Surgical Studies of Ontogeny, Aging and the Gut

胃肠(GI)激素调节许多重要的生理功能，包括肠道分泌、运动 和营养物质的消化。此外，某些肠道激素已被证明能刺激粘膜的增殖。 神经降压素(NT)是一种重要的调节激素，定位于成人专门的肠内分泌细胞(N细胞) 小肠，促进脂肪酸移位，影响肠道运动、分泌和粘膜生长。我们的研究成果 NT基因(指定为NT/N)被认为是帮助定义复杂分化的一个优秀的分子模型 肠道发育和成熟的途径以及“去分化”的过程 癌症。在胃肠道中，NT/N基因的表达受严格的时间和空间特异性调控。 NT/N基因表达和NT多肽分泌的诱导受信号通路的调节，但尚不清楚 完全定义好了。NT通过其细胞表面受体(NTR)作用，激活一系列信号通路， 从而导致正常肠粘膜的增殖。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的调节，并依赖于信号通路的组合。 下游转录因子的激活，在某些情况下，基因甲基化；NT多肽分泌可能是 通过调节基因表达的相似信号途径来调节。确定这些监管机制 对于更好地了解正常的肠道内稳态和受 新界别。为了检验这一假说，我们计划进行实验，具体目的如下：1)进一步阐明 体内NT/N表达的机制：2)阐明调控NT/N的信号机制 基因诱导，3)确定NT多肽分泌的机制，4)进一步评估增殖性 NT对肠道的影响。了解调节NT/N表达和NT肽分泌的因素将提供 关于一种重要的肠道激素的功能及其对靶组织的影响的新的和重要的信息， 如正常肠粘膜。对导致“模型”表达的细胞过程的深入分析 Nal基因NT/N有助于更好地了解肠道的正常发育和功能 某些细胞因子会导致肠道肿瘤。

Gastrointestinal (GI) hormones regulatea numberofimportantphysiologic functions, includingintestinalsecretion,motility and digestion ofnutrients. In addition,certain intestinal hormones havebeen shown to stimulategutmucosal proliferation. Neurotensin (NT), an importantregulatory hormone localized to specialized enterocndocrine cells (Ncells) of theadult small bowel,facilitatesfatty acid translocationand affects gut motility, secretion and mucosal growth. Our studieshave identified the NT gene (designated NT/N) as an excellent molecular model to help define the complex differentiation pathways leading to gut development and maturationas wellas the process of "dedifferentiation" noted incertaincolon cancers. Expression of the NT/N gene is regulated in a strict temporal- and spatial-specific patern 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 proliferationof normal gut mucosa. The central hypothesis of our proposal continues to bethat NT/N gene expression is developmentallyregulatedin the gut and isdependent upon acombinationof signaling pathways, activation of downstream transcription factors, and, in certaininstances,gene methylation; NT peptide secretion may be mediated by similar signalingpathwaysthat regulate gene expression. Identifying these regulatory mechanismsare critical to a better understanding of normal intestinal homeostasis and the function of target tissues that are affected by NT. To examine thishypothesis,we haveplannedexperiments with the following Specific Aims: 1)to further elucidate the mechanisms contributingto NT/N expression in vivo, 2) to delineate the signaling mechanisms regulating NT/N gene induction,3) to define the mechanisms contributingto NT peptide secretion, 4) to further assess proliferateve effects of NT in the gut. Understanding the factors regulating NT/N expression and NT peptide secretion will provide novel and importantinformation regarding the function of an important intestinal hormone and its effects on target tissues, such as normal gut mucosa. The in-depth analysisof the cellular processes leading to the expression of the "model" intest;nal gene NT/N will provide a better understanding of normal gut development and function as well aspossibly defini ngcertain cellularevents leadingto gut neoplasia.