Surgical Study of Intestinal Proliferative Signaling

肠道增殖信号的外科研究

• 批准号: 6948380
• 负责人: HONGMIAO SHENG
• 金额: $ 23.28万
• 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: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6948380
• 关键词: RNA interference; biological signal transduction; cell cycle proteins; cell proliferation; cyclins; gastrointestinal epithelium; gastrointestinal surgery; gene induction /repression; gene targeting; genetically modified animals; growth factor; intestinal mucosa; laboratory mouse; phosphatidylinositol 3 kinase; protein structure function

DESCRIPTION (provided by applicant): Determination of the intracellular signaling pathways that control intestinal epithelial proliferation is fundamental to the understanding of the integrity and function of the intestinal tract under normal and diseased conditions. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway transduces signals initiated by growth factors and is involved in cell proliferation, cell differentiation, and programmed cell death. Our in vivo and in vitro studies demonstrate that PI3K transduces mitogenic signals initiated by growth factors, regulates expression of important cell cycle-related proteins, and controls intestinal epithelial proliferation. Specific Aim 1 of this application is to determine the critical role of PI3K in intestinal epithelial proliferation using animal models in which gut mucosal proliferation will be induced by growth factors and small bowel resection. Intestinal localization of PI3K activity, cyclin D1 protein, and epithelial proliferation will be evaluated. The second Specific Aim will delineate the molecular mechanisms by which PI3K and its downstream effectors regulate intestinal epithelial cell proliferation. The regulation and functional role of cyclin D1 and p27/Kip in PI3K-mediated intestinal epithelial proliferation will be elucidated. In Specific Aim 3, we will determine whether functional gain in PI3K improves intestinal mucosal proliferation employing knockout mice and transgenic mice in which PI3K activity is functionally upregulated. Regulation of intestine-specific genes by PI3K activation will be investigated in these animal models. The long-term goal of this proposal is to provide a complete assessment of intracellular signaling mechanisms that control intestinal epithelial proliferation and to provide clinically relevant information regarding stimulation of intestinal growth during periods of gut disuse, after small bowel resection, or with administration of chemotherapeutic agents.

描述（由申请人提供）： 确定控制肠上皮增殖的细胞内信号通路是对正常和患病条件下肠道完整性和功能的理解至关重要的。磷脂酰肌醇3-激酶（PI3K）/AKT途径会导致生长因子引发的信号，并参与细胞增殖，细胞分化和程序性细胞死亡。我们的体内和体外研究表明，PI3K传递了由生长因子引发的有丝分裂信号，调节重要细胞周期相关蛋白的表达并控制肠上皮上皮增殖。本应用的特定目的1是使用动物模型来确定PI3K在肠上皮增殖中的关键作用，在这种动物模型中，肠粘膜增殖将由生长因子和小肠切除诱导。将评估PI3K活性，细胞周期蛋白D1蛋白和上皮增殖的肠道定位。第二个特定目的将描述PI3K及其下游效应子调节肠上皮细胞增殖的分子机制。 Cyclin D1和P27/KIP在PI3K介导的肠上皮增殖中的调节和功能作用将得到阐明。在特定的目标3中，我们将确定PI3K的功能增益是否使用敲除小鼠和PI3K活性在功能上上调的转基因小鼠和转基因小鼠的肠粘膜增殖。在这些动物模型中将研究通过PI3K激活来调节肠道特异性基因。该提案的长期目标是对控制肠道上皮增殖的细胞内信号传导机制进行完整评估，并提供有关在肠道破坏时期，小肠切除后或化学治疗剂的施用肠道期间刺激肠道生长的临床相关信息。