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Sarcomere inefficiency at the heart of hypertrophic cardiomyopathy.


De strijd tegen toxisch eiwit in erfelijke hartziekten

Erfelijke hartspierziekte wordt veroorzaakt door een toxisch eiwit. Wij hebben sterke aanwijzingen dat dit toxische eiwit een energietekort veroorzaakt dat leidt tot hartfalen en hartstilstand. Dit project onderzoekt de veranderingen in het hart die veroorzaakt worden door het energietekort en daardoor leiden tot nieuwe therapieën die het ziekteproces voorkomen.

Battling toxic protein in inherited cardiac disease

Inherited cardiac disease is caused by a toxic protein. We have strong indications that the toxic protein triggers an energy deficit in the heart which causes cardiac disease and sudden death. This project will establish key pathomechanisms triggered by the energy deficit leading to novel therapeutic approaches to treat disease.


Samenvatting van de aanvraag

Clinical problem: Hypertrophic cardiomyopathy (HCM) is a genetic heart disease affecting ~60,000 people in the Netherlands. Cardiomyopathy develops between 20 and 50 years of age. HCM is caused by mutations in genes encoding proteins of the sarcomere, the contractile building blocks of heart muscle. As the chain of events leading from mutation to disease is currently unknown, there is no specific treatment available. My VICI-program will define key pathomechanisms of HCM and thereby identify drug targets to treat disease. Recent studies funded by my VIDI and FP7 grants revealed that 1) mutations resulting in altered sarcomere proteins cause inefficient contraction of the heart and 2) this cardiac inefficiency is already present in mutation carriers before onset of cardiomyopathy. Based on these important findings, I hypothesize that the mutation-induced cardiac inefficiency triggers disease: it causes metabolic and mitochondrial abnormalities, which impair relaxation (diastolic dysfunction) and cause hypoperfusion of the heart before onset of hypertrophy. I have evidence that the early cellular pathomechanisms can be halted pharmacologically. Approach & innovation: We combine innovative in vivo imaging modalities with ex vivo tissue analyses in humans and mouse models to define the sequence of metabolic, mitochondrial and cardiovascular changes that lead from the mutation to disease. Basic studies using genetic and drug interventions in unique, human engineered heart tissue and HCM mouse models will establish causal relations between energy deficiency, mitochondrial dysfunction and impaired muscle relaxation. We will test the novel concept of intermittent drug-therapy as compared to chronic therapy using clinically available drugs in mouse models to translate basic findings to the clinic. Impact: My team will (1) prove the new concept of sarcomere inefficiency in the propagation of HCM and provide a comprehensive understanding of the cellular events leading to cardiomyopathy. We will (2) identify targets for therapeutic interventions to treat HCM.



Looptijd: 79%
Looptijd: 79 %
Gerelateerde subsidieronde:
Projectleider en penvoerder:
prof. dr. J. Velden
Verantwoordelijke organisatie:
Amsterdam UMC Locatie VUmc