Nuclear envelope stress in laminopathy patient-derived cardiomyocytes (NStrC).

Dilated cardiomyopathy is the primary cause of heart transplants worldwide. Hereditary variants of the disease are driven by mutations in the LMNA gene, which encodes A-type lamins, structural components of the nuclear envelope (NE). The pleiotropic nature of lamins and the limited availability of patient material complicate the identification of pathological processes underlying heart failure. We and others have shown that lamin perturbations predispose cells for nuclear dysmorphy and rupture, which compromises cell homeostasis and elicits DNA damage. We hypothesize that this so-called NE stress represents a common hallmark of cardiac laminopathies. Hence, we intend to gauge the impact of pathogenic lamin variants on this process in a cellular model that is relevant to the disease. To this end, we will generate induced pluripotent stem cell-derived cardiomyocytes from cardiac patient fibroblasts harboring diverse LMNA mutations. In these cells, we will quantify structural defects of the NE and its susceptibility to rupture with advanced microscopy. In addition, we will perform a comparative transcriptomics experiment to reveal gene regulatory programs that accompany NE stress and evaluate the influence of two major NE stress elicitors by pharmacological modulation. This way, we intend to expose the role of NE stress in the development of cardiac laminopathies and unveil potential leads for its therapeutic targeting.

Keywords:CARDIOMYOPATHY, NUCLEUS, LAMINOPATHIES, MICROSCOPY

Disciplines:Cytoskeleton, Data visualisation and high-throughput image analysis, Cardiology, Stem cell biology, Molecular and cell biology not elsewhere classified