Project Details
Projekt
CaMKII-dependent mechanisms in RBM20 cardiomyopathy
Subject Area
Cardiology, Angiology
Cell Biology
Cell Biology
Term
from 2019 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 422319743
Dilated cardiomyopathy (DCM) is one of the major causes of heart failure. 30-50% of all DCM cases are familial, and in 3-7% of familial DCM cases a mutation in RNA-binding motif protein 20 (RBM20) seems to be the cause. RBM20 mutations often lead to a clinically aggressive form of DCM, and are associated with progressive cardiac dysfunction, disturbed cardiac Ca2+ handling, and an increased risk of malignant ventricular arrhythmias. We have previously identified misspliced CaMKIIδ as a candidate target that may contribute to the disturbed calcium handling and increased arrhythmic burden of RBM20 mutation carriers, but it is yet unknown to what extent and how misspliced CaMKIIδ contributes to this phenotype. This projects overall aim is to further unravel the molecular mechanisms that cause arrhythmias and cardiac dysfunction in RBM20 mutation carriers. In WP1, we will cross Rbm20-/- mice to CaMKIIδ-/- mice to provide proof of concept that CaMKIIδ indeed serves as a critical splicing target of RBM20. In parallel, in order to investigate why specifically the splice variant CaMKIIδA causes disturbed calcium handling and arrhythmias, we will perform unbiased IP-mass spectrometry and phospho-proteomics to identify the specific target profiles of the different cardiac CaMKIIδ splice isoforms (WP2). Third, as a translational approach, we will test the potential therapeutic strategy of lowering intracellular Ca2+ with the use of verapamil and the recently disclosed new CaMKII inhibitor GS-680 from Gilead to reduce the arrhythmia burden Rbm20-/- mice (WP3). Furthermore, we will investigate transcriptional and metabolic dysregulation in Rbm20-/- mice (WP4). Lastly, we will interrogate the contribution of CaMKII-mediated HDAC4 transcriptional regulation and how this impacts on arrhythmias and cardiac dysfunction in Rbm20-/- mice (WP5).
DFG Programme
Research Grants
