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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
AASLD/ALF Liver Scholar Award
University of Pittsburgh, Pittsburgh, Pennsylvania
Mechanisms Regulating Early Liver Development: Liver Specification and Hepatic Competence
Dr. Shin is proposing two aims in this application. 1) Elucidate the mechanisms by which Wnt and Fgf signaling regulate liver specification and hepatic competence, respectively. He discovered that Wnt signaling is necessary and sufficient for liver specification and that Fgf signaling mediated by Fgf10a negatively regulates hepatic competence. To understand the mechanisms underlying these developmental processes, he will identify downstream target genes of these signaling pathways that regulate liver specification or hepatic competence. Based on gene expression profiles obtained from microarray analyses of embryos, in which Wnt or Fgf signaling is manipulated, candidate downstream target genes will be selected and their expression patterns will be carefully examined by in situ hybridization. Then, the function of these genes will be investigated through loss- and gain-of-function approaches such as an anti-sense oligonucleotide and an endoderm-targeted transplantation approach. Dr. Shin anticipates that downstream effector genes, which mediate the effect of Wnt or Fgf signaling on liver specification or hepatic competence, will be identified and provide mechanistic understanding of these processes. 2) Characterize slurpee, a zebrafish liver mutant. From a forward-genetic screen, Dr. Shin isolated a mutant named slurpee, exhibiting ectopic expression of a liver-specific transgene in the pharyngeal endoderm. He will analyze this and other phenotypes in detail at the molecular and cellular levels using diverse endoderm markers combined with confocal microscopy, and identify the affected gene by positional cloning. Once the gene is identified, gain-of-function studies will be performed with RNA injection or by generating a transgenic line that expresses the gene upon heat-shock. Dr. Shin will further investigate the mechanisms underlying this mutant phenotype, which will provide further insights into liver specification.
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