The discovery of new and effective treatments for human cardiovascular diseases requires the Identification and validation of novel disease mechanisms. Recently, studies of genomic variation entered a new phase. In which unbiased genome-wide association studies (GWAS) can identify novel genetic loci associated with common diseases. We have recently described 95 loci associate with blood lipid levels-LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), or triglycerides, which are strongly associated with risk for myocardial infarction (Ml) In the NHLBl Framingham Heart Study (FHS) and other population cohorts. Much work will be needed to convert the novel associations into functional insights and, ultimately, therapies to reduce the risk of Ml. A key step is to determine how these genetic loci affect phenotypes in human tissue types relevant to lipid metabolism, principally liver and adipose. We have performed expression quantitative trait locus (eQTL) analyses of genotype vs. gene expression in surgical liver and adipose tissue samples from patients;from this work, we found a strong association between an LDL-C- and Ml-associated SNP on chromosome 1p13-rs12740374-and hepatic expression of the S0RT1 gene. However, these studies were limited by scarcity of tissue and the inability to address key cellular phenotypes such as lipoprotein secretion. Thus, there is a need to establish infinitely renewable sources of hepatocytes and adipocytes from patients of defined genotypes. We have developed the ability to obtain reprogrammed induced pluripotent stem (IPS) cells via peripheral blood cell (PBC) collection. We have also developed a novel technology to accelerate and scale up IPS generation, without any genomic alteration, using in vitro transcribed RNAs encoding reprogramming factors. Finally, we have established protocols to differentiate iPS cells into functional hepatocytes and adipocytes. Our consortium comprises investigators from the FHS, the Harvard Stem Cell Institute (HSCI), Massachusetts General Hospital (MGH), and Harvard Medical School (HMS). We are uniquely positioned to develop a library of IPS cell lines and iPS- derived hepatocytes and adipocytes from several hundred FHS participants, who have genome-wide genotype data as well as many cardiovascular phenotypes. We propose to leverage these resources to: (1) develop efficient protocols to obtain IPS cell lines from blood samples, followed by differentiation into functional hepatocytes and adipocytes;(2) scale up these protocols to enable high-throughput generation of IPS cell lines, hepatocytes, and adipocytes from ~400 Individuals In the Framingham Offspring Cohort;and (3) perform gene expression and metaboiomic profiling from these hepatocytes and adipocytes, enabling Integrative statistical analyses of genotypes with gene expression and metabolite levels, as well as existing phenotype data such as subclinical measures of atherosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHL1)
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Srinivas, Pothur R
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Massachusetts General Hospital
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Hendriks, William T; Warren, Curtis R; Cowan, Chad A (2016) Genome Editing in Human Pluripotent Stem Cells: Approaches, Pitfalls, and Solutions. Cell Stem Cell 18:53-65
Yu, Haojie; Cowan, Chad A (2016) Minireview: Genome Editing of Human Pluripotent Stem Cells for Modeling Metabolic Disease. Mol Endocrinol 30:575-86
Gutierrez-Martinez, Paula; Rossi, Derrick J; Beerman, Isabel (2016) DNA Damage and Aging Around the Clock. Trends Mol Med 22:635-7
Dykstra, Brad; Lee, Jungmin; Mortensen, Luke J et al. (2016) Glycoengineering of E-Selectin Ligands by Intracellular versus Extracellular Fucosylation Differentially Affects Osteotropism of Human Mesenchymal Stem Cells. Stem Cells 34:2501-2511
Peters, Derek T; Henderson, Christopher A; Warren, Curtis R et al. (2016) Asialoglycoprotein receptor 1 is a specific cell-surface marker for isolating hepatocytes derived from human pluripotent stem cells. Development 143:1475-81
Cheng, Susan; Larson, Martin G; McCabe, Elizabeth L et al. (2015) Distinct metabolomic signatures are associated with longevity in humans. Nat Commun 6:6791
Vedantham, Vasanth; Galang, Giselle; Evangelista, Melissa et al. (2015) RNA sequencing of mouse sinoatrial node reveals an upstream regulatory role for Islet-1 in cardiac pacemaker cells. Circ Res 116:797-803
TaÅŸan, Murat; Musso, Gabriel; Hao, Tong et al. (2015) Selecting causal genes from genome-wide association studies via functionally coherent subnetworks. Nat Methods 12:154-9
Zou, Jun; Tran, Diana; Baalbaki, Mai et al. (2015) An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish. Elife 4:e09406
Deo, Rahul C (2015) Machine Learning in Medicine. Circulation 132:1920-30

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