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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01HL107442-02S1
Application #
8527970
Study Section
Special Emphasis Panel (ZHL1-CSR-N (F1))
Program Officer
Jaquish, Cashell E
Project Start
2011-07-15
Project End
2016-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$72,560
Indirect Cost
$25,747
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Panopoulos, Athanasia D; D'Antonio, Matteo; Benaglio, Paola et al. (2017) iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types. Stem Cell Reports 8:1086-1100
van Vliet, Patrick P; Lin, Lizhu; Boogerd, Cornelis J et al. (2017) Tissue specific requirements for WNT11 in developing outflow tract and dorsal mesenchymal protrusion. Dev Biol 429:249-259
DeBoever, Christopher; Li, He; Jakubosky, David et al. (2017) Large-Scale Profiling Reveals the Influence of Genetic Variation on Gene Expression in Human Induced Pluripotent Stem Cells. Cell Stem Cell 20:533-546.e7
Lindström, Sara; Germain, Marine; Crous-Bou, Marta et al. (2017) Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study. Hum Genet 136:897-902
Panopoulos, Athanasia D; Smith, Erin N; Arias, Angelo D et al. (2017) Aberrant DNA Methylation in Human iPSCs Associates with MYC-Binding Motifs in a Clone-Specific Manner Independent of Genetics. Cell Stem Cell 20:505-517.e6
Nariai, Naoki; Greenwald, William W; DeBoever, Christopher et al. (2017) Efficient Prioritization of Multiple Causal eQTL Variants via Sparse Polygenic Modeling. Genetics 207:1301-1312
D'Antonio, Matteo; Woodruff, Grace; Nathanson, Jason L et al. (2017) High-Throughput and Cost-Effective Characterization of Induced Pluripotent Stem Cells. Stem Cell Reports 8:1101-1111
Panopoulos, Athanasia D; D'Antonio, Matteo; Benaglio, Paola et al. (2017) iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types. Stem Cell Reports :
Greenwald, William W; Li, He; Smith, Erin N et al. (2017) Pgltools: a genomic arithmetic tool suite for manipulation of Hi-C peak and other chromatin interaction data. BMC Bioinformatics 18:207
D'Antonio, Matteo; Woodruff, Grace; Nathanson, Jason L et al. (2017) High-Throughput and Cost-Effective Characterization of Induced Pluripotent Stem Cells. Stem Cell Reports :

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