Intestinal PepT1 in Health and Disease

项目摘要 PepT1主要表达在小肠的肠细胞刷状缘膜上。 PepT1在小肠中有不同的表达模式。沿着垂直轴， PepT1在绒毛顶端最丰富，向隐窝表达逐渐减少， 而在纵轴方向上，PepT1水平从十二指肠到回肠逐渐升高。 然而，PepT1的mRNA或蛋白在非常低的水平表达，或者在 冒号。与这些发现一致的是，hPepT1在小肠样细胞系中表达 在结肠样细胞系HT29-Cl.19A中未见表达。尽管PepT1不是正常的 在结肠上皮细胞中表达，我们和其他人已经报道了hPepT1在 慢性炎症性结肠和短肠患者结肠黏膜上皮细胞 综合征，证实hPepT1在结肠上皮细胞中被诱导表达。 病理情况。最近，我们发现hPepT1转运抗炎物质。 已被证明可以减少肠道炎症的三肽KPV。我们的Main 假设PepT1沿隐窝绒毛轴的调节表达是其必需的 在营养吸收中的生理作用，而在结肠中的异常表达 病理条件调节疾病的表现。我们建议的第一个目标是 研究miR-619在PepT1沿隐窝绒毛差异表达中的调节作用 Axis和PepT1基因上miR-619的序列靶点。第二，我们的目标是确定 转录因子CDX2和miR-619在决定结肠PepT1水平中的作用 并将在第三个目标中评估其对结肠上皮功能的影响。 了解PepT1在小肠中的表达调控非常重要 因为PepT1通过PepT1介导的二/三肽控制蛋白质的整体吸收 对个人保持健康至关重要的交通工具。此外，还包括 能够控制PepT1表达的治疗策略对肠道可能很重要 营养和PepT1介导的药物传递。最后，了解 PepT1表达的转录和转录后机制 结肠上皮细胞及其表达的病理生理学后果。这个 最终目标是确定和开发控制异常PepT1的治疗策略 病理条件下的表达。

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.