We study the pathogenic mechanisms of cardiac disease due to mutation in nuclear factors,
all the while working towards a cardioprotective therapy
all the while working towards a cardioprotective therapy
Ongoing Projects
We are studying how Mendelian disease mutations and common genetic variants functionally affect intra and inter-chromosomal nuclear structure in the heart
In collaboration with the Brancaccio lab, we are using hiPSCs to identify druggable mechanisms in the the cardioprotective pathway downstream of Melusin
We are studying how Mendelian disease mutations and common genetic variants functionally affect intra and inter-chromosomal nuclear structure in the heart
In collaboration with the Brancaccio lab, we are using hiPSCs to identify druggable mechanisms in the the cardioprotective pathway downstream of Melusin
Earlier Contributions
We performed disease modelling experiments using hiPSC-CMs from patients with cardiac laminopathy, a dilated cardiomyopathy (DCM) with severe conduction disease due to mutations in LMNA, which encodes for the nuclear intermediate filament proteins Lamin A/C. We specifically tested the so-called “chromatin hypothesis”, which postulates that laminopathy is driven by alterations in gene expression that are due to aberrant chromatin compartmentalization. We examined the effect of a lamin A/C haploinsufficient mutation, revealing that this markedly alters electrophysiology, contractility, gene expression, and chromosomal topology. Contrary to expectations, however, changes in chromatin compartments involved just few regions, and most dysregulated genes lie outside these hotspots. Exception included the gene encoding for neuronal P/Q-type calcium channel CACNA1A, whose current contributes to the electrophysiological abnormalities in hiPSC-CMs. We also collaborated with the Di Pasquale and Condorelli groups to examine the effect of a lamin A/C missense mutation, which we demonstrated to induce selective epigenetic silencing of the fast sodium channel gene SCN5A and thus aberrant action potential generation and propagation.
We also performed disease modeling of DCM due to mutations in the muscle specific splicing factor RBM20. By collaborating with the Salomonis and Conklin labs, we showed that missense RBM20 mutations in the RS domain "hotspot" lead to accumulation of RBM20 in cytoplasm processing bodies and stress granules. This not only dysregulating alternative splicing, but possibly mediates protein aggregate-mediated cardiotoxicity.
We leveraged on mouse models to begin dissecting the molecular mechanisms involved in the cardioprotective ability of the muscle-specific protein Melusin, whose activity was still largely an enigma. We performed biochemical, pharmacological, and mouse genetic experiments that provided key contributions to: (1) demonstrate that Melusin responds to mechanical stimuli by leading to the activation of ERK1/2 through physical interactions with FAK and the scaffold protein IQGAP1; (2) determine the essential function of IQGAP1 in the cardiac hypertrophic response. These findings have shed light on a novel cardioprotective pathway that has a strong potential for translational applications.
We performed disease modelling experiments using hiPSC-CMs from patients with cardiac laminopathy, a dilated cardiomyopathy (DCM) with severe conduction disease due to mutations in LMNA, which encodes for the nuclear intermediate filament proteins Lamin A/C. We specifically tested the so-called “chromatin hypothesis”, which postulates that laminopathy is driven by alterations in gene expression that are due to aberrant chromatin compartmentalization. We examined the effect of a lamin A/C haploinsufficient mutation, revealing that this markedly alters electrophysiology, contractility, gene expression, and chromosomal topology. Contrary to expectations, however, changes in chromatin compartments involved just few regions, and most dysregulated genes lie outside these hotspots. Exception included the gene encoding for neuronal P/Q-type calcium channel CACNA1A, whose current contributes to the electrophysiological abnormalities in hiPSC-CMs. We also collaborated with the Di Pasquale and Condorelli groups to examine the effect of a lamin A/C missense mutation, which we demonstrated to induce selective epigenetic silencing of the fast sodium channel gene SCN5A and thus aberrant action potential generation and propagation.
We also performed disease modeling of DCM due to mutations in the muscle specific splicing factor RBM20. By collaborating with the Salomonis and Conklin labs, we showed that missense RBM20 mutations in the RS domain "hotspot" lead to accumulation of RBM20 in cytoplasm processing bodies and stress granules. This not only dysregulating alternative splicing, but possibly mediates protein aggregate-mediated cardiotoxicity.
We leveraged on mouse models to begin dissecting the molecular mechanisms involved in the cardioprotective ability of the muscle-specific protein Melusin, whose activity was still largely an enigma. We performed biochemical, pharmacological, and mouse genetic experiments that provided key contributions to: (1) demonstrate that Melusin responds to mechanical stimuli by leading to the activation of ERK1/2 through physical interactions with FAK and the scaffold protein IQGAP1; (2) determine the essential function of IQGAP1 in the cardiac hypertrophic response. These findings have shed light on a novel cardioprotective pathway that has a strong potential for translational applications.