REGULATION OF THE GASTRIC INHIBITORY PEPTIDE GENE

胃抑制肽(GIP)是由人分泌的一种由42个氨基酸组成的激素。 K细胞，一种特殊的肠道内分泌上皮细胞，被命名为 因为它有抑制酸分泌的能力。对ITS的后续分析 生理特性表明，GIP是一种有效的刺激物 内源性胰岛素的释放，并且它在 维持血糖和血脂动态平衡。这些研究已经确立了 GIP作为代谢功能的生理调节剂，提供了至关重要的 消化道和包括肝脏在内的其他器官之间的联系 还有胰腺。尽管它在营养代谢中很重要，但几乎没有 关于GIP基因调控的信息是可用的。因为荷尔蒙 基因的表达可以在几个不同的步骤中进行调节 生物合成途径，深入分析分子机制 参与营养调节的GIP生物合成将极大地改善我们的 了解这种重要多肽的生物学特性。在现在 提案，我们将从GIP基因的检测开始顺序进行 通过测定营养后十二指肠GIP mRNA在体内的表达 对营养调节的十二指肠GIP基因的评价 抄写。最后，在提案的最后部分， 控制GIP基因转录的分子机制将是 调查过了。具体地说，该项目的目标是： (1)研究GIP基因表达的营养依赖性调控。 大鼠十二指肠黏膜GIP和GIP mRNA水平的测定 对葡萄糖、脂肪和蛋白质餐的反应。在检测了GIP基因之后 翻译前层面的监管， (2)检测大鼠十二指肠组织GIP基因转录。 使用体外核连续试验进行营养管理。之后 证明了对营养调节基因转录的影响， (3)分离和鉴定大鼠GIP基因。 下一个目标，将有助于确定和描述 基因中可能的转录调控元件，以及 (4)研究基础和营养刺激下的GIP基因转录 并确定了与营养依赖和 GIP基因的组织特异性转录调控。 总的来说，从这项提案中获得的信息将增加一个 我们对分子机制的理解有了新的意义 参与营养物质对GIP基因的调控。此外，由于 GIP与其他胃肠肽的结构和功能关系密切， 这样的研究将促进我们对分子的总体理解。 涉及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 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 分泌和糖脂的动态平衡。

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.