System-wide identification of FGFR1/2-regulated proteins in the regenerating liver

再生肝脏中 FGFR1/2 调节蛋白的全系统鉴定

• 批准号: 201437283
• 负责人: Dr. Tobias Speicher
• 金额: --
• 依托单位: Institute of Molecular Biology and Biophysics
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/201437283?language=en
• 关键词: System; wide; identification; FGFR1; regulated

The liver is the only organ in mammals that can fully regenerate after injury. Hepatic tissue loss initiates a well-defined program, which results in restoration of the initial liver mass and re-establishment of the livers essential functions in metabolic regulation and compound detoxification. The process of liver regeneration after partial hepatectomy (PH) and the underlying molecular mechanisms have only partially been characterized. In particular, changes in protein levels and in their subcellular localization during PH have not been previously analyzed on a proteome-wide basis. We recently identified crucial roles of fibroblast growth factor receptors (FGFR) 1 and 2 in compound detoxification in the regenerating liver. To study the underlying mechanisms and to improve our understanding of liver regeneration, I will identify cytosolic and nuclear proteins of normal and regenerating liver at the early stages of the regeneration process using iTRAQ proteomics. The levels of these proteins and their intracellular distribution will be compared between control and FGFR1/2-deficient mice. Further functional analysis will focus on differentially expressed proteins involved in compound detoxification, which may explain the regeneration phenotype of the FGFR mutant mice. In addition, we are interested in proteins that translocate from the cytoplasm to the nucleus upon PH in an FGF-dependent manner. The latter are candidate transcriptional regulators orchestrating liver regeneration, in particular the functions that are controlled by FGF signaling. 1-2 proteins, which fulfill these criteria, will be functionally characterized in vitro and in vivo. These experiments are expected to provide further insight into the molecular mechanisms underlying the liver regeneration process and the role of FGFR signaling therein. Some of the identified proteins may also represent novel targets for the development of pharmaceuticals for the enhancement of liver regeneration.

肝脏是哺乳动物中唯一可以在损伤后完全再生的器官。肝组织损失启动了一个明确的程序，这导致恢复最初的肝脏质量和重建肝脏在代谢调节和化合物解毒方面的基本功能。部分肝切除术（PH）后肝再生的过程和潜在的分子机制只有部分特征。特别是，蛋白质水平的变化，并在他们的亚细胞定位在PH过程中还没有以前分析的蛋白质组范围内的基础上。我们最近确定了成纤维细胞生长因子受体（FGFR）1和2在再生肝脏的化合物解毒中的关键作用。为了研究潜在的机制并提高我们对肝再生的理解，我将使用iTRAQ蛋白质组学在再生过程的早期阶段鉴定正常和再生肝脏的胞质和核蛋白。将在对照和FGFR 1/2缺陷小鼠之间比较这些蛋白质的水平及其细胞内分布。进一步的功能分析将集中在差异表达的蛋白质参与化合物解毒，这可能解释FGFR突变小鼠的再生表型。此外，我们对PH后以FGF依赖性方式从细胞质转移到细胞核的蛋白质感兴趣。后者是协调肝再生的候选转录调节因子，特别是由FGF信号传导控制的功能。1-2满足这些标准的蛋白质将在体外和体内进行功能表征。这些实验有望进一步深入了解肝再生过程的分子机制以及FGFR信号在其中的作用。一些鉴定的蛋白质也可能代表用于开发增强肝再生的药物的新靶点。