SURGICAL STUDIES OF ONTOGENY, AGING AND THE GUT

肠道的分化和随后的发展代表着一种 这是一个重要的临床话题，但到目前为止，人们对此知之甚少。 一组基因以有序和同步的方式打开或关闭 肠道从未分化的内胚层进化为 其成体分化形式；这些基因表达的变化是 主要由基因的激活或抑制所介导 抄写。我们之前的发现已经确定了最终的- 分化神经降压素(NT)基因(指定为NT/N)是一种优秀的 描述复杂细胞调控机制的分子模型 导致分化的特定区域表达模式 和专业化的功能。我们已经证明了NT/N表达式是 以一种独特的时间和空间-发展调节- 特定的模式；NT/N最初在胎儿中的表达很低，但 出生后迅速增长以呈现独特的成体 沿河流的地形分布随NT/N表达的增加 小肠的纵轴。在人类的结肠中，NT/N是 在胎儿中瞬时表达，但在成人中被抑制； 然而，NT/N在某些结肠癌中重新表达。中环 我们建议的假设仍然是严格的表达 肠道中的NT/N模式受到多种机制的调节，包括 主要是转录调控。为了检验这一假设，我们有 具体目标是：(L)我们将进一步 界定制约NT/N发展模式的因素 在肠子里的表情。(二)我们将确定导致 结肠癌组织中NT/N的异位表达(3)我们将描述 神经营养因子NT/N表达的增龄性变化及NT介导的生长 直觉。(4)我们将在体内分析所需的NT/N调控元件 因为肠子里的严格表达模式。为了实现这一目标，我们 将开发具有人类NT/N调控区的转基因株系 链接到报告基因，以确定需要哪些元素来 概括NT/N表达的正常发育模式。这个 我们研究的最终目标是确定分子机制。 在体内调节NT/N的表达。理解蛋白质-DNA 限制NT/N表达所需的交互作用将 提供有关监管和实现的重要信息 分化的肠道表型。此外，对这些细胞的分析 过程将不仅提供对正常肠道的更好的理解 开发和功能，但也可能提供一个模式，以更好地 阐明导致肠道肿瘤的细胞事件。

Differentiation and subsequent development of the gut represents an important clinical topic but one that is, to date, poorly understood. Sets of genes are turned on or off in an ordered and synchronized pattern as the intestine evolves from an undifferentiated endoderm into its adult differentiated form; these changes in gene expression are mediated primarily by the activation or repression of gene transcription. Our previous findings have identified the terminally- differentiated neurotensin (NT) gene (designated NT/N) as an excellent molecular model to delineate the complex cellular mechanisms regulating the region-specific patterns of expression which lead to differentiation and specialized function. We have shown that NT/N expression is developmentally regulated in a distinctive temporal- and spatial- specific pattern; NT/N expression is initially low in the fetus but rapidly increases after birth to assume the distinctive adult topographical distribution with increasing NT/N expression along the longitudinal axis of the small bowel. In the human colon, NT/N is transiently expressed in the fetus but is repressed in the adult; however, NT/N is reexpressed in certain colon cancers. The central hypothesis of our proposal continues to be that the strict expression pattern of NT/N in the gut is regulated by mechanisms which involve mainly transcriptional regulation. To examine this hypothesis we have panned experiments with the following SPECIFIC AIMS: (l) We will further define the factors regulating the developmental pattern of NT/N expression in the gut. (2) We will determine the mechanisms leading to ectopic NT/N expression in colon cancers. (3) We will characterize the age-related alterations of NT/N expression and NT-mediated growth in the gut. (4) We will analyze in vivo the NT/N regulatory elements required for the strict expression pattern in the gut. To achieve this goal, we will develop transgenic lines with the human NT/N regulatory region linked to a reporter gene to determine the elements that are required to recapitulate the normal developmental pattern of NT/N expression. The ultimate goal of our studies is to define the molecular mechanisms regulating NT/N expression in vivo. Understanding the protein-DNA interactions that are required for restricting NT/N expression will yield important information on the regulation and attainment of the differentiated gut phenotype. In addition, analysis of these cellular processes will provide a better understanding of not only normal gut development and function but may also provide a model to better elucidate the cellular events leading to gut neoplasia.