Surgical Studies of Ontogeny, Aging and the Gut

描述（由申请人提供）：胃肠道（GI）激素调节 许多重要的生理功能，包括肠道分泌， 运动和消化营养物质。此外，某些肠道激素 已经显示刺激肠粘膜增殖。神经降压素（NT）， 定位于特化肠内分泌细胞（N）的重要调节激素 细胞），促进脂肪酸易位， 影响肠道运动、分泌和粘膜生长。我们的研究发现 NT基因（命名为NT/N）作为一个很好的分子模型，以帮助定义 导致肠道发育和成熟的复杂分化途径 以及在某些结肠癌中注意到的“去分化”过程。 NT/N基因的表达受到严格的时间和生物学调控。 胃肠道中的空间特异性模式。NT/N基因表达的诱导和 NT肽的分泌受信号传导途径的调节， 完全定义。NT通过其细胞表面受体（NTR）起作用， 激活了一系列信号通路， 正常的肠粘膜。我们建议的核心假设仍然是 NT/N基因表达在肠道中受到发育调控， 依赖于信号通路的组合，下游信号通路的激活， 转录因子，并且在某些情况下，基因甲基化; NT肽 分泌可能是由调节基因的类似信号通路介导的。 表情确定这些监管机制对于更好地 了解正常肠道稳态和靶点功能 受NT影响的组织。为了验证这一假设，我们计划 具有以下具体目的的实验：1）进一步阐明 有助于NT/N在体内表达的机制，2）描绘 调节NT/N基因诱导的信号传导机制，3）确定 有助于NT肽分泌的机制，4）进一步评估 NT在肠道中的增殖作用。了解调节因素 NT/N表达和NT肽分泌将提供新的和重要的 关于一种重要的肠道激素的功能及其 对靶组织如正常肠粘膜的作用。深入分析 导致“模型”肠基因表达的细胞过程 NT/N将提供对正常肠道发育和功能的更好理解 以及可能定义导致肠道肿瘤的某些细胞事件。

DESCRIPTION (provided by applicant): Gastrointestinal (GI) hormones regulate a number of important physiologic functions, including intestinal secretion, motility and digestion of nutrients. In addition, certain intestinal hormones have been shown to stimulate gut mucosal proliferation. Neurotensin (NT), an important regulatory hormone localized to specialized enteroendocrine cells (N cells) of the adult small bowel, facilitates fatty acid translocation and affects gut motility, secretion and mucosal growth. Our studies have identified the NT gene (designated NT/N) as an excellent molecular model to help define the complex differentiation pathways leading to gut development and maturation as well as the process of "dedifferentiation" noted in certain colon cancers. Expression of the NT/N gene is regulated in a strict temporal- and spatial-specific pattern in the GI tract. Induction of NT/N gene expression and NT peptide secretion is regulated by signaling pathways which have yet to be completely defined. NT, acting through its cell-surface receptor (NTR), activates a cascade of signaling pathways, which results in the proliferation of normal gut mucosa. The central hypothesis of our proposal continues to be that NT/N gene expression is developmentally regulated in the gut and is dependent upon a combination of signaling pathways, activation of downstream transcription factors, and, in certain instances, gene methylation; NT peptide secretion may be mediated by similar signaling pathways that regulate gene expression. Identifying these regulatory mechanisms are critical to a better understanding of normal intestinal homeostasis and the function of target tissues that are affected by NT. To examine this hypothesis, we have planned experiments with the following Specific Aims: 1) to further elucidate the mechanisms contributing to NT/N expression in vivo, 2) to delineate the signaling mechanisms regulating NT/N gene induction, 3) to define the mechanisms contributing to NT peptide secretion, 4) to further assess proliferative effects of NT in the gut. Understanding the factors regulating NT/N expression and NT peptide secretion will provide novel and important information regarding the function of an important intestinal hormone and its effects on target tissues, such as normal gut mucosa. The in-depth analysis of the cellular processes leading to the expression of the "model" intestinal gene NT/N will provide a better understanding of normal gut development and function as well as possibly defining certain cellular events leading to gut neoplasia.