This proposal focuses on the potential role of reduced FGF10 signaling in the setting of ethanol (EtOH) impaired liver regeneration. FgflO, expressed in the embryonic foregut mesoderm, normally interacts with the adjacent endoderm through Fibroblast Growth Factor Receptor 2 1Mb (FGFR2b). Absence of signaling through FGFR2b results in atresias of numerous gastrointestinal tract structures. We have preliminary evidence showing that FGF10 activates canonical WNT signaling in the developing liver through FGFR2b. Our studies indicate that Fgf 10 is expressed by activated hepatic stellate cells, which play a key role in liver fibrogenesis, and that Fgfr2b is expressed by progenitor cells, hepatoblasts prenatally and oval cells postnatally. Consistent with the observation that FGFR2b signaling is activated during liver regeneration, we have evidence that Fgf 10 expression, which is upregulated after partial hepatectomy, is reduced in the setting of ethanol-induced impaired liver regeneration. We hypothesize that ethanol suppresses signaling through the FGF10/FGFR2b, thus, impairing progenitor cell proliferation. We thus propose the following specific aims: (1) To determine the role of FGF10 signaling via FGFR2b during liver regeneration following partial hepatectomy (PH) in the absence or presence of EtOH in transgenic mice. Liver-specific induced overexpression of the dominant negative soluble FGFR2b isoform or of Fgf 10 in the setting of EtOH impaired liver regeneration following PH will be performed for loss-of-function or gain-of-function analyses, respectively. (2) To determine the identity and role of Fgf 10-expressing cells in hepatogenesis and EtOHimpaired liver regeneration. Cells expressing Fgf 10 from transgenic embryo livers and PH livers exposed to EtOH will be sorted by fluorescence activated cell sorting (FACS) and characterized by real-time PCR. (3) To determine the identity of cells undergoing FGF10-mediated canonical WNT activation. Cells with activated canonical WNT signaling will be sorted by FACS. Loss and gain-of function analyses for FgflO will be performed to determine relative levels of canonical WNT activiation. Alcohol impairs the liver's ability to repair and regenerate itself. This contributes to the development of liver cirrhosis. We postulate that the mechanism by which alcohol impairs liver regeneration may be due to impaired signaling through the FGF10/FGFR2b pathway we show normally promotes liver regeneration.
