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.

Public Health Relevance

; 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130020-02
Application #
9196384
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Burns, Kristin
Project Start
2015-12-16
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Garg, Priyanka; Garg, Vivek; Shrestha, Rajani et al. (2018) Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes as Models for Cardiac Channelopathies: A Primer for Non-Electrophysiologists. Circ Res 123:224-243
Churko, Jared M; Garg, Priyanka; Treutlein, Barbara et al. (2018) Defining human cardiac transcription factor hierarchies using integrated single-cell heterogeneity analysis. Nat Commun 9:4906
Chang, Alex C Y; Chang, Andrew C H; Kirillova, Anna et al. (2018) Telomere shortening is a hallmark of genetic cardiomyopathies. Proc Natl Acad Sci U S A 115:9276-9281
Lee, Jaecheol; Shao, Ning-Yi; Paik, David T et al. (2018) SETD7 Drives Cardiac Lineage Commitment through Stage-Specific Transcriptional Activation. Cell Stem Cell 22:428-444.e5
Knowles, Joshua W; Ashley, Euan A (2018) Cardiovascular disease: The rise of the genetic risk score. PLoS Med 15:e1002546
Wnorowski, Alexa; Yang, Huaxiao; Wu, Joseph C (2018) Progress, obstacles, and limitations in the use of stem cells in organ-on-a-chip models. Adv Drug Deliv Rev :
Paik, David T; Tian, Lei; Lee, Jaecheol et al. (2018) Large-Scale Single-Cell RNA-Seq Reveals Molecular Signatures of Heterogeneous Populations of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells. Circ Res 123:443-450
Ma, Ning; Zhang, Joe Z; Itzhaki, Ilanit et al. (2018) Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells. Circulation 138:2666-2681
Liu, Chun; Oikonomopoulos, Angelos; Sayed, Nazish et al. (2018) Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development 145:
Garg, Priyanka; Oikonomopoulos, Angelos; Chen, Haodong et al. (2018) Genome Editing of Induced Pluripotent Stem Cells to Decipher Cardiac Channelopathy Variant. J Am Coll Cardiol 72:62-75

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