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

• Applicant: Dr. Tobias Speicher
• Subject Area: Cell Biology
• Term: from 2011 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 201437283

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.

• DFG Programme: Research Fellowships
• International Connection: Switzerland
• Host: Professorin Dr. Sabine Werner