 2AZ London
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Scott Wheatley (Mr.)