At The HEart of laminopathies: development of subtype-specific cardiomyocyte models to unravel distinct cellular mechanisms of LMNA-cardiomyopathy (ATHENA)

Central focus of the proposal is LMNA-Cardiomyopathy (LMNA-CMP), an inherited form of cardiomyopathy – a disease of the heart muscle – caused by mutations in the Lamin A/C gene (LMNA). LMNA-CMP is part of a group of diseases, called laminopathies, characterized by diverse clinically-distinct phenotypes, mostly tissue-specific. The main cardiac phenotype is dilated cardiomyopathy associated with various conduction abnormalities and arrhythmias, which can show extremely heterogeneous presentation, regardless of the type of mutation. Indeed, heterogeneity is a hallmark in all laminopathies, and the underlying mechanism is yet to be established.
Similarly, the biological functions of Lamin A/C in the heart are still under-assessed, and knowledge gained so far mostly comes from animal models and non-cardiac cells, which can lack some tissue-specific Lamin A/C functions. While Lamin A/C role as structural component of the nucleus and in the nucleo-cytoscheletal coupling is well established, the understanding of their action as modulators of gene transcription is still at its infancy, especially in cardiac cells.  
Main goal of this proposal is to determine whether Lamin A/C may have distinct roles in the diverse cardiomyocytes subtypes composing the myocardium (atrial, ventricular, sino-atrial node cells) and verify whether these distinct functions may be at the basis of the heterogenous manifestation of the disease.
To this aim, we will employ cell-specific models generated through differentiation of induced pluripotent stem cells and integrate a comprehensive set of functional and molecular methodologies, to identify new disease mechanisms and targets for the development of more specific therapies for LMNA-CMP.