THE INTERPLAY BETWEEN HEPATIC GROWTH AND METABOLISM

描述：(改编自申请人的摘要)这一次的具体重点 该项目研究的是在生长和新陈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在小鼠肝脏生长发育过程中表达高度上调 再生发展。它的表达在禁食期间也会上调 并被高胰岛素水平下调。IGFBP-1可导致血管内皮生长因子上调 血糖水平及其抑制血清IGF的机制研究 功能。在初步研究中，申请人证明增加了 肝再生过程中IGFBP-1基因的转录在一定程度上是受调节的 白介素6(IL-6)是再生反应中的关键细胞因子。目标1 将研究IL-6对IGFBP-1转录的激活是否被介导 通过STAT-3共激活HNF-1转录的IGFBP-1启动子和 确定IL-6阻断胰岛素介导的血管紧张素转换酶抑制的机制 IGFBP-1启动子的表达。还建议进行实验，以确定 IL-6上调AP-1活性的机制 IGFBP-1基因表达。已经创建了IGFBP-1基因缺失或基因敲除小鼠 它们在葡萄糖调节和肝脏再生异常方面存在缺陷 修理。目标2将检查IGFBP-1零肝脏再生和 急性和慢性肝部分切除后机械性缺陷的修复和探索 慢性四氯化碳(CCl4)所致肝损伤与Fas介导 肝脏损伤。申请者将评估葡萄糖代谢的基本参数。 在IGFBP-1基因缺失的小鼠中，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.