Objective
Diastolic dysfunction, i.e. impaired cardiac relaxation and filling, is a hallmark shared by various heart diseases, including hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). It is often driven by excessive calcium sensitivity of the cardiac myofilaments, and in HCM and HFpEF alike, is associated with disrupted adrenergic signalling, culminating in reduced responsiveness of the heart to adrenaline. In the healthy heart, adrenergic stimulation normally decreases myofilament calcium sensitivity via phosphorylation of the N-terminus of cardiac troponin I (cTnI). Remarkably, this effect can also be mimicked by truncation of the cTnI N-terminus. We recently discovered that small mammals such as bats and shrews, which have extraordinarily high cardiac demands, have evolved to skip the exon encoding the cTnI N-terminus via alternative splicing or genomic deletion. This creates a permanently desensitized cTnI, bypassing the need for sustained β-adrenergic signalling. While alternative splicing of cTnI does not naturally occur in humans or most other mammals, it could be therapeutically induced using antisense oligonucleotides (AONs) in order to increase myocardial relaxation rate. TROPOSplice aims to develop a splice-switching antisense therapeutic that induces cTnI exon 3 skipping to mimic the myofilament desensitizing effect of adrenaline, leveraging a bioinspired strategy “from bats to bedside”. Crucially, as this approach acts downstream of adrenergic receptors, it is compatible with mainstay cardiovascular treatments such as beta-blockers. We will adopt a translational approach, from cultured cardiomyocytes to in vivo mouse models, to optimise AON design and delivery and to investigate the physiological effects of induced cTnI exon 3 skipping. This project offers a novel, evolution-guided therapeutic strategy to treat diastolic dysfunction and could ultimately benefit patients with HCM, HFpEF, and related heart conditions.
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Keywords
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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.1.1 - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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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-ERC - HORIZON ERC Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2026-STG
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28029 Madrid
Spain
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