Luminal factors affecting duodenal protection and chemosensing

影响十二指肠保护和化学传感的管腔因素

• 批准号: 8517440
• 负责人: Jonathan D. Kaunitz
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517440
• 关键词: Acids; Affect; Alkalinization; Amino Acids; Basic Science; Bicarbonates; Bile Acids; Blood flow; Brush Border; Calcium-Sensing Receptors; Cells; Chemicals; Clinical; Colon; Defense Mechanisms; Diabetes Mellitus; Dipeptidyl-Peptidase IV; Duodenum; Eating; Endocrine; Enterocytes; Enteroendocrine Cell; Enzymes; Epithelial; Funding; G-Protein-Coupled Receptors; Gastrointestinal Hormones; Glucose; Glutamates; Half-Life; Health; Hormonal; Hormone Receptor; Hormones; Hypertrophy; Ibuprofen; Individual; Inflammatory Bowel Diseases; Ingestion; Injury; Inosine Monophosphate; Intestinal Mucosa; Intestines; Investigation; L Cells; Laboratories; Ligands; Lipids; Measures; Mediating; Medicine; Metabolism; Metabotropic Glutamate Receptors; Methods; Modeling; Mucous Membrane; Mucous body substance; Non-Steroidal Anti-Inflammatory Agents; Nutrient; Peptides; Perfusion; Pharmaceutical Preparations; Plasma; Population; Proctitis; Proteins; Publications; Purines; Radiation; Rattus; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Rewards; Signal Transduction; Taste Perception; Therapeutic; Toxic effect; Translations; Ulcer; Veterans; cost; detection of nutrient; glucagon-like peptide; glucagon-like peptide 1; glucose transport; glucose uptake; improved; incretin hormone; inhibitor/antagonist; insulin secretion; interest; metabotropic glutamate receptor 4; novel; peptide hormone; purine; receptor; repaired; response; sensor; solute; sugar

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.

描述(由申请人提供)： 溃疡性肠病，如非类固醇抗炎药(NSAID)肠病、放射性直肠炎或特发性炎症性肠病，在退伍军人中很常见。到目前为止，由于缺乏疗效、成本和毒性，治疗这些疾病的方法只有一定程度上令人满意。肠道含有分泌激素的内分泌细胞，这些细胞对摄入的营养物质做出反应。我们最近发现肠营养激素类高血糖素样多肽-2(GLP-2)是对肠道中的氨基酸作出反应而分泌的。此外，GLP-2主要由糖尿病药物二肽基肽酶IV(DPPIV)代谢。因此，我们建议通过摄取适当的营养来增加GLP-2的分泌，并通过抑制DPPIV来减缓其代谢，从而增加GLP-2的全身浓度。最近，几种G蛋白偶联受体(GPCRs)在肠内分泌细胞上被发现，它们似乎与腔内营养感知有关。方法：我们用与营养感知有关的GPCRs配体灌流大鼠的肠段，以确定它们是否能刺激GLP-2的分泌。GPCRs将免疫定位于肠道。我们还将确定味觉GPCR配体是否增加了粘膜防御机制，如粘膜血流量、粘液分泌、肠细胞碱化和碳酸氢盐分泌。最后，我们将在标准REED NSAID肠病模型中联合DPPIV抑制剂给大鼠灌胃GPCRL，以确定它们是否改善NSAID胃病。