Intestinal Mucosal Growth in Health & Surgical Diseases

肠粘膜生长的抑制通常发生在各种严重的外科疾病中。以来 涉及粘膜生长调节的机制仍然不清楚，维持粘膜生长的有效疗法是， 严重外科疾病患者的粘膜上皮完整性有限，导致粘膜萎缩， 延迟愈合、屏障功能受损和细菌移位。在上一个资助期内，我们 已经确定，肠粘膜隐窝中的分裂细胞的多胺供应， 这是正常粘膜生长所必需的，多胺的减少会抑制细胞增殖， 在关键的手术条件下稳定p53和其他生长抑制蛋白。但具体 多胺在分子水平上调节p53稳定性的机制仍不清楚， 这是竞争性更新应用程序的重点。我们的初步结果表明，d）多胺缺乏， 诱导核磷蛋白（NPM）蛋白，和V）通过siRNA策略抑制NPM使p53不稳定， 降低多胺缺陷细胞中p53依赖性转录活性。根据这些观察，我们 假设多胺缺失诱导的NPM与p53相互作用并稳定p53，从而介导 在关键外科条件下抑制肠粘膜生长。提出了三个具体目标来测试 假设。1)确定细胞多胺调节NPM活性的分子机制。 2)表征多胺耗竭后NPM与p53的功能和物理相互作用。3)到 确定NPM/p53相互作用在调节肠粘膜生长中的作用和机制， 在存在或不存在细胞多胺的情况下，在外科疾病期间的细胞凋亡。完成这些 具体的目的将提供关于在外科手术下控制肠粘膜生长的新信息， 条件希望这些研究将确定潜在的治疗靶点和药物， 将来用于维持危重外科疾病患者的肠粘膜完整性。

Inhibition of intestinal mucosal growth occurs commonly in various critical surgical disorders. Since the mechanisms involved in regulation of mucosal growth are still obscure, effective therapies to maintain the mucosal epithelial integrity in patients with critical surgical illnesses are limited, leading to mucosal atrophy, delayed healing, impaired barrier function, and bacterial translocation. During previous funding period, we have established that a supply of polyamines to the dividing cells in the crypts of the intestinal mucosa is absolutely required for normal mucosal growth and that decreased polyamines inhibit cell proliferation by stabilizing p53 and other growth-inhibiting proteins in critical surgical conditions. However, the exact mechanisms by which polyamines modulate p53 stability at the molecular level remain unclear and are the focus of this competitive renewal application. Our preliminary results indicate that d) polyamine depletion induces nucleophosmin (NPM) protein and V) inhibition of NPM by siRNA strategy destabilizes p53 and decreases p53-dependent transcriptional activity in polyamine-deficient cells. Based on these observations, we HYPOTHESIZE that polyamine depletion-induced NPM interacts with and stabilizes p53, thus mediating inhibition of intestinal mucosal growth in critical surgical conditions. Three specific aims are proposed to test the hypothesis. 1) To define the molecular mechanisms by which cellular polyamines modulate NPM activity. 2) To characterize functional and physical interactions of NPM with p53 following polyamine depletion. 3) To determine the roles and mechanisms of NPM/p53 interaction in regulation of intestinal mucosal growth and apoptosis during surgical disorders in the presence or absence of cellular polyamines. Completion of these specific aims will provide novel information regarding control of intestinal mucosal growth under surgical conditions. It is hoped that these studies will identify potential therapeutic targets and agents which could be used in the future to maintain intestinal mucosal integrity in patients with critical surgical illnesses.