Biological roles of galectins

描述（由申请人提供）：复杂碳水化合物中编码的结构信息介导细胞之间或细胞与细胞外基质（ECM）之间的相互作用。该信息由高度特异性的碳水化合物结合受体（包括凝集素）解码。 β-半乳糖苷结合凝集素家族之一，半乳糖凝集素，在细胞质中合成并释放到细胞外空间。独特的表达模式、组织分布及其对内源配体（ECM 糖蛋白）和外源配体（细菌病原体）的亲和力导致人们提出半乳糖凝集素参与多种功能。然而，它们在体内的生物学作用尚未明确确定，部分原因是哺乳动物模型的半乳糖素库高度多样化（且功能冗余）。斑马鱼是这些研究的首选模型，因为它比哺乳动物模型具有优势，例如体外受精、发育周期短、透明的胚胎、大量突变体，以及根据我们的初步结果，半乳糖素库多样性较低。我们对选定的斑马鱼进行了部分表征。半乳糖凝集素，开发了一套有用的分子工具，并启动了旨在阐明其生物学作用的研究，通过针对斑马鱼半乳糖凝集素（哺乳动物半乳糖凝集素-1的同源物，并显示出独特的表达模式）的“功能丧失”方法，我们发现了一种在肌肉细胞组织中存在缺陷的暂定表型：（a）半乳糖凝集素可能通过介导细胞迁移和粘附在组织发育和组织中发挥关键作用，并间接参与细胞分化；和（b）半乳糖凝集素通过直接与潜在病原体相互作用和/或将吞噬细胞（巨噬细胞和中性粒细胞）招募到感染部位来参与炎症。预期的好处包括用于半乳糖凝集素功能分析的新型分子工具和资源（可通过功能糖组学联盟获得），以及有关其与细胞、ECM 和病原体相互作用的新信息，从而调节其在脊椎动物中的多种功能。

DESCRIPTION (provided by applicant): Structural information encoded in complex carbohydrates mediates interactions between cells, or between cells and the extracellular matrix (ECM). The information is decoded by highly specific carbohydrate-binding receptors including lectins. One such family of beta-galactoside-binding lectins, the galectins, are synthesized in the cytosol and released into the extracellular space. Unique expression patterns, tissue distribution, and their affinity for endogenous ligands (ECM glycoproteins) and exogenous ligands (bacterial pathogens) have led to propose that galectins are involved in multiple functions. However, their biological roles are yet to be unequivocally established in vivo, due in part to the highly diversified (and functionally redundant") galectin repertoire of mammalian models. Zebrafish is a model of choice for these studies because it offers advantages over mammalian models, such as external fertilization, a short development period, transparent embryos, a large collection of mutants, and, based on our preliminary results, a less diversified galectin repertoire. We have partially characterized selected zebrafish galectins, developed a useful suite of molecular tools, and initiated studies aimed at elucidating their biological roles. By a "loss-of-function" approach targeted to a zebrafish galectin, which is a homologue of the mammalian galectin-1 and displays a unique expression pattern, we identified a tentative phenotype with a defect in muscle cell organization. We propose that: (a) galectins play a critical role in tissue development and organization, possibly by mediating cell migration and adhesion, and are indirectly involved in cell differentiation; and (b) galectins are involved in inflammation by interacting directly with potential pathogens and/or recruiting phagocytic cells (macrophages and neutrophils) to the infection sites. To test these hypotheses we will specifically: (a) complete the molecular characterization of the zebrafish galectin repertoire, including the identification of their ligands, and their patterns of spatial and temporal expression; (b) experimentally modulate/disrupt galectin function to assess their biological roles. Expected benefits include novel molecular tools and resources (available through the Consortium for Functional Glycomics) for functional analysis of galectins, and novel information on their interactions with cells, ECM and pathogens, that modulate their multiple functions in vertebrates.