Biological roles of galectins

描述(申请人提供)：复杂碳水化合物中编码的结构信息调节细胞之间或细胞与细胞外基质(ECM)之间的相互作用。这种信息由包括凝集素在内的高度特异的碳水化合物结合受体来解码。这种β-半乳糖苷结合凝集素家族，Galectins，是在胞浆中合成的，并释放到细胞外空间。Galectins独特的表达模式、组织分布及其与内源配体(ECM糖蛋白)和外源配体(细菌病原体)的亲和力导致了Galectins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Galectin谱系高度多样化(和功能冗余)。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、较短的发育期、透明的胚胎、大量突变，以及根据我们的初步结果，半乳糖凝集素的多样性较低。我们已经对选定的斑马鱼Galectins进行了部分表征，开发了一套有用的分子工具，并开始了旨在阐明它们的生物学作用的研究。斑马鱼Galectin是哺乳动物Galectin-1的同源物，具有独特的表达模式，通过针对斑马鱼Galectin-1的“功能丧失”方法，我们发现了一个肌肉细胞组织缺陷的暂定表型。我们认为：(A)Galectins在组织发育和组织中发挥关键作用，可能通过介导细胞迁移和黏附，并间接参与细胞分化；以及(B)Galectins通过直接与潜在病原体相互作用和/或招募吞噬细胞(巨噬细胞和中性粒细胞)到感染部位而参与炎症。为了验证这些假说，我们将具体：(A)完成斑马鱼Galectin谱系的分子表征，包括确定它们的配体，以及它们的空间和时间表达模式；(B)通过实验调节/破坏Galectin功能，以评估它们的生物学作用。预期的好处包括用于Galectins功能分析的新的分子工具和资源(可通过功能糖联盟获得)，以及关于Galectins与细胞、细胞外基质和病原体相互作用的新信息，这些信息调节了它们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.