Surgical Study of Prostaglandins in Intestinal Biology

肠道生物学中前列腺素的外科研究

• 批准号: 6948631
• 负责人: HONGMIAO SHENG
• 金额: $ 24.68万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6948631
• 关键词: biological signal transduction; cell proliferation; cell transformation; chemoprevention; enzyme linked immunosorbent assay; epidermal growth factor; gastrointestinal epithelium; growth factor receptors; nonsteroidal antiinflammatory agent; phosphatidylinositol 3 kinase; prostaglandin E; prostaglandin endoperoxide synthase; surgery

DESCRIPTION (provided by applicant): The stress of major surgical procedures and nutritional deprivation lead to atrophic changes in gut epithelium which significantly affect the outcome of surgical patients. In contrast, hyperplastic growth of intestinal epithelium results in colorectal neoplasm. Cyclooxygenase (COX) enzymes catalyze a key step in the conversion of arachidonic acid to prostaglandins (PGs) which play important roles in modulation of cell proliferation and cell death. Nonsteroidal antiinflammatory drugs (NSAIDs), inhibitors of COX enzymes, suppress growth of transformed intestinal epithelial cells, whereas PGs stimulate intestinal epithelial cell proliferation. The mechanism by which PGs promote intestinal epithelial growth and transformation is poorly understood. Our preliminary studies show that PGE2 induces expression of amphiregulin, an EGF family member, and transactivates receptor tyrosine kinase (RTK)-dependent signaling pathways, including the Ras and the phosphatidylinositol 3-kinase (PI3K) pathways which are essential for intestinal epithelial cell proliferation and transformation. Specific Aim 1 of this application will use an improved 3-dimensional cell growth model to elucidate the mechanisms by which PGE2 and celecoxib regulate intestinal epithelial cell growth. Functional roles of PGE2 and celecoxib in surgical animal models, including fasting/refeeding and small bowel resection, will be assessed. These experiments will delineate the basic mechanism by which PGs regulate intestinal epithelial proliferation. Specific Aim 2 will study the signaling mechanisms governing PGE2 trophic action in intestinal epithelial cells. Our focus will be the induction of EGF receptor ligands and transactivation of the PI3K signaling pathway by COX-2/PGE2. In Specific Aim 3, we will investigate the involvement of COX-2/PGs in Ras-mediated transformation of intestinal epithelial cells. Novel in vitro and in vivo models will be employed to address this question. The long-term goal of this proposal is to provide a complete assessment of molecular mechanisms mediating the trophic action of PGs and the chemopreventive effect of NSAIDs on intestinal epithelial transformation. Our results will provide a novel molecular basis for the development of more effective therapeutic strategies in the regulation of intestinal epithelial growth and transformation.

描述（由申请人提供）： 主要的手术程序和营养剥夺的压力导致肠道上皮的萎缩变化，这显着影响了手术患者的结局。相反，肠上皮的增生生长导致结直肠肿瘤。环氧酶（COX）酶催化了蛛网膜酸转化为前列腺素（PGS）的关键步骤，这些步骤在调节细胞增殖和细胞死亡中起着重要作用。非甾体类抗炎药（NSAIDS），COX酶的抑制剂，抑制转化的肠上皮细胞的生长，而PGS刺激肠上皮细胞增殖。 PG促进肠上皮生长和转化的机制知之甚少。我们的初步研究表明，PGE2诱导了EGF家族成员两次末期的表达，并诱导受体酪氨酸激酶（RTK）依赖性信号传导途径，包括RAS和磷脂酰肌醇3-激酶（PI3K）途径，这些途径是肠道上的细胞上皮泛质和转化的必不可少的途径。本应用的特定目的1将使用改进的3维细胞生长模型来阐明PGE2和Celecoxib调节肠上皮细胞生长的机制。将评估PGE2和Celecoxib在手术动物模型中的功能作用，包括禁食/再进发和小肠切除术。这些实验将描述PGS调节肠上皮增殖的基本机制。具体目标2将研究肠上皮细胞中PGE2营养作用的信号传导机制。我们的重点是诱导EGF受体配体和COX-2/PGE2对PI3K信号通路的反式激活。在特定的目标3中，我们将研究COX-2/PGS参与RAS介导的肠上皮细胞的转化。新颖的体外和体内模型将被用来解决这个问题。该提案的长期目标是对介导PG的营养作用以及NSAID对肠上皮上皮转化的化学预防作用的分子机制进行完整评估。我们的结果将为开发更有效的治疗策略在调节肠上皮生长和转化时提供新的分子基础。