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

9728911段拟议的项目涉及研究胰岛素样生长因子（IGFs），肽生长因子/激素是正常生长和发育所必需的，用于控制体内胚胎组织形成和分化的分子机制。 最近的研究利用培养的哺乳动物细胞表明，胰岛素样生长因子的生物活性可以调制特定的，高亲和力的胰岛素样生长因子结合蛋白（IGFBPs）在体外。 每种IGFBP在控制特定胚胎组织中IGF可用性的体内作用尚未确定。 这一领域的研究严重依赖啮齿动物模型，但由于无法接近封闭在子宫内的哺乳动物胎儿，因此这些尝试受到了阻碍。 在这个项目中，段博士提出利用一种硬骨鱼模型，斑马鱼（Danio rerio）来检验IGFs进入特定胚胎组织的途径是由局部表达的特定IGFBPs调节的假设，并且这种调节对于正常组织的生长和分化至关重要。 斑马鱼胚胎的可获得性、透明性和快速发育性以及许多遗传突变体的可用性使其特别适合研究IGFs/IGFBPs的发育作用及其潜在机制。 该提案的具体目标是：1）确定斑马鱼IGFBP-3的结构和生物活性; 2）确定IGFBP-3与IGFs和IGF-1受体一起的发育表达模式; 3）确定IGFBP-3在发育斑马鱼胚胎中控制IGF作用的作用。 预期的结果应提供直接的证据，在体内的作用IGFBP-3在控制IGF的行动在脊椎动物胚胎，并将进一步了解如何IGF系统的作用，以控制脊椎动物的生长和发育。 鱼类IGFBP-3结构的确定以及相应蛋白、cDNA探针和抗血清的开发将首次为研究IGFBP在硬骨鱼中的作用提供有价值的工具。 从这些研究中获得的信息可能对水产养殖业有效生产动物蛋白质以满足不断增长的人口的需求很有价值。

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.