IDENTIFICATION & FUNCTIONAL CHARACTERIZATION OF SNPS IN RXRA GENE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该项目的总体目标是：确定类维生素A-X-受体α（RXR α）基因的遗传多态性，确定美国人群中的主要单倍型，并表征所定义的单倍型对RXR α靶基因表达的转录调控的功能影响。主要假设是RXR α基因的遗传多态性存在于美国人群中;这些多态性在不同种族群体中以特定的单倍型组织;可能导致RXR α基因表达个体间变异的单倍型尚未确定;并且这种变异可能通过改变转录调控引起RXR α靶基因表达的差异。RXR α是9-顺式-视黄酸的核受体，在基因转录调控中起核心作用。RXR α与其他视黄酸受体（RAR α、β和γ）形成异二聚体，导致各种类视黄酸介导的信号通路的激活，以控制正常细胞分化和增殖。RXR α在肝脏中高度表达，其中不同的含有RXR α的异二聚体（FXR、PXR、CAR、PPARalpha、PPARgamma等）在肝脏中表达。与靶基因启动子中的特异性DNA反应元件结合，以调节其转录并控制重要功能，如维持葡萄糖和脂质稳态、胆汁酸合成和药物代谢。本研究的主要目的有三：（1）识别遗传多态性通过对来自四个主要的美国种族群体（高加索人、非洲裔美国人、东亚人和墨西哥裔美国人）的100名人类受试者进行测序，在RXR α基因的外显子、内含子/外显子边界、3 ′-非翻译区和5 ′-启动子区中检测（主要是单核苷酸多态性，SNP）;（2）通过对来自4个主要美国种族群体的400个样本（每个群体100个）中均匀分布在RXR α基因中的12-15个鉴定的SNP进行基因分型来确定主要单倍型模式;（3）通过使用体外和体内方法来表征所定义的单倍型对RXR α靶基因表达的功能影响。在这个项目完成后，我们希望了解我们的人群中存在哪些遗传多态性，它们如何在不同的单倍型中组织，以及它们如何影响RXRa靶基因的表达。

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 (RXRalpha) gene, determine major haplotypes in American populations, and characterize functional effects of the defined haplotypes on the transcriptional regulation of RXRalpha-target-gene expression. The main hypothesis is that genetic polymorphisms in the RXRalpha 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 RXRalpha-gene expression, have not yet been defined; and that such variations may cause differences of RXRalpha-target-gene expression by altering transcriptional regulation. RXRalpha is a nuclear receptor for 9-cis-retinoic acid and plays a central role for gene transcriptional regulation. RXRalpha forms heterodimers with the other retinoic-acid receptors (RARalpha, beta, and gamma) resulting in activation of various retinoid-mediated-signal pathways for controlling normal cell differentiation and proliferation. RXRalpha is highly expressed in liver, where different RXRalpha-containing heterodimers (FXR, PXR, CAR, PPARalpha, PPARgamma, 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 RXRalpha 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 RXRalpha 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.