Surgical Studies of Ontogeny, Aging and the Gut

胃肠激素调节许多重要的生理功能，包括胃肠分泌、运动 和营养的消化。此外，某些肠激素已被证明刺激肠粘膜增生。 神经降压素（NT）是一种重要的调节激素，定位于成体肠内分泌细胞（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 确定了NT基因（指定NT/N）作为一个很好的分子模型，以帮助确定复杂的分化 导致肠道发育和成熟的途径以及“去分化”的过程 癌的NT/N基因的表达在胃肠道中以严格的时间和空间特异性模式进行调节。 NT/N基因表达和NT肽分泌的诱导受信号通路调节，这些信号通路尚未被阐明。 完全定义。NT通过其细胞表面受体（NTR）起作用，激活一系列信号通路， which哪一个results结果in the proliferation增殖of normal正常gut肠mucosa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节，并依赖于信号通路的结合， 下游转录因子的激活，以及在某些情况下，基因甲基化; NT肽的分泌可能是 由调节基因表达的类似信号通路介导。识别这些调节机制是 这对于更好地理解正常肠内稳态和受肠内稳态影响的靶组织的功能至关重要。 NT。为了验证这一假设，我们计划了以下具体目标的实验：1）进一步阐明 NT/N在体内的表达机制; 2）阐明NT/N的信号转导机制 基因诱导，3）确定NT肽分泌的机制，4）进一步评估增殖性T细胞， NT在肠道中的作用了解调节NT/N表达和NT肽分泌的因素将提供 关于一种重要的肠激素的功能及其对靶组织的作用的新的和重要的信息， 例如正常肠粘膜。深入分析导致“模型”表达的细胞过程 肠道基因NT/N的研究将有助于更好地了解正常肠道的发育和功能， 确定某些导致肠道肿瘤的细胞事件。

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.