Core Support for Collaborative Research in Glycobiology

过去20年的基因组测序项目已经产生了惊人的发现，即人类的基因总数与蠕虫和植物等许多模式生物没有太大区别。这一发现突出了基因组信息在基因翻译成蛋白质后发生大量扩增的事实。糖基化涉及将糖添加到选定的蛋白质氨基酸侧链，是这些翻译后修饰中最丰富且可以说是最重要的。事实上，所有的细胞都被称为糖萼的富含糖的层所覆盖。位于糖萼外围的糖链（称为聚糖）与伴侣细胞上的特异性糖识别蛋白（称为凝集素）结合。许多重要的生物学过程依赖于细胞通过这些糖-凝集素相互作用适当地彼此通信并相应地响应的能力。例如，已知病毒和细菌表面的凝集素识别靶细胞上的糖并附着在它们上，这是感染的第一步。相反，当病原体表面的糖与宿主免疫系统细胞表达的凝集素结合时，适应性免疫系统被触发。虽然这些聚糖-凝集素识别的例子现在已经相对较好地理解，但许多可能类似地由聚糖-凝集素相互作用控制的生物过程仍然是谜。例如，肠道中的免疫细胞如何区分有益微生物和有害微生物，以及发育中的胎儿如何逃脱母亲的排斥，尽管是半个“外来”？了解聚糖在这些过程中的功能首先是了解它们的结构。我们专注于使用称为质谱的复杂分析技术进行聚糖结构测定。我们与来自国内外许多生物学科的数十名科学家合作，他们与我们一起探索聚糖-凝集素结构/功能关系。我们特别感兴趣的是表征参与宿主微生物相互作用，免疫调节和介导哺乳动物生殖过程中的识别事件的聚糖。除了有助于对聚糖功能的基本理解外，我们还旨在提供结构数据，以支持用于控制病原体和寄生虫的新药和疫苗的靶标鉴定。我们期望我们对哺乳动物受精和生殖的糖生物学的研究将为自然避孕开辟新的途径，并帮助不孕夫妇。我们的另一个目标是了解参与调节糖基化的途径。这一点很重要，不仅因为糖基化改变与许多慢性健康和衰老问题有关，而且还因为这一知识将有助于有效生产定义明确的糖蛋白生物药物。糖是糖蛋白的重要组成部分，也是构成植物细胞壁的多糖的主要组成部分。有一个迫切需要更好地了解植物细胞壁组装所涉及的生物过程，如果生物质作为一种可再生能源的潜力和替代化石燃料的高价值的化学品的生产是要充分实现。我们的目标是与英国和澳大利亚的植物科学家合作，阐明细胞壁多糖生物合成的分子机制。我们的分析方法产生了大量复杂的数据，因此我们的另一个目标是创建糖信息学工具，以帮助和加快数据解释和注释，这些工具将提供给科学界。我们还将开发和填充公开可用的数据库与我们的聚糖结构数据，这将有利于来自世界各地的许多学科的科学家的资源。

The genome sequencing projects of the past two decades have yielded the startling revelation that the total number of genes in humans is not very different from many model organisms such as worms and plants. This discovery served to highlight the fact that substantial amplification of genomic information occurs after genes are translated into proteins. Glycosylation, which involves the addition of sugars to selected protein amino acid side-chains, is the most abundant and arguably the most important of these post-translational modifications. Indeed, all cells are coated with a sugar-rich layer called the glycocalyx. Chains of sugars, called glycans, on the periphery of the glycocalyx bind to specific sugar-recognition proteins, called lectins, on partner cells. Many important biological processes depend on the ability of cells to appropriately communicate with each other via these sugar-lectin interactions and to respond accordingly. For example, lectins on the surfaces of viruses and bacteria are known to recognise sugars on target cells and attach to them as the first step of infection. Conversely the adaptive immune system is triggered when sugars on the surfaces of pathogens bind to lectins expressed by cells of the host immune system. Although these examples of glycan-lectin recognition are now relatively well understood, many biological processes that are likely to be similarly controlled by glycan-lectin interactions remain enigmatic. For example, how do immune cells in the gut distinguish between beneficial and harmful microbes, and how does a developing foetus escape rejection by the mother despite being half "foreign"? Pivotal to learning how glycans function in these processes is knowing their structures. We specialize in glycan structural determination using a sophisticated analytical technique called mass spectrometry. We do this in collaboration with dozens of scientists from many biological disciplines both nationally and internationally, who are working with us to explore glycan-lectin structure/function relationships. We are particularly interested in characterizing the glycans that are involved in host microbe interactions, in immune regulation and in mediating recognition events during mammalian reproduction. As well as contributing to fundamental understanding of glycan function, we aim to provide structural data to underpin the identification of targets for new drugs and vaccines for the control of pathogens and parasites. We anticipate that our studies of the glycobiology of mammalian fertilization and reproduction will open up new avenues for natural contraception as well as helping infertile couples. Another of our goals is to understand the pathways involved in regulating glycosylation. This is important, not only because altered glycosylation is associated with many chronic health and aging problems, but also because this knowledge will assist the efficient production of well defined glycoprotein biopharmaceuticals. As well as being important constituents of glycoproteins, sugars are the major building blocks of the polysaccharides that constitute the walls of plant cells. There is an urgent need to better understand the biological processes involved in plant cell wall assembly if the potential of biomass as a renewable energy resource and an alternative to fossil fuels for the production of high value chemicals is to be fully realised. We aim to work with plant scientists in the UK and Australia to elucidate the molecular mechanisms of cell wall polysaccharide biosynthesis. Our analytical methods generate large volumes of complex data, so another of our objectives is to create glycoinformatic tools to assist and speed up data interpretation and annotation, and these tools will be made available to the scientific community. We will also develop and populate openly available databases with our glycan structural data, a resource that will benefit scientists from many disciplines around the world.