Plasma concentrations of lipids (LDL-C, HDL-C and triglycerides) are important risk factors for atherosclerotic cardiovascular disease and have proven fertile territory for genome-wide association studies (GWAS). The Global Lipids Genetics Consortium, a consortium of lipid GWAS totaling approximately 100,000 subjects, has identified a total of 95 loci that are genome-wide significantly associated with at least one plasma lipid trait. While this list includes most of the genes that are known causes of Mendelian lipid disorders, the majority are not previously associated with lipoprotein metabolism. It is key to determine how these genetic loci affect phenotypes in human tissue types relevant to lipid metabolism, especially the liver. This will lead to a greater understanding of the physiological regulation of lipoprotein metabolism and identify novel therapeutic targets for reducing LDL-C and TG and raising HDL-C. There is a need to establish infinitely renewable sources of functional hepatocytes from patients with defined genotype in order to study the cellular mechanisms by which genotype influences hepatocyte lipid biology and plasma lipid traits. We have developed the ability to use adipose stem cells (ASCs) to serve as the basis for obtaining reprogrammed induced pluripotent stem (iPS) cells and have a core dedicated to both ASC isolation and to scaling up iPS generation. Through collaboration between Penn and Medical College of Wisconsin we have established protocols for the differentiation of human iPS cells into hepatocytes. Our consortium comprises investigators expert in iPS generation, hepatocyte generation, and hepatocyte lipid metabolism. We will develop a library of iPS cell lines and iPS-derived hepatocytes from ~300 hundred subjects with defined genotypes and will use them to (1) develop highly efficient and reliable protocols to obtain iPS cell lines from ASCs, followed by differentiation into functional hepatocytes;(2) scale up these protocols to enable high- throughput generation of iPS cell lines and hepatocytes;and (3) perform metabolic profiling from these hepatocytes. These studies should provide novel insights into the molecular mechanisms by which some of the most compelling GWAS loci for plasma lipid traits influence lipoprotein metabolism.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HG006398-02
Application #
8293065
Study Section
Special Emphasis Panel (ZHL1-CSR-N (F1))
Program Officer
Bookman, Ebony B
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$1,280,948
Indirect Cost
$339,316
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Mallanna, Sunil K; Cayo, Max A; Twaroski, Kirk et al. (2016) Mapping the Cell-Surface N-Glycoproteome of Human Hepatocytes Reveals Markers for Selecting a Homogeneous Population of iPSC-Derived Hepatocytes. Stem Cell Reports 7:543-56
Lin, Jennie; Hu, Yu; Nunez, Sara et al. (2016) Transcriptome-Wide Analysis Reveals Modulation of Human Macrophage Inflammatory Phenotype Through Alternative Splicing. Arterioscler Thromb Vasc Biol 36:1434-47
Yang, Wenli; Liu, Ying; Slovik, Katherine J et al. (2015) Generation of iPSCs as a Pooled Culture Using Magnetic Activated Cell Sorting of Newly Reprogrammed Cells. PLoS One 10:e0134995
Nagaoka, Masato; Kobayashi, Motohiro; Kawai, Chie et al. (2015) Design of a Vitronectin-Based Recombinant Protein as a Defined Substrate for Differentiation of Human Pluripotent Stem Cells into Hepatocyte-Like Cells. PLoS One 10:e0136350
Twaroski, Kirk; Mallanna, Sunil K; Jing, Ran et al. (2015) FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1. Genes Dev 29:2463-74
Zhang, Hanrui; Xue, Chenyi; Shah, Rhia et al. (2015) Functional analysis and transcriptomic profiling of iPSC-derived macrophages and their application in modeling Mendelian disease. Circ Res 117:17-28
Noto, Fallon K; Determan, Megan R; Cai, Jun et al. (2014) Aneuploidy is permissive for hepatocyte-like cell differentiation from human induced pluripotent stem cells. BMC Res Notes 7:437
Shan, Jing; Schwartz, Robert E; Ross, Nathan T et al. (2013) Identification of small molecules for human hepatocyte expansion and iPS differentiation. Nat Chem Biol 9:514-20
Mallanna, Sunil K; Duncan, Stephen A (2013) Differentiation of hepatocytes from pluripotent stem cells. Curr Protoc Stem Cell Biol 26:Unit 1G.4.
Fox, Ira J; Duncan, Stephen A (2013) Engineering liver tissue from induced pluripotent stem cells: a first step in generating new organs for transplantation? Hepatology 58:2198-201

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