Surgical Studies of Ontogeny, Aging and the Gut

说明(申请人提供)：胃肠(GI)激素调节一些重要的生理功能，包括肠道分泌， 营养物质的运动和消化。此外，某些肠道激素 已被证明可以刺激肠道粘膜的增殖。神经降压素(NT) 重要的调节激素定位于专门的肠内分泌细胞(N 细胞)，促进脂肪酸移位和 影响肠道运动、分泌和粘膜生长。我们的研究发现 NT基因(指定为NT/N)作为一种优秀的分子模型来帮助定义 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发现的“去分化”过程。 NT/N基因的表达在严格的时间-和 胃肠道的空间特异性模式。诱导NT/N基因表达和 NT多肽的分泌受尚未被调节的信号通路的调节 完全定义好了。NT通过其细胞表面受体(NTR)起作用， 激活一系列信号通路，从而导致细胞增殖 正常的肠道粘膜。我们提案的中心假设仍然是 NT/N基因的表达在肠道中受到发育调节，并且 依赖于信号通路的组合，下游的激活 转录因子，在某些情况下，基因甲基化；NT肽 分泌可能通过类似的信号通路来调节基因 表情。确定这些监管机制对于更好地 对正常肠道内环境平衡和靶点功能的认识 受NT影响的组织。为了检验这一假设，我们计划了 有以下具体目的的实验：1)进一步阐明 促进体内NT/N表达的机制，2)描绘 调控NT/N基因诱导的信号机制，3)定义 促进NT多肽分泌的机制，4)进一步评估 NT在肠道中的增殖作用。对调控因素的认识 NT/N的表达和NT肽的分泌将提供新的和重要的 关于一种重要的肠道激素及其功能的信息 对靶组织的影响，如正常肠粘膜。深入分析了 导致“模型”肠道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.