Project description
How FLNC deficiency causes heart mechano-electric dysfunction
Heart failure affects 2-3 % of the Western population, with dilated cardiomyopathy (DCM) being a major contributor to both morbidity and mortality. DCM is associated with mutations in cytoskeletal proteins, which can result in mechanical pump failure and sudden cardiac death. Studies have shown that genetic mutations and reduced levels of filamin C (FLNC) are linked to an increased risk of arrhythmias and sudden death. Supported by the Marie Skłodowska-Curie Actions programme, the RhythMEC project will investigate how FLNC deficiency leads to mechanical and electrical dysfunction in the heart. The research will employ experimental and mathematical models to explore these processes from the protein level to the whole organ.
Objective
Heart failure is a major cause of death in the Western world, with an estimated prevalence of 2-3\% of the population. A subgroup of heart failure patients is characterised by dilated cardiomyopathy (DCM) which results in substantial morbidity and mortality due to progressive mechanical pump failure (70\%) or sudden cardiac death from ill-predictable electrical disturbances (30\%). DCM is commonly linked to mutations encoding cytoskeletal proteins, but our understanding of why a loss of cardiac myocyte cytoskeletal integrity in inherited DCM phenotypes results in detrimental changes to calcium handling, and how this causes arrhythmias and sudden cardiac death, remains limited. Human studies have associated genetic mutations and loss in the cytoskeletal protein filamin C (FLNC) with arrhythmogenic DCM and sudden death. To explore the biomechanical and mechano-electric mechanisms by which FLNC deficiency leads to mechanical and electrical dysfunction, I will use experimental and mathematical models that span multiple spatial and temporal scales from the protein level up to the whole heart. I hypothesise that FLNC regulates myofilament lattice spacing and that loss of this structure leads to impaired contractile force development by the sarcomere. I postulate that these perturbations in mechanics may contribute to the generation of substrate for the induction and maintenance of lethal ventricular arrhythmias via a variety of mechano-electric coupling mechanisms. Particularly, stretch-induced alterations may affect cardiomyocyte electrophysiology, which may contribute to both the trigger and the substrate for arrhythmias. Thus, altered myocardial mechanics in the FLNC-null mouse model of DCM may contribute to the triggering or maintenance of life-threatening reentrant ventricular arrhythmias via a variety of mechano-electric coupling mechanisms.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences clinical medicine cardiology cardiovascular diseases cardiac arrhythmia
- social sciences sociology demography mortality
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-GF - HORIZON TMA MSCA Postdoctoral Fellowships - Global Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2023-PF-01
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79098 Freiburg
Germany
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