Utrecht researchers Magdalena Harakalova, Frank van Steenbeek, Folkert Asselbergs and Jeroen Bakkers have received prestigious funding to further build the infrastructure around genetic cardiomyopathies, serious diseases of the heart muscle.
Researchers from the groups of Folkert Asselbergs and Magdalena Harakalova (UMC Utrecht), Jeroen Bakkers (Hubrecht Institute) and Frédéric Vaz (Amsterdam UMC) received €936,000 from the ZonMw Open Competition program for their CONTRACT project. They will investigate how mutations in the PLN gene affect the energy supply of the heart. The results will contribute to the development of new treatments for heart muscle diseases.
Cardiomyopathies are a group of diseases that severely affect the heart muscle, which can lead to heart failure and death. The phospholamban R14 deletion (PLN-R14del or PLN) is the most common mutation related to cardiomyopathy in the Netherlands. Carriers of this mutation have a high risk of developing heart failure. However, despite decades of research, very little is known about the mechanisms underlying this devastating disease.
With the CONTRACT project, researchers from UMC Utrecht, the Hubrecht Institute and Amsterdam UMC want to investigate the consequences of PLN mutations on the heart. To this end, they have developed two disease models – a human stem cell model and a zebrafish model.
With these models, the researchers aim to elucidate how mutations in PLN can affect the heart’s energy supply. The results will provide insight into the mechanisms underlying pathological changes in the heart, and help identify new risk factors and potential treatments.
The ZonMw funding will allow the collaborative project to continue for the next four years, with room for 2 PhD students and one postdoc. In addition, the researchers can use the grant to purchase a new device for screening heart muscle cells and zebrafish larvae.
A multicenter PROPER-THERAPY team consisting of Jolanda van der Velden (VUMC), Riekelt Houtkooper (AMC), Diederik Kuster (VUMC), Magdalena Harakalova (UMC Utrecht), Frank van Steenbeek (Utrecht University/UMC Utrecht), Miranda Nabben (MUMC), Daphne Merkus (Erasmus MC), Andreas Dendorfer (LMU Munich) and Michiel Helmes (Ionoptix) received €859.014 from NWO Human Measurement Models 2.0 to perform disease modeling and treatment trials on 2D/3D models of iPSC cardiomyocytes for carriers of MYBPC3 and VLCAD mutations causing cardiomyopathies.
Hereditary heart muscle diseases such as hypertrophic cardiomyopathy (HCM) are common worldwide. HCM is a heterogeneous disease: the severity of the disease and response to drugs varies greatly between patients, even between patients with the same genetic defect. This project will simulate severe HCM phenotypes using stem cell technology to create better human heart models.
PROPER-THERAPY will validate stem cell models by comparing them with patient material and patient data. This model will be exposed to various metabolic stressors and drugs to show the effectiveness of the stem cell models in patient-specific treatment strategies.
Artificial intelligence is being applied to build a high-throughput system in which drugs can be screened. Validating these human heart models is an essential first step toward clinical applications of stem cell technologies to tailor treatments for patients with inherited heart disease.
