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.

Public Health Relevance

This study will provide much needed information to understand the complex cardiomyopathy induced by LMNA mutations. LMNA cardiolaminopathy is a common cause of familial cardiac disease, accounting for 6% of all cases, and more than 160 mutations have been identified as pathogenic. However, the detailed molecular mechanisms LMNA cardiolaminopathy remain elusive due to lack of appropriate disease models. In the proposed studies, we will use induced pluripotent stem cells (iPSCs) from LMNA cardiolaminopathy patients and genome-edited isogenic iPSC lines to elucidate the molecular pathogenesis. Our preliminary data have revealed specific deregulated signaling pathways in LMNA iPSC-CMs and iPSC-ECs that might represent potential targets for focused drug screening assays. Results obtained here may provide further insights into the molecular pathogenesis of LMNA cardiolaminopathy and promote the development of novel therapeutic drugs that can rescue the disease phenotype.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Wong, Renee P
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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