This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The overall goals of this project are to: identify genetic polymorphisms in the retinoid-X-receptor a (RXRa) gene, determine major haplotypes in American populations, and characterize functional effects of the defined haplotypes on the transcriptional regulation of RXRa-target-gene expression. The main hypothesis is that genetic polymorphisms in the RXRa gene exist in American populations; these polymorphisms are organized in specific haplotypes in different ethnic groups; that the haplotypes, which may contribute to inter-individual variations of RXRcc-gene expression, have not yet been defined; and that such variations may cause differences of RXRa-target-gene expression by altering transcriptional regulation. RXRa is a nuclear receptor for 9-cis-retinoic acid and plays a central role for gene transcriptional regulation. RXRa forms heterodimers with the other retinoic-acid receptors (RARa, p, and y) resulting in activation of various retinoid-mediated-signal pathways for controlling normal cell differentiation and proliferation. RXRa is highly expressed in liver, where different RXRa-containing heterodimers (FXR, PXR, CAR, PPARa, PPARy, etc.) bind to specific DNA- response elements in the promoters of target genes, to regulate their transcription and to control important functions, such as the maintenance of glucose and lipid homeostasis, synthesis of bile acids, and the metabolism of drugs.
Three specific aims will be addressed in this project: (1) to identify genetic polymorphisms (mostly single nucleotide polymorphisms, SNPs) in exons, intron/exon boundaries, 3'-untranslated region, and 5'-promoter region of the RXRa gene by sequencing 100 human subjects from the four major American ethnic groups: Caucasian, African-American, East-Asian and Mexican-American; (2) To determine major haplotype patterns by genotyping 12-15 identified SNPs evenly distributed in the RXRa gene in 400 samples from the 4 major American ethnic groups (100 from each); (3) to characterize functional effects of the defined haplotypes on RXRa-target-gene expression by using both in vitro and in vivo approaches. After completion of this project, we expect to learn what genetic polymorphisms exist in our population, how they are organized in different haplotypes, and how they affect RXRa-target-gene expression.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR021940-02
Application #
7610776
Study Section
Special Emphasis Panel (ZRR1-RI-8 (01))
Project Start
2007-05-01
Project End
2008-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2007
Total Cost
$226,846
Indirect Cost
Name
University of Kansas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Zhao, Jie; Adams, Abby; Roberts, Ben et al. (2018) Protein arginine methyl transferase 1- and Jumonji C domain-containing protein 6-dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice. Hepatology 67:1109-1126
Butler, Merlin G; Hossain, Waheeda A; Tessman, Robert et al. (2018) Preliminary observations of mitochondrial dysfunction in Prader-Willi syndrome. Am J Med Genet A 176:2587-2594
Wang, Yifeng; Li, Jibiao; Matye, David et al. (2018) Bile acids regulate cysteine catabolism and glutathione regeneration to modulate hepatic sensitivity to oxidative injury. JCI Insight 3:
Wang, Yifeng; Matye, David; Nguyen, Nga et al. (2018) HNF4? Regulates CSAD to Couple Hepatic Taurine Production to Bile Acid Synthesis in Mice. Gene Expr 18:187-196
Kumar, Dhruv; New, Jacob; Vishwakarma, Vikalp et al. (2018) Cancer-Associated Fibroblasts Drive Glycolysis in a Targetable Signaling Loop Implicated in Head and Neck Squamous Cell Carcinoma Progression. Cancer Res 78:3769-3782
Borude, Prachi; Bhushan, Bharat; Apte, Udayan (2018) DNA Damage Response Regulates Initiation of Liver Regeneration Following Acetaminophen Overdose. Gene Expr 18:115-123
Huck, Ian; Beggs, Kevin; Apte, Udayan (2018) Paradoxical Protective Effect of Perfluorooctanesulfonic Acid Against High-Fat Diet-Induced Hepatic Steatosis in Mice. Int J Toxicol 37:383-392
Jiang, Lu; Fang, Pingping; Septer, Seth et al. (2018) Inhibition of Mast Cell Degranulation With Cromolyn Sodium Exhibits Organ-Specific Effects in Polycystic Kidney (PCK) Rats. Int J Toxicol 37:308-326
Wang, Yifeng; Ding, Wen-Xing; Li, Tiangang (2018) Cholesterol and bile acid-mediated regulation of autophagy in fatty liver diseases and atherosclerosis. Biochim Biophys Acta Mol Cell Biol Lipids 1863:726-733
Li, Jibiao; Chen, Cheng; Li, Yuan et al. (2017) Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3T3-L1 adipocytes. Biochim Biophys Acta Mol Basis Dis 1863:2924-2933

Showing the most recent 10 out of 366 publications