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.

葡聚糖是覆盖在每个活细胞表面的糖链。这些链是由连接在一起的不同类型的糖单体组成的，因此与DNA(连接在一起的核苷酸单体)和蛋白质(连接在一起的氨基酸单体)没有太大区别。然而，与DNA和蛋白质不同的是，DNA和蛋白质是使用模板(DNA或RNA)来确定单体的顺序的，而多糖没有模板。相反，许多不同的酶被组织在称为高尔基体的细胞结构中，以产生不同的多糖。高尔基体的特征形状看起来很像一组层叠在一起的煎饼，反映了它组织产生多糖的酶的功能。我们知道这些酶是如何向不断生长的糖链中添加糖的，但我们不知道它们在高尔基煎饼(称为“池子”)中的分布如何影响形成哪些多糖，以及重要的是，多糖如何影响细胞行为。我们提议的工作将结合使用细胞生物学生成具有不同糖链模式的细胞，使用分析生物化学测量这些糖链模式，以及使用计算生物学对糖链生成过程进行建模。我们的方法将理解这种复杂的细胞机制并破译高尔基体中的酶组织如何产生不同的多糖所需的不同学科结合在一起。然而，仅靠这一点并不能完成我们对多糖产生的理解，因为我们还需要理解高尔基体产生的糖链的哪些部分对细胞功能是重要的。为了理解这一点，我们将测量各种不同的细胞属性，包括大小、生长速度、细胞移动的情况，使用显微镜中对细胞的自动跟踪，以及一个可以从图像中提取细胞行为的软件。除此之外，我们还将研究附着在多糖上的蛋白质的行为，最后研究多糖本身在自然环境中的行为。通过将这些功能数据与大量具有改变的糖链的细胞系的糖链生成的解码相结合，我们可以拼凑出哪些糖链特征负责哪些行为，并了解最关键的糖链特征是如何在高尔基体中编码的。我们的工作最终将导致破译细胞中的多糖合成，类似于破译“DNA到蛋白质”的范例。这将开启更系统地研究多糖功能的可能性；其影响很难估计或夸大。