Growth Regulation in Surgical Diseases of the Gut

肠道外科疾病的生长调节

• 批准号: 6743233
• 负责人: TIEN C KO
• 金额: $ 35.39万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6743233
• 关键词: DNA binding protein; apoptosis; biological signal transduction; cell cycle; cell growth regulation; cell line; cyclin dependent kinase; cyclins; gastrointestinal epithelium; gene expression; gene mutation; inflammatory bowel diseases; intestinal mucosa; messenger RNA; microarray technology; nuclear runoff assay; protein structure function; transfection; transforming growth factors

DESCRIPTION (Provided by Applicant): The specific focus of this proposal is to define the transforming growth factor-n (TGF-B) signaling pathway in gut epithelial cells. The human gut epithelium is maintained by a continuous process of self-renewal, which requires a balance between cell division and apoptosis. Alteration in gut renewal is a hallmark of many diseases of the gut, such as neoplastic growth and inflammatory bowel diseases, all of which contribute to a major health care burden for the United States' population. Progress in the treatment of these diseases has been hampered by the lack of insight into the molecular mechanisms regulating gut renewal. TGF-B is a most important physiological regulator of gut renewal. TGF-B signal is transduced from the receptor complex to the nucleus through a novel class of proteins, the Smads. The goal of this proposal is to determine whether TGF-f3 regulation of cell division and apoptosis is mediated through Smad proteins. We have planned experiments with the following two specific aim. In specific aim 1, we will characterize the role of Smads in TGF-B regulation of cell division. We will determine 1) which endogenous Smads are activated by TGF-B in gut epithelial cells 2) whether endogenous Smads are essential for TGF-B signaling in gut epithelial cells, and 3) whether endogenous Smads are essential for TGF-B inhibition of cyclin Dl expression, Cdk4 activity and cell cycle progression. In specific aim 2, we will characterize the role of Smads in TGF-B-induced apoptosis. We will determine 1) whether Smad3 expression correlates with sensitivity to TGF-B-induced apoptosis, 2) whether Smad3 is essential for TGF-B-induced apoptosis in gut epithelial cells, 3) which domain(s) of Smad3 is required for TGF-B-induced apoptosis, 4) which structural differences between Smad2 and Smad3 are responsible for different apoptosis responses, and 5) the changes in gene expression in TGF-B-induced apoptosis. The studies in the current proposal will extend our previous findings by further delineating the molecular mechanisms that mediate TGF-B's effects in the gut. By delineating the role of Smads in the gut, we hope to determine whether they are potential therapeutic targets for the management of human diseases of the gut.

描述（由申请人提供）：该提案的具体重点是 定义肠道中转化的生长因子-N（TGF-B）信号通路 上皮细胞。人肠上皮由连续的 自我更新过程，需要在细胞分裂和 凋亡。肠道更新的改变是肠道许多疾病的标志， 例如肿瘤生长和炎症性肠病，所有这些 为美国人口造成重大医疗保健负担。 由于缺乏，这些疾病治疗的进展受到了阻碍 深入了解调节肠道更新的分子机制。 TGF-B是最大的 肠道更新的重要生理调节剂。 TGF-B信号被转导 从受体复合物到细胞核通过一种新型的蛋白质， Smads。该提案的目的是确定TGF-F3的规定是否 细胞分裂和凋亡是通过SMAD蛋白介导的。我们已经计划了 实验以下两个特定目标。在特定目标1中，我们将 表征SMAD在细胞分裂TGF-B调节中的作用。我们将 确定1）肠上皮中的TGF-B激活了哪些内源性SMADS 细胞2）内源性smads是否对于肠道中的TGF-B信号至关重要 上皮细胞和3）内源性smads是否对TGF-B至关重要 抑制细胞周期蛋白DL表达，CDK4活性和细胞周期进程。 在特定的目标2中，我们将表征SMAD在TGF-B诱导的 凋亡。我们将确定1）SMAD3表达是否与 对TGF-B诱导凋亡的敏感性，2）SMAD3是否对 TGF-B诱导肠道上皮细胞的凋亡，3）SMAD3的域是哪个域 TGF-B诱导的细胞凋亡所必需的，4） SMAD2和SMAD3负责不同的凋亡反应，5） TGF-B诱导的凋亡中基因表达的变化。研究 当前的提议将通过进一步描述以前的发现来扩展我们以前的发现 介导TGF-B在肠道中的作用的分子机制。通过描绘 Smads在肠道中的作用，我们希望确定它们是否具有潜力 治疗肠道疾病的治疗靶标。