Chemical intervention in heparan sulphate-dependent growth factor signalling systems using engineered heparin saccharides

我们的实验室在研究存在于所有细胞表面的复杂多糖硫酸乙酰肝素的结构和活性以及研究细胞和发育生物学中的生物过程方面拥有专业知识。这些糖具有相当大的结构多样性，并与许多特定的蛋白质结合，如生长因子，负责控制所有组织中的细胞行为。我们的实验室感兴趣的是更多地了解它们活动的分子基础，并通过将它们用作工具来对生物系统进行化学干扰来利用它们令人兴奋的自然特性。在这个项目中，我们计划开发一种新的方法来创建具有不同结构的HS糖库，以研究一些生长因子的结构和活性之间的关系。我们将使用试管、细胞和整个动物实验来研究结构差异如何影响这些糖在生物检测中改变生长因子活性的能力。这将使我们能够在生物系统中进行实验，其中将对已知的途径及其生物结果进行有针对性的干预。我们将收集和比较筛选分析的数据，以确定不同生长因子之间的结构特异性，并确定激活和抑制糖分子作为生物系统中选择性化学干预工具的应用。我们还将利用这些信息来设计选定的结构，用于全面的化学合成和测试，目的是为未来的干预实验提供定义的分子。最终目标将是建立工程肝素糖的应用，作为揭示特定HS序列在调节生物系统中的功能作用的新的洞察力的有力工具。这些研究将提供新的信息，帮助我们了解这些糖-蛋白质相互作用是如何调节细胞功能的。它们符合理事会广泛职权范围内的一些领域，即增加对生物如何运作的了解(在这种情况下，与细胞信号和调节相关的分子相互作用)，并提供可用于开发医药和工业新技术和产品的知识。

Our labs have expertise in studying the structure and activities of the complex polysaccharide heparan sulphate, which is found on the surface of all cells, and in studying biological processes in cell and developmental biology. These sugars have considerable structural diversity, and bind to many specialised proteins, such as growth factors, responsible for controlling cell behaviour in all tissues. Our labs are interested in finding out more about the molecular basis for their actions and exploiting their exciting natural properties by using them as tools to chemically interfere in biological systems. In this project we are planning to exploit a new approach we have developed for creating libraries of HS sugars with diverse structures, to study the relationships between structure and activity for a number of growth factors. We will examine how differences in structure affect the ability of these sugars to alter growth factor activities in biological assays using test tube, cell and whole animal assays. This will allow us to carry out experiments in a biological system in which targeted intervention of a known pathway and its biological outcome will be conducted. We will collect and compare the data from screening assays to both determine structural specificity amongst diverse growth factors, and identify activating and inhibitory saccharide molecules for application as selective chemical intervention tools in biological systems. We will also use the information to design selected structures for full chemical synthesis and testing, with the aim of providing a supply of defined molecules for future intervention experiments. The ultimate goal will be to establish the application of engineered heparin saccharide as a powerful tool for revealing novel insights into the functional roles of specific HS sequences in regulation of biological systems. These studies will provide new information which will help us to understand how these sugar-protein interactions regulate the functions of cells. They fit into a number of areas within the broad Council remit of increasing understanding of how living organisms function (in this case, molecular interactions relevant to cell signaling and regulation) and providing knowledge which can be used to develop new technologies and products for medicine and industry.