Luminal factors affecting duodenal protection and chemosensing

描述（由申请人提供）： 溃疡性肠病，如非甾体抗炎药（NSAID）肠病，放射性直肠炎或特发性炎症性肠病是常见的退伍军人群体。到目前为止，由于缺乏疗效、成本和毒性，这些病症的治疗仅在一定程度上令人满意。肠道内含有内分泌细胞，它们分泌激素以响应摄入的营养。我们最近发现，胰高血糖素样肽-2（GLP-2）是响应肠中的氨基酸而分泌的。此外，GLP-2主要由二肽基肽酶IV（DPPIV）（一种糖尿病药物）代谢。因此，我们建议通过摄入适当的营养素来增强GLP-2的分泌，并通过DPPIV抑制来减缓其代谢，从而增加GLP-2的全身浓度。最近，几个G蛋白偶联受体（GPCR）已被确定肠内分泌细胞，似乎参与腔营养传感。研究方法：我们将用与营养感测有关的GPCR的配体灌注大鼠的肠段，以确定它们是否引起GLP-2分泌。GPCR将免疫定位于肠道。我们还将确定味觉GPCR配体是否增加粘膜防御机制，例如粘膜血流、粘液分泌、肠上皮细胞碱化和碳酸氢盐分泌。最后，我们将通过管饲法将GPCR配体与DPPIV抑制剂一起给予标准参考NSAID肠病模型中的大鼠，以确定它们是否改善NSAID胃病。

DESCRIPTION (provided by applicant): Ulcerative enteropathies, such as nonsteroidal anti-inflammatory drug (NSAID) enteropathy, radiation proctitis or idiopathic inflammatory bowel disease are common among the veteran population. Thus far, the treatments for these conditions is only somewhat satisfactory due to lack of efficacy, cost, and toxicity. The gut contains endocrine cells that secrete hormones in response to ingested nutrients. We have found recently that the intestinotrophic hormones glucagon-like peptide-2 (GLP-2) is secreted in response to amino acids in the intestine. Furthermore, GLP-2 is metabolized principally by the enzyme dipeptidyl peptidase IV (DPPIV), a diabetes drug. We therefore propose to augment GLP-2 systemic concentrations by enhancing its secretion by the ingestion of the appropriate nutrients and by slowing its metabolism with DPPIV inhibition. Recently, several G-protein-coupled receptors (GPCRs) have been identified on enteroendocrine cells that appear to be involved with luminal nutrient sensing. Methods: We will perfuse intestinal segments of rats with ligands of GPCRs implicated in nutrient sensing in order to determine if they elicit GLP-2 secretion. GPCRs will be immunolocalized to the gut. We will also determine if taste GPCR ligands increase mucosal defense mechanism such as mucosal blood flow, mucus secretion, enterocyte alkalinization, and, bicarbonate secretion. Last, we will give GPCR ligands by gavage to rats in a standard refed NSAID enteropathy model in conjunction with DPPIV inhibitors in order to determine if they ameliorate NSAID gastropathy.