The successful derivation of human induced pluripotent stem cells (hiPSCs) from somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC-derived cardiac cells can now provide incredible potential for disease modeling in vitro and regenerative medicine therapies in vivo. Recently, several exciting demonstrations of the disease modeling capability of hiPSC- derived cardiac cells have been published (e.g., Timothy syndrome, LEOPARD syndrome). These patient-specific hiPSC-CMs have been found to recapitulate the disease phenotypes. In contrast to Timothy and LEOPARD syndrome (which are considered orphan diseases), familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and hence places a tremendous burden on the healthcare system in the US and worldwide. Here we seek to derive hiPSCs from patients with familial dilated cardiomyopathy (Aim 1), determine the phenotype of hiPSC-cardiac cells from DCM patients versus healthy controls (Aim 2), and evaluate their functionality after genetic rescue using homologous recombination (Aim 3). We believe the findings here should have broad clinical and scientific impact toward better understanding on the molecular and cellular basis of DCM.
Familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and places a tremendous burden on the healthcare system in the US and worldwide. From the early beginnings of the genomic era and since the description of the first familial DCM causing mutations, investigators have attempted to study its mechanistic basis by correlating genotype with clinical phenotype expression. Unfortunately, these studies have been severely hampered by the inaccessibility of human cardiomyocytes. In this grant proposal, we will generate human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with DCM. We will perform detailed and mechanistic analyses to determine the functional and molecular phenotypes of DCM. This approach will dramatically enhance our ability to perform future high-throughput drug screening, evaluate gene and cell therapies, and assess potential novel therapies of DCM.
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