Decoding functional glycan biosynthesis

解码功能性聚糖生物合成

• 批准号: BB/Y000102/1
• 负责人: Daniel Ungar
• 金额: $ 78.15万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY000102%2F1
• 关键词: Decoding; functional; glycan; biosynthesis

Glycans are sugar chains that cover the surface of every living cell. These chains are made up of of different types of sugar monomers linked together, and as such not that different from DNA (nucleotide monomers linked together) and proteins (amino acid monomers linked together). However, in contrast to DNA and proteins, which are made using a template (DNA or RNA) to determine the order of the monomers, glycans do not have a template. Instead, many different enzymes are organised in a structure of the cell called the Golgi, to generate different glycans. The characteristic shape of the Golgi, which looks rather like a set of pancakes stacked on top of each other, reflects its function of organising the enzymes that generate glycans. We know how these enzymes work to add sugars to growing glycan chains, but we do not understand how their distribution in the Golgi's pancakes (called "cisternae") influences which glycans are made, and importantly, how glycans influence cell behaviour. The work we are proposing will combine the generation of cells with different glycan patterns using cell biology, the measurement of these glycan patterns using analytical biochemistry with the modelling of the glycan generation process using computational biology. Our approach brings together the different disciplines needed to understand this complex cellular machinery and decode how enzyme organisation in the Golgi generates different glycans. This alone, however, will not complete our understanding of glycan generation, because we also need to comprehend which parts of the glycan chains generated by the Golgi are important for cell functions. To understand this, we will measure a variety of different cellular properties, including size, growth rate, how well cells move around, using automated tracking of cells in a microscope, and a software that can extract the cells' behaviours from the images. Added to this, we will also investigate how the proteins to which glycans are attached behave, and finally how the glycans themselves behave in their natural environment. By combining such functional data with the decoding of glycan generation for a large number of cell lines with altered glycans, we can piece together which glycan features are responsible for which behaviours, and understand how the most critical glycan features are encoded in the Golgi. Our work will ultimately lead to the decoding of glycan synthesis in cells, similar to the decoding of the "DNA to protein" paradigm. This will open up the possibility of investigating glycan functions more systematically; the impact of which is hard to estimate or overstate.

Glycans是覆盖每个活细胞表面的糖链。这些链由连接在一起的不同类型的糖单体组成，因此与DNA（链接在一起的核苷酸单体）和蛋白质（将蛋白（氨基酸单体链接在一起）并没有什么不同。但是，与使用模板（DNA或RNA）确定单体的DNA和蛋白质相比，聚糖没有模板。取而代之的是，许多不同的酶在称为高尔基体的细胞结构中组织，以生成不同的聚糖。高尔基体的特征形状看起来像是一组煎饼彼此堆叠在一起，反映了其组织产生聚糖的酶的功能。我们知道这些酶如何为生长的聚糖链添加糖，但我们不了解它们在高尔基煎饼中的分布如何影响糖是制造聚糖的影响，并且重要的是聚糖如何影响细胞行为。我们提出的工作将使用分析生物化学与使用计算生物学的聚糖生成过程建模，将细胞的产生与不同的聚糖模式结合在一起。我们的方法汇集了了解这种复杂的细胞机制所需的不同学科，并解码高尔基体中的酶组织如何产生不同的聚糖。但是，仅此一项就无法完成我们对聚糖产生的理解，因为我们还需要理解高尔基体产生的聚糖链的哪些部分对于细胞功能很重要。为了理解这一点，我们将测量各种不同的细胞特性，包括尺寸，生长速率，使用显微镜中细胞自动跟踪细胞的移动方式以及可以从图像中提取细胞行为的软件。除此之外，我们还将调查如何与聚糖相关的蛋白质，最后是聚糖本身在自然环境中的行为。通过将这种功能数据与用于大量细胞系的聚糖生成的解码和变化的聚糖结合在一起，我们可以将聚糖特征归根结合地组合，这些特征负责哪些行为，并了解如何在高尔基体中编码最关键的Glycan特征。我们的工作最终将导致细胞中聚糖合成的解码，类似于“ DNA对蛋白质”范式的解码。这将开辟更系统地研究聚糖功能的可能性。其影响很难估计或夸大其词。