Human Induced Pluripotent Stem Cells for Cardiovascular Disease Modeling

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PROJECT SUMMARY Among the familial cardiomyopathies, cardiac laminopathy caused by LMNA mutations accounts for approximately 6% of all cases. Compared to other DCM patients with left ventricular dilation, LMNA cardiolaminopathy patients exhibit a severe clinical course, conduction abnormalities, and a high rate of heart failure. LMNA DCM has a complex pathophysiology and it has been hypothesized that this form of cardiac disease is due to defects in function of cardiomyocytes (CMs) as well as defects in non-CM populations such as endothelial cells (ECs). However, the detailed molecular mechanisms of LMNA cardiolaminopathy remain elusive due to limited patient-derived bio-specimens and lack of appropriate disease models. To overcome the problem, in this R01 grant renewal application, we will generate human induced pluripotent stem cell- derived cardiomyocytes (iPSC-CMs) from LMNA DCM patients as well as matched family controls and healthy unrelated controls. To clarify the detailed molecular mechanisms, we will conduct structural, electrophysiological, developmental, transcriptome, and mechanistic analyses using patient-specific as well as genome-edited isogenic iPSC-CMs and iPSC-ECs. Importantly, we will perform drug screening studies targeting dysregulated signaling pathways. To confirm the beneficial action of identified targeting compounds, we will then conduct transcriptomic and functional analysis of isogenic LMNA iPSC-CM and iPSC-ECs using high throughput platforms. Collectively, these studies will uncover mechanistic insights of LMNA cardiolaminopathy, a major cause of DCM, which may help identify novel therapeutic candidates that can target CMs and ECs, two key cell populations.