THE INTERPLAY BETWEEN HEPATIC GROWTH AND METABOLISM

描述：（改编自申请人的摘要） 该项目是关于在生长和代谢中发挥作用的基因， 肝脏，主要侧重于胰岛素样生长因子结合蛋白-1 （IGFBP-1）。IGFBP-1的表达在肝脏生长过程中高度上调， 再生和发展。它的表达在禁食期间也上调 并被高胰岛素水平下调。IGFBP-1可导致 葡萄糖水平与基于其抑制血清IGF的拟议机制 功能在初步研究中，申请人证明， 在肝再生过程中IGFBP-1基因的转录部分是由 白细胞介素-6（IL-6）是再生反应中的关键细胞因子。要求1 将检测IL-6对IGFBP-1转录的激活是否介导 通过STAT-3共激活IGFBP-1启动子的HNF-1转录， 确定IL-6阻断胰岛素介导的抑制的机制， IGFBP-1启动子表达。实验还提出了识别 IL-6上调AP-1活性的机制介导了 IGFBP-1基因表达。已经建立了IGFBP-1缺失或敲除小鼠， 它们显示葡萄糖调节缺陷和异常肝再生， 修复.目的2将检测IGFBP-1缺失肝再生的能力， 修复和探索部分肝切除术后的机械缺陷，急性和 慢性四氯化碳（CCl 4）介导的肝损伤和FAS介导的肝损伤 肝损伤申请人将评估葡萄糖代谢的基本参数 在IGFBP-1敲除小鼠中，并确定任何异常的基础。

DESCRIPTION: (Adapted from the applicant's abstract) The specific focus of this project is on genes that play a role in both growth and metabolism in the liver, with a major emphasis on insulin-like growth factor binding protein-1 (IGFBP-1). Expression of IGFBP-1 is highly upregulated during liver growth in regeneration and development. Its expression is also upregulated during fasting and downregulated by high insulin levels. IGFBP-1 can cause upregulation of glucose levels with a proposed mechanism based on its inhibition of serum IGF function. In preliminary studies, the applicant demonstrates that increased transcription of the IGFBP-1 gene during liver regeneration is mediated in part by interleukin-6 (IL-6) a critical cytokine in the regenerative response. Aim 1 will examine whether IL-6 activation of IGFBP-1 transcription is mediated through STAT-3 co-activation of HNF-1 transcription of the IGFBP-1 promoter and identify the mechanism by which IL-6 blocks insulin-mediated repression of IGFBP-1 promoter expression. Experiments are also proposed to identify the mechanism by which IL-6 upregulation of AP-1 activity mediates increased IGFBP-1 gene expression. IGFBP-1 null or knockout mice have been created and they display defects in glucose regulation and abnormal liver regeneration and repair. Aim 2 will examine the ability of IGFBP-1 null livers to regenerate and repair and explore mechanistic defects after partial hepatectomy, acute and chronic carbon tetrachloride (CCl4) mediated liver injury and FAS mediated liver injury. The applicant will assess basic parameters of glucose metabolism in IGFBP-1 null mice and determine the basis for any abnormalities.