Intestinal PepT1 in Health and Disease

项目摘要 PepT 1主要表达于小肠上皮细胞刷状缘膜。 PepT 1在小肠中具有不同的表达模式。沿着垂直轴， PepT 1在绒毛尖端最丰富，表达朝向隐窝降低， 而沿着纵轴，PepT 1水平从十二指肠到回肠增加。 然而，PepT 1 mRNA或蛋白质以非常低的水平表达或不表达于细胞中。 结肠与这些发现一致，hPepT 1在小的类精氨酸细胞系中表达， Caco 2-BBE，但在结肠样细胞系HT 29-C1.19A中没有。虽然PepT 1通常不是 hPepT 1在结肠上皮细胞中表达，我们和其他人已经报道hPepT 1在结肠上皮细胞中表达， 慢性炎症结肠和短肠患者结肠粘膜的上皮细胞 综合征，证实hPepT 1表达在结肠上皮细胞中被诱导， 病理条件。最近，我们已经证明了hPepT 1可以转运蛋白质， 三肽KPV已被证明可以减少肠道炎症。我们的主要 有一种假说认为，受调控的PepT 1表达沿着隐窝绒毛轴是其生长所必需的。 营养吸收的生理作用，而异常表达在结肠下， 病理条件调节疾病表现。我们建议的第一个目标是 研究miR-619在PepT 1沿绒毛沿着差异表达中的调节作用 轴和PepT 1基因上的miR-619的序列靶标。第二，我们的目标是确定 转录因子Cdx 2和miR-619在决定结肠PepT 1水平中的作用 表达，并将在第三个目标中评估其对结肠上皮功能的影响。 了解PepT 1在小肠中的表达调控是很重要的 因为PepT 1通过PepT 1介导的二肽/三肽控制总体蛋白质吸收 运输是个人保持健康的必要条件。此外，发展 能够控制PepT 1表达的治疗策略对于肠内 营养和PepT 1介导的药物递送。最后，了解 转录和转录后机制，PepT 1可以表达在 结肠上皮细胞和这种表达的病理生理学后果。的 最终目标是确定和开发控制异常PepT 1的治疗策略 在病理条件下表达。

Project Summary PepT1 is mainly expressed in brush-border membranes of enterocytes in the small intestine. PepT1 has a differential pattern of expression in the small intestine. Along the vertical axis, PepT1 is most abundant at the villous tip, with expression decreasing towards the crypt, whereas along the longitudinal axis, the PepT1 level increases from the duodenum to the ileum. However, PepT1 mRNA or protein is expressed at very low levels or is not expressed in the colon. Consistent with these findings, hPepT1 is expressed in the small intestine-like cell line Caco2-BBE but not in the colonic-like cell line HT29-Cl.19A. Although PepT1 is not normally expressed in colonic epithelial cells, we and others have reported that hPepT1 is expressed in epithelial cells of the chronically inflamed colon and in the colonic mucosa of patients with shortbowel syndrome, confirming that hPepT1 expression is induced in colonic epithelial cells under pathological conditions. Recently, we have demonstrated that hPepT1 transports the antiinflammatory tripeptide KPV that has been shown to reduce intestinal inflammation. Our main hypothesis is that regulated PepT1 expression along the crypt¿villus axis is required for its physiological role in nutrient absorption, whereas aberrant expression in the colon under pathological conditions modulates disease manifestation. The first aim of our proposal will investigate the regulatory role of miR-619 in PepT1 differential expression along the crypt¿villus axis and the sequence target of miR-619 on the PepT1 gene. Second, we aim to determine the roles of the transcription factor Cdx2 and miR-619 in determining the levels of colonic PepT1 expression and will assess its effects on colonic epithelial functions in the third aim. It is important to understand the regulation of PepT1 expression in the small intestine because PepT1 controls overall protein absorption via the PepT1-mediated di/tripeptide transport that is essential for individuals to remain healthy. In addition, the development of therapeutic strategies capable of controlling PepT1 expression could be important for enteral nutrition and PepT1-mediated drug delivery. Finally, it is also important to understand the transcriptional and post-transcriptional mechanisms by which PepT1 can be expressed in colonic epithelial cells and the pathophysiological consequences of this expression. The ultimate goal is to identify and develop therapeutic strategies to control abnormal PepT1 expression under pathological conditions.