This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.
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