The incidence of obesity and a cluster of disorders associated with obesity such as type 2 diabetes, hepatosteatosis, dyslipidemia and cardiovascular disease have risen to alarming proportions and there is great need for effective therapeutic and preventive measures against these health threats. Metabolic disorders often affect an intertwined network of signaling and metabolic pathways and it is crucial to understand the interactions of these pathways in a patient-specific setting for drug target discovery and therapy development. We have obtained diabetes patient skin fibroblasts with insulin receptor mutations and Dunning-type familial partial lipodystrophy samples with lamin A/C mutation, and have converted them into iPS cells. Using transcription activator-like effector nucleases (TALENs) technology, we are also producing iPS cells carrying a known mutation in the promoter region of peroxisome proliferators-activated receptor γcoactivator 1αpolymorphism (PPARGC1A) that is associated with hepatosteatosis. We are differentiating these iPS cells into hepatocytes or adipocytes. We will screen for altered metabolic and signaling pathways in these functional metabolic cells with known mutations and confirm their pathological role in immunodeficient NSG mice that are engrafted with the control and mutant cells.

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Project End
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Budget End
Support Year
2
Fiscal Year
2013
Total Cost
$550,467
Indirect Cost
Name
National Heart, Lung, and Blood Institute
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Type
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Ruan, Xiangbo; Li, Ping; Cao, Haiming (2018) Identification of Transcriptional Regulators That Bind to Long Noncoding RNAs by RNA Pull-Down and RNA Immunoprecipitation. Methods Mol Biol 1783:185-191
Yamazaki, Tomoko; Li, Wenling; Yang, Ling et al. (2018) Whole-Mount Adult Ear Skin Imaging Reveals Defective Neuro-Vascular Branching Morphogenesis in Obese and Type 2 Diabetic Mouse Models. Sci Rep 8:430
Yang, Ling; Li, Ping; Yang, Wenjing et al. (2016) Integrative Transcriptome Analyses of Metabolic Responses in Mice Define Pivotal LncRNA Metabolic Regulators. Cell Metab 24:627-639
Ruan, Xiangbo; Li, Ping; Cangelosi, Andrew et al. (2016) A Long Non-coding RNA, lncLGR, Regulates Hepatic Glucokinase Expression and Glycogen Storage during Fasting. Cell Rep 14:1867-75
Li, Ping; Ruan, Xiangbo; Yang, Ling et al. (2015) A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice. Cell Metab 21:455-67
Cao, Haiming (2014) Adipocytokines in obesity and metabolic disease. J Endocrinol 220:T47-59