Biological roles of galectins

半乳糖凝集素的生物学作用

• 批准号: 6950355
• 负责人: GERARDO Raul VASTA
• 金额: $ 20.79万
• 依托单位: UNIVERSITY OF MD BIOTECHNOLOGY INSTITUTE
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950355
• 关键词: affinity chromatography; carbohydrate receptor; cell adhesion; cell differentiation; cell migration; extracellular matrix; galactosides; lectin; polymerase chain reaction; protein protein interaction; protein structure function; proteomics; zebrafish

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.

描述（由申请人提供）：复合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。这些信息被包括凝集素在内的高度特异性的碳水化合物结合受体解码。β-半乳糖苷结合凝集素的一个这样的家族，半乳糖凝集素，在胞质溶胶中合成并释放到细胞外空间中。独特的表达模式、组织分布及其对内源性配体（ECM糖蛋白）和外源性配体（细菌病原体）的亲和力已导致提出半乳糖凝集素参与多种功能。然而，它们的生物学作用尚未在体内明确建立，部分原因是哺乳动物模型的高度多样化（和功能冗余）的半乳糖凝集素库。斑马鱼是这些研究的首选模型，因为它提供了优于哺乳动物模型的优势，如外部受精，发育期短，透明的胚胎，大量的突变体，以及根据我们的初步结果，较少多样化的半乳糖凝集素库。我们已经部分确定了斑马鱼半乳糖凝集素的特征，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。通过针对斑马鱼半乳糖凝集素的“功能丧失”方法，我们确定了一种肌肉细胞组织缺陷的暂定表型，该方法是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。我们建议：（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起关键作用，并且间接参与细胞分化;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（巨噬细胞和嗜中性粒细胞）募集到感染部位而参与炎症。为了验证这些假设，我们将具体：（a）完成斑马鱼半乳糖凝集素库的分子表征，包括其配体的鉴定，以及其时空表达模式;（B）实验调节/破坏半乳糖凝集素功能，以评估其生物学作用。预期的益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），以及关于它们与细胞、ECM和病原体相互作用的新信息，这些信息调节它们在脊椎动物中的多种功能。