Biological roles of galectins

描述（由申请人提供）：在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。这些信息被高度特异的碳水化合物结合受体解码，包括凝集素。其中一种-半乳糖苷结合凝集素是在细胞质中合成并释放到细胞外空间的。独特的表达模式、组织分布以及它们对内源性配体（ECM糖蛋白）和外源性配体（细菌病原体）的亲和力使得人们认为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中凝集素的高度多样化（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，例如外部受精，发育周期短，透明胚胎，大量突变体，并且根据我们的初步结果，凝集素种类较少。我们已经对选定的斑马鱼凝集素进行了部分表征，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。通过针对斑马鱼的“功能缺失”方法，我们发现了一种具有肌肉细胞组织缺陷的试探性表型。斑马鱼的半乳糖凝集素是哺乳动物半乳糖凝集素-1的同源物，具有独特的表达模式。我们提出：(a)凝集素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粘附，并间接参与细胞分化；(b)凝集素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）到感染部位参与炎症。为了验证这些假设，我们将具体地：(a)完成斑马鱼凝集素库的分子表征，包括它们的配体的鉴定，以及它们的空间和时间表达模式；(b)通过实验调节/破坏凝集素功能来评估其生物学作用。预期的好处包括新的分子工具和资源（可通过功能糖组学协会获得）用于半乳糖凝集素的功能分析，以及它们与细胞、ECM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.