INTESTINAL MUCOSAL GROWTH IN HEALTH & SURGICAL DISEASE

胃肠粘膜生长抑制是常见的疾病 病情危重，包括各种外科疾病。数据来自 调查员的实验室和其他人表明，向 细胞分裂是正常肠道调节的重要步骤 粘膜生长和细胞多胺的减少抑制了细胞的更新。 这个项目的目标是阐明 多胺对肠粘膜更新过程的损害 耗尽。假设是多胺合成的抑制抑制了 通过改变P53基因的表达来促进肠粘膜生长。四 具体目标是：1)识别表达之间的关系 活体小肠粘膜中P53基因的表达与生长抑制 确定细胞多胺在肠道P53基因表达中的作用 体外培养的隐窝细胞。调查人员将首先定义 多胺对P53基因表达的影响发生并集中在 了解多胺调节转录后蛋白的机制 P53基因，3)确定P53基因表达增加在 多胺耗尽后的生长抑制。调查人员将 确定是通过反义寡核苷酸还是通过 通过转染条件p53表达载体提高P53水平 在存在或不存在的情况下改变肠上皮细胞生长 多胺，4)以确定P53导致 多胺耗尽后的生长抑制。调查人员将 P21cip1/waf1在P53介导的肠道抑制中的作用 多胺缺乏细胞中上皮细胞的增殖。调查人员 建议这些研究将加强对黑猩猩生物学的了解 肠粘膜生长和对病理生理学有更广泛的影响 在危重疾病中的粘膜生长抑制。

The inhibition of gastrointestinal mucosal growth occurs commonly in critical illness including a variety of surgical conditions. Data from the Investigator's laboratory and others indicate that the supply of polyamines to the dividing cells is an important step in the regulation of normal intestinal mucosal growth and that decreasing cellular polyamines inhibits cell renewal. The goal of this project is to elucidate the fundamental mechanisms by which the intestinal mucosal renewal process is impaired following polyamine depletion. The hypothesis is that inhibition of polyamine synthesis suppresses intestinal mucosal growth by altering expression of the p53 gene. Four specific aims are proposed: 1) to identify the relationship between expression of the p53 gene and growth inhibition in small intestinal mucosa in vivo, 2) to determine the role of cellular polyamines in p53 gene expression in intestinal crypt cells in vitro. The Investigators will first define the level where the effect of polyamines on p53 gene expression occurs and then concentrate on understanding the mechanism by which polyamines modulate post-transcription of the p53 gene, 3) to determine the role of increased p53 gene expression in growth inhibition following polyamine depletion. The Investigators will determine whether decreasing p53 levels by antisense oligonucleotides or increasing p53 levels by transfecting a conditional p53 expression vector alters intestinal epithelial cell growth in the presence or absence of polyamines, 4) to identify the basic mechanism by which p53 results in the growth inhibition following polyamine depletion. The Investigators will elucidate the role of p21cip1/waf1 in p53-mediated inhibition of intestinal epithelial cell proliferation in polyamine-deficient cells. The Investigators propose that these studies will enhance understanding of the biology of intestinal mucosal growth and have broader implications for the pathophysiology of mucosal growth inhibition in critical illness.