The overarching goal of our project is to use IPSC derived cardiomyocytes from genotyped individuals as cellular models to investigate how human genetic variation influences the gene regulatory networks Involved In cardiac biology and disease. Despite current treatment regimens, cardiovascular diseases remain the leading cause of morbidity and mortality in the United States and developed countries. Genome-wide association studies have identified a number of loci associated with cardiovascular disease susceptibility. Our Study will clarify the functional significance of these findings by combining cellular reprogramming Strategies with integrated molecular profiling and cellular assays. We have assembled a team of highly accomplished researchers in stem cell biology, cardiac cell biology, genomics, molecular genetics/epigenetics, biostatistics, and clinical medicine, and are well positioned to achieve the project goals within five years. After collecting fibroblasts and keratinocytes from individuals in the UCSD TSP cohort, the project will be carried out in three phases. In PHASE I, we will establish standardized reagents and procedures for the generation of iPSCs. Additionally, we will take advantage of our ongoing research efforts to increase the efficiency of cardiomyocyte differentiation to 80%, a substantial increase over current protocols (~20%). In PHASE II, we will develop cutting-edge technologies for high throughput generation of IPSCs, which will enable us to generate 600 iPSC lines (3 lines each from 200 individuals) in ~ 24 months. We will also scale our optimized protocols for deriving cardiomyocytes from the IPSC lines. In PHASE III we will initially perform validation experiments to measure the genomic profile variability between isogenic (derived from the same individual) cardiomyocytes. We will then use the derived cardiomyocytes to 1) Identify and characterize the causal DNA variants underlying strong GWAS signals with electrocardiographic traits;and 2) Identify expressed quantitative traits loci (eQTL) in the cohort of IPSC derived cardiomyocytes at baseline (untreated) and after stimulation.

National Institute of Health (NIH)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Jaquish, Cashell E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
Zip Code
Sancho-Martinez, Ignacio; Nivet, Emmanuel; Xia, Yun et al. (2016) Establishment of human iPSC-based models for the study and targeting of glioma initiating cells. Nat Commun 7:10743
Hashem, Sherin I; Perry, Cynthia N; Bauer, Matthieu et al. (2015) Brief Report: Oxidative Stress Mediates Cardiomyocyte Apoptosis in a Human Model of Danon Disease and Heart Failure. Stem Cells 33:2343-50
Kurian, Leo; Aguirre, Aitor; Sancho-Martinez, Ignacio et al. (2015) Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development. Circulation 131:1278-90
Hansson, Magnus L; Albert, Silvia; González Somermeyer, Louisa et al. (2015) Efficient delivery and functional expression of transfected modified mRNA in human embryonic stem cell-derived retinal pigmented epithelial cells. J Biol Chem 290:5661-72
Krause, Marie N; Sancho-Martinez, Ignacio; Izpisua Belmonte, Juan Carlos (2015) RE: stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy. J Natl Cancer Inst 107:368
Pulecio, Julian; Nivet, Emmanuel; Sancho-Martinez, Ignacio et al. (2014) Conversion of human fibroblasts into monocyte-like progenitor cells. Stem Cells 32:2923-38
Aguirre, Aitor; Montserrat, Nuria; Zacchigna, Serena et al. (2014) In vivo activation of a conserved microRNA program induces mammalian heart regeneration. Cell Stem Cell 15:589-604
Lyon, Robert C; Mezzano, Valeria; Wright, Adam T et al. (2014) Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model. Hum Mol Genet 23:1134-50
Gorkin, David U; Leung, Danny; Ren, Bing (2014) The 3D genome in transcriptional regulation and pluripotency. Cell Stem Cell 14:762-75
Zhu, Xiping; Fu, Lina; Yi, Fei et al. (2014) Regeneration: making muscle from hPSCs. Cell Res 24:1159-61

Showing the most recent 10 out of 33 publications