REGULATION OF THE GASTRIC INHIBITORY PEPTIDE GENE

胃抑制肽（GIP）是由胃粘膜分泌的42个氨基酸的激素， K细胞是一种特殊的肠内分泌上皮细胞， 因为它能抑制胃酸分泌随后对其进行分析， 生理特性已经证明GIP是一种有效的刺激剂， 内源性胰岛素的释放，它在 维持葡萄糖和脂质的体内平衡。这些研究建立了 GIP作为代谢功能的生理调节剂， 消化道和其他器官之间的联系，包括肝脏 和胰腺。尽管它在营养代谢中很重要， 关于GIP基因调控的信息是可获得的。因为荷尔蒙 基因表达可以在几个不同的步骤沿着 生物合成途径，分子机制的彻底分析 参与营养调控的GIP生物合成将大大提高我们的 了解这种重要肽的生物学。本 建议，我们将继续从检查GIP基因 体内表达，通过测量营养后十二指肠GIP mRNA 施用，以评估营养调节的十二指肠GIP基因 转录。最后，在提案的最后部分， 控制GIP基因转录的分子机制将是 研究了具体而言，该项目的目标是： (1)为了研究GIP基因表达的营养依赖性调控， 通过测定大鼠十二指肠粘膜GIP和GIP mRNA水平， 对葡萄糖、脂质和蛋白质膳食的反应。 在检测GIP基因后， 在翻译前水平的调节， (2)检测GIP基因在大鼠十二指肠的转录， 使用体外核连续测定进行营养物施用。后 证明了对营养调节的基因转录的影响， (3)目的：分离大鼠GIP基因，并对其进行鉴定，该基因沿着 下一个目标，将有助于确定和划定 基因中推定的转录调控元件，和 (4)研究GIP基因的基础转录和营养刺激转录 并确定参与营养依赖和 GIP基因的组织特异性转录调控。 总的来说，从本提案中获得的信息将增加一个 对我们理解分子机制的重要新维度 参与营养素对GIP基因的调控。此外，由于 GIP与其他GI肽的结构和功能关系密切， 这些研究将促进我们对分子生物学的全面理解。 参与营养调节激素基因表达的机制。 最后，这些研究应该使我们能够探索的可能性， GIP基因调控的差异可能有助于 以胃酸异常为特征的疾病的发病机制 分泌以及葡萄糖和脂质体内平衡。

Gastric inhibitory peptide (GIP) is a 42-amino acid hormone secreted by the K-cell, a specific intestinal endocrine epithelial cell, and was named for its ability to inhibit acid secretion. Subsequent analysis of its physiological properties has demonstrated that GIP is a potent stimulator of endogenous insulin release and that it plays an important role in maintaining glucose and lipid homeostasis. These studies have established GIP as a physiological modulator of metabolic function, providing a vital link between the alimentary tract and other organs, including the liver and pancreas. Despite its importance in nutrient metabolism, little information regarding GIP gene regulation is available. Because hormone gene expression can be modulated at several different steps along the biosynthetic pathway, a thorough analysis of the molecular mechanisms involved in nutrient-regulated GIP biosynthesis would greatly improve our understanding of the biology of this important peptide. In the present proposal, we will proceed sequentially from an examination of GIP gene expression in vivo, by measuring duodenal GIP mRNA after nutrient administration, to an assessment of nutrient-regulated duodenal GIP gene transcription. Finally, during the last portion of the proposal, the molecular mechanisms governing GIP gene transcription will be investigated. Specifically, the aims of this project are: (1) To study nutrient-dependent regulation of GIP gene expression in the rat duodenum by measuring duodenal mucosal GIP and GIP mRNA levels in response to glucose, lipid, and protein meals. After examining GIP gene regulation at the pretranslational level, (2) To examine GIP gene transcription in the rat duodenum following nutrient administration using in vitro nuclear run-on assays. After demonstrating an effect on nutrient-regulated gene transcription, (3) To isolate and characterize the rat GIP gene, which, along with the next goal, will facilitate the identification of and delineation of putative transcriptional regulatory elements in the gene, and (4) To investigate basal and nutrient-stimulated GIP gene transcription and determine the molecular mechanisms involved in nutrient-dependent and tissue-specific transcriptional regulation of the GIP gene. Collectively, the information gained from this proposal will add a significant new dimension to our understanding of the molecular mechanisms involved in GIP gene regulation by nutrients. Moreover, because of the close structural and functional relationship of GIP to other GI peptides, such studies will advance our general understanding of the molecular mechanisms involved in nutrient-regulated hormone gene expression. Finally, these studies should enable us to explore the possibility of differences in GIP gene regulation that could contribute to the pathogenesis of disorders characterized by abnormalities in gastric acid secretion and glucose and lipid homeostasis.