Regulation of Intestinal Nutrient Transporters

描述：(申请人提供)钠/葡萄糖共转运蛋白(SGLT1) 主要由小肠细胞表达，并运输 单糖，葡萄糖和半乳糖，穿过顶膜。作为 腔内葡萄糖和半乳糖的独家转运体，SGLT1‘S的功能是 对于充分吸收富含乳制品和其他食品的饮食是必不可少的 加工过的糖。SGLT1基因的遗传突变导致 常染色体隐性遗传病，葡萄糖/半乳糖吸收不良，典型的 出生后不久就出现了严重的危及生命的吸收不良。在……里面 SGLT1在人类中的表达，它主要被控制在 转录，在一天的模式中变化。调查员小心翼翼地 对SGLT1基因启动子-近端元件进行了解剖，并测定了其启动子-近端元件 SP1和HNF-1在不同细胞系中驱动罗勒表达的关键作用 细胞系。然而，仅靠这一区域还不足以建立 报告的荧光素酶在猪肠道中的一致表达 转基因小鼠品系。这些数据被解读为表明其他 必须存在末端调节元件才能驱动肠道特异性 SGLT1的表达。开始确定关键轨迹控制区 SGLT1基因，研究人员已经克隆了40kb的5-上游区域和 它的全部核苷酸序列已经确定。他现在提议测试 SGLT1基因表达受远端调控的假说 监管区域。这将通过实现两个具体目标来实现。第一 是确定组织特异性的DNase1超敏部位 SGLT1基因周围的区域。第二种是在体内和体内都使用 用体外模型评估被鉴定的DNA元件的潜在作用 DNase1超敏试验控制SGLT1的表达。监管机构 SGLT1基因的控制区必须含有各种核蛋白 控制其转录调控的调控元件 组织和时间的表达模式。该标识并进一步 对这些顺应性要素的表征将提供对 肠细胞特异性细胞命运的分子机制及其影响因素 调解它的监管。

DESCRIPTION: (provided by applicant) The sodium/glucose cotransporter (SGLT1) is expressed primarily by small intestinal cells and transports the monosaccharides, glucose and galactose, across the apical membrane. As the exclusive transporter of luminal glucose and galactose, SGLT1's function is essential for adequate assimilation of a diet rich in dairy products and other processed sugars. Inherited mutations of the SGLT1 gene result in the autosomal recessive disorder, glucose/galactose malabsorption, that typically presents shortly after birth with severe life-threatening malabsorption. In humans expression of SGLT1, which is controlled primarily at the level of transcription, varies in a diurnal pattern. The investigator has carefully dissected the promoter-proximal element of the SGLT1 gene and determined the critical role that SP1 and HNF-1 play in driving basil expression in various cell lines. However, this region alone is not sufficient to establish consistent expression of the luciferase reported in the intestine of transgenic mouse lines. These data were interpreted to suggest that other distal regulatory elements must exist in order to drive intestine-specific expression of SGLT1. To begin identifying the critical locus control region of the SGLT1 gene, the investigator has cloned 40 kb of the 5-upstream region and its entire nucleotide sequence has been determined. He now proposes to test the hypothesis that expression of SGLT1 gene is controlled by a distal regulatory locus. This will be done by achieving two specific aims. The first is to identify the tissue-specific DNase1 hypersensitivity sites in the regions surrounding the SGLT1 gene. The second is to use both in vivo and in vitro models to assess the potential role of the DNA elements identified by DNase1 hypersensitivity assays to control SGLT1 expression. The regulatory control regions of the SGLT1 gene must contain various nuclear protein regulatory elements that control its transcriptional regulation in a unique tissue and temporal pattern of expression. The identification and further characterization of these cis elements will provide better insight into the molecular mechanism of enterocyte-specific cell fate and the various factors mediating its regulation.