Intestinal PepT1 in Health and Disease

肠道 PepT1 在健康和疾病中的作用

• 批准号: 8413086
• 负责人: DIDIER MERLIN
• 金额: $ 24.23万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413086
• 关键词: Intestinal; PepT1; Health; Disease

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.

项目概要 PepT1 主要表达于小肠肠细胞的刷状缘膜中。 PepT1 在小肠中具有不同的表达模式， PepT1 在绒毛尖端最丰富，向隐窝表达逐渐减少， 而沿着纵轴，PepT1 水平从十二指肠到回肠逐渐增加。 然而，PepT1 mRNA 或蛋白质的表达水平非常低，或者在细胞中不表达。 与这些发现一致的是，hPepT1 在小肠样细胞系中表达。 Caco2-BBE 但不在结肠样细胞系 HT29-Cl.19A 中，尽管 PepT1 通常不存在。 hPepT1 在结肠上皮细胞中表达，我们和其他人报道 hPepT1 在 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 hPepT1 表达在结肠上皮细胞中被诱导 最近，我们已经证明 hPepT1 转运抗炎物质。 三肽 KPV 已被证明可以减少肠道炎症。 假设是沿着隐窝调节 PepT1 表达¿绒毛轴是其所必需的 在营养吸收中发挥生理作用，而在结肠中异常表达 我们建议的首要目标是病理条件调节疾病表现。 研究 miR-619 在 PepT1 沿隐窝差异表达中的调节作用¿绒毛 其次，我们的目标是确定 PepT1 基因上的 miR-619 的轴和序列目标。 转录因子 Cdx2 和 miR-619 在确定结肠 PepT1 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。 了解小肠中 PepT1 表达的调节非常重要 因为 PepT1 通过 PepT1 介导的二肽/三肽控制总体蛋白质吸收 此外，交通对于个人保持健康至关重要。 能够控制 PepT1 表达的治疗策略对于肠内治疗可能很重要 最后，了解营养和 PepT1 介导的药物输送也很重要。 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。 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。