Among the congenital cardiomyopathies, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and left ventricular non-compaction (LVNC) are the most prevalent forms. These cardiomyopathies cause either dilated (systolic) or restrictive (diastolic) physiology, life-threatening arrhythmias, and increased risk or thromboembolism. It is well known that many genetic causes are overlapping among DCM, HCM and LVNC; however, the prediction of specific phenotype is not yet possible because of lack of understanding on their molecular mechanisms. To overcome the problem, in this R01 grant, we will generate human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients with inherited DCM, HCM and LVNC as well as matched family controls and healthy unrelated controls. In order to clarify the detailed genotype-phenotype correlations, we will elucidate structural, electrophysiological, developmental, transcriptome, and mechanistic analyses using these patient-specific lines as well as genome-edited isogenic iPSC lines. Importantly, we will also perform studies among groups that manifest (a) same disease phenotype but different mutation genes, and (b) different disease phenotype which have different mutant alleles in the same genes. Collectively, these studies will uncover not only phenotype- specific underlying pathogenesis but also the mutation-specific pathogenesis in common genetic causes of congenital cardiomyopathies.
; This study will provide much needed information on understanding the complexity of the genotype- phenotype correlation in congenital cardiomyopathies. In particular, LVNC, DCM and HCM are the three major causes of congenital cardiomyopathies. However, development of disease-specific phenotypes for these 3 conditions is not clearly understood because of lack of tissue accessibility. Here we will use induced pluripotent stem cells (iPSCs) from congenital cardiomyopathy patients and genome-edited isogenic iPSC lines to help us elucidate the genotype-phenotype pathogenesis. Results obtained here may help provide us with important clues for the estimation of severity as well as the development of disease- specific intervention strategies.
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