Molecular Mechanisms of Insulin-like Growth Factor (IGF) Actions in Fish: Role of IGF Binding Protein-3

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9728911 Duan The proposed project involves studying the molecular mechanisms by which insulin-like growth factors (IGFs), peptide growth factors/hormones which are essential for normal growth and development, act to control embryonic tissue formation and differentiation in vivo. Recent studies utilizing cultured mammalian cells suggest that the bioactivity of IGFs could be modulated by specific, high-affinity IGF-binding proteins (IGFBPs) in vitro. The in vivo role of each IGFBP in controlling the availability of IGFs in specific embryonic tissues has not been determined. Research in this area has relied heavily on rodent models, and attempts have been hampered by the inaccessibility of the mammalian fetus which is enclosed in the uterus. In this project, Dr. Duan proposes to utilize a model teleost fish, the zebrafish (Danio rerio) to test the hypothesis that the access of IGFs to specific embryonic tissues is regulated by specific IGFBPs expressed locally and that this regulation is crucial for normal tissue growth and differentiation. The accessible, transparent and fast-developing embryos and the availability of numerous genetic mutants make zebrafish particularly suited for investigating the developmental role of IGFs/IGFBPs and the underlying mechanisms. The specific aims of the proposal are to: 1) determine the structure and biological activities of zebrafish IGFBP-3; 2) determine the developmental expression patterns of IGFBP-3 together with IGFs and the IGF-1 receptor; 3) determine the role of IGFBP-3 in controlling IGF actions in developing zebrafish embryos. The expected results should provide direct evidence for the in vivo role of IGFBP-3 in controlling IGF actions in a vertebrate embryo and will further our understanding of how the IGF system acts to control growth and development in vertebrates. Determination of the structures of fish IGFBP-3 and development of the corresponding protein, cDNA probe and antiserum will make available, for the first time, valuable tools for investigation of IGFBP actions in a teleost fish. Information gained from these studies may prove to be valuable to aquaculture for efficient production of animal protein to meet the needs of a continually growing human population.