Biological Roles of Galectins

半乳糖凝集素的生物学作用

• 批准号: 8015394
• 负责人: GERARDO Raul VASTA
• 金额: $ 30万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015394
• 关键词: Acute; Address; Adhesions; Adult; Affinity; Animal Model; Basophils; Binding Proteins; Biochemical; Biological; Biological Process; Cells; Chimera organism; Communities; Crystalline Lens; Cytosol; Development; Developmental Process; Dominant-Negative Mutation; Drug or chemical Tissue Distribution; Embryo; Embryonic Development; Exhibits; Extracellular Matrix; Extracellular Space; Family; Fertilization; Fibronectins; Galactose Binding Lectin; Galactosides; Galectin 1; Galectin 2; Generations; Genes; Genetic; Genomics; Glycoproteins; Goals; Heart; Immune; Immune response; Immunity; Immunology; In Situ Hybridization; Inflammation; Invertebrates; Knowledge; Laboratories; Laminin; Ligands; Mammals; Mediating; Microbe; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Molecular Structure; Mus; Muscle Fibers; Myoblasts; Natural Immunity; Nature; Neural tube; Nuclear; Pattern; Phagocytes; Phase; Play; Principal Investigator; Property; Recruitment Activity; Research; Resources; Role; Signal Transduction; Site; Specificity; Staging; Surface; System; Tandem Repeat Sequences; Testing; Time; Vertebrates; Zebrafish; adaptive immunity; allergic response; cardiogenesis; cell motility; chemokine; cytokine; eosinophil; hatching; immune function; in vivo Model; insight; lens; macrophage; man; member; microbial; mutant; notochord; notochord development; novel; pathogen; programs; public health relevance; receptor; response; retinal regeneration; somitogenesis; teleost fish; tool; zebrafish development

DESCRIPTION (provided by applicant): Galectins are a family of soluble 2-galactoside-binding proteins. Several galectin types have been described (proto, chimera, and tandem-repeat), each endowed with a unique molecular structure, biochemical properties, and taxonomic distribution. Embryonic expression patterns and affinity for extracellular matrix glycoproteins have led to propose that galectins mediate developmental processes, whereas their expression in macrophages, eosinophils and basophils suggests, and their recently established recognition properties for microbes, suggest their functions in immunity. Because of its external fertilization and development, transparent embryos, short generation time, powerful genetic systems, and extensive genomic resources, the zebrafish (Danio rerio) is a useful model for in vivo studies of development and immunology. We have made substantial contributions to the biochemical, structural, and evolutionary characterization of galectins in zebrafish: we identified proto, chimera, tandem-repeat, and chimeric tandem-repeat galectins, and characterized their developmental expression and tissue distribution. We performed preliminary functional analyses: knockdown embryos for proto type galectins exhibit disrupted muscle fiber organization, retinal regeneration, and an underdeveloped heart, while chimera, tandem-repeat, and chimeric tandem-repeat galectins are up-regulated upon immune challenge. We hypothesize that (I) the proto galectins Drgal1-L2 and Drgal1-L4 play a critical role in notochord development, and are indirectly involved in myoblast differentiation and heart development through signals from the notochord or neural tube. Further, (II) the proto galectin DrGRIFIN plays an important role in eye lens development. Finally, (III) the chimeric and tandem-repeat galectins (Drgal3-L1, Drgal9-L3, and Drgal9-L4) are directly involved in innate immune responses by interacting with potential pathogens and/or by recruiting phagocytic cells to sites of acute inflammation, and/or indirectly, by interacting with receptors on their surface, inducing their activation upon infectious challenge. The proposed studies will yield (a) novel information on the biological role(s) of galectins in development and immunity in the zebrafish model; (b) novel information concerning the molecular mechanisms of cell-cell, cell-ECM, and cell-pathogen interactions that modulate embryonic development and immune functions shared between teleost fish and higher vertebrates, including man, and (c) molecular tools and resources for functional analysis of galectins in the zebrafish model that will be shared with the scientific community. PUBLIC HEALTH RELEVANCE: The goal of the proposed studies is to gain further insight into the biological functions of galectins (2- galactoside-binding proteins) using zebrafish (Danio rerio) as a model organism. Results will yield fundamental knowledge concerning their roles in embryonic development and immune functions in higher vertebrates, including man, and useful molecular tools/resources for the scientific community.

描述（由申请人提供）：半乳糖凝集素是可溶性2-半乳糖苷结合蛋白家族。已经描述了几种半乳糖凝集素类型（原体、嵌合体和串联重复），每种都具有独特的分子结构、生物化学性质和分类学分布。胚胎表达模式和细胞外基质糖蛋白的亲和力已经导致提出半乳糖凝集素介导发育过程，而它们在巨噬细胞、嗜酸性粒细胞和嗜碱性粒细胞中的表达表明，它们最近建立的对微生物的识别特性表明它们在免疫中的功能。 斑马鱼（Danio rerio）具有体外受精和发育、透明胚胎、短世代、强大的遗传系统和丰富的基因组资源等特点，是研究发育和免疫学的重要模型。我们在斑马鱼半乳糖凝集素的生物化学、结构和进化特征方面做出了重大贡献：我们鉴定了原、嵌合体、串联重复和嵌合串联重复半乳糖凝集素，并表征了它们的发育表达和组织分布。我们进行了初步的功能分析：原型半乳糖凝集素的敲低胚胎表现出破坏的肌纤维组织，视网膜再生，和不发达的心脏，而嵌合体，串联重复，嵌合串联重复半乳糖凝集素上调免疫挑战。 我们假设（I）原半乳糖凝集素Drgal 1-L2和Drgal 1-L4在脊索发育中起关键作用，并且通过来自脊索或神经管的信号间接参与成肌细胞分化和心脏发育。此外，（II）原半乳糖凝集素DrGRIFIN在眼透镜发育中起重要作用。最后，（III）嵌合和串联重复半乳糖凝集素（Drgal 3-L1、Drgal 9-L3和Drgal 9-L4）通过与潜在病原体相互作用和/或通过将吞噬细胞募集到急性炎症部位，和/或通过与其表面上的受体相互作用，在感染性攻击时诱导其活化，直接参与先天免疫应答。 拟议的研究将产生（a）关于半乳糖凝集素在斑马鱼模型中的发育和免疫中的生物学作用的新信息;（B）关于调节硬骨鱼和高等脊椎动物（包括人）之间共有的胚胎发育和免疫功能的细胞-细胞、细胞-ECM和细胞-病原体相互作用的分子机制的新信息，以及（c）将与科学界分享的用于斑马鱼模型中半乳糖凝集素功能分析的分子工具和资源。 公共卫生关系：本研究的目的是以斑马鱼（Danio rerio）为模式生物，进一步了解半乳糖凝集素（2-半乳糖苷结合蛋白）的生物学功能。结果将产生关于它们在高等脊椎动物（包括人类）的胚胎发育和免疫功能中的作用的基础知识，以及科学界有用的分子工具/资源。