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

使用工程肝素糖对硫酸乙酰肝素依赖性生长因子信号系统进行化学干预

基本信息

批准号：
BB/D006325/1
负责人：
Jeremy Turnbull
金额：
$ 69.58万
依托单位：
University of Liverpool
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FD006325%2F1
关键词：
Chemical intervention heparan sulphate dependent

项目摘要

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.

我们的实验室拥有研究复杂多糖硫酸乙酰肝素（存在于所有细胞表面）的结构和活性以及研究细胞和发育生物学中的生物过程的专业知识。这些糖具有相当大的结构多样性，并与许多专门的蛋白质结合，例如负责控制所有组织中细胞行为的生长因子。我们的实验室有兴趣更多地了解其作用的分子基础，并通过使用它们作为化学干扰生物系统的工具来利用其令人兴奋的自然特性。在这个项目中，我们计划利用我们开发的一种新方法来创建具有不同结构的 HS 糖库，以研究许多生长因子的结构和活性之间的关系。我们将使用试管、细胞和整个动物测定来研究结构差异如何影响这些糖在生物测定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，其中将对已知途径及其生物学结果进行有针对性的干预。我们将收集和比较筛选测定的数据，以确定不同生长因子之间的结构特异性，并识别活化和抑制性糖分子，以用作生物系统中的选择性化学干预工具。我们还将利用这些信息来设计选定的结构以进行完整的化学合成和测试，目的是为未来的干预实验提供确定的分子。最终目标是建立工程肝素糖的应用作为一种强大的工具，以揭示特定 HS 序列在生物系统调节中的功能作用的新见解。这些研究将提供新的信息，帮助我们了解这些糖蛋白相互作用如何调节细胞的功能。它们符合理事会广泛职责范围内的许多领域，即增进对生物体如何发挥作用（在本例中为与细胞信号传导和调节相关的分子相互作用）的了解，并提供可用于开发医药和生物制品新技术和产品的知识。行业。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nanoscale self-assembled multivalent (SAMul) heparin binders in highly competitive, biologically relevant, aqueous media

DOI：
10.1039/c4sc00298a
发表时间：
2014-01-01
期刊：
CHEMICAL SCIENCE
影响因子：
8.4
作者：
Bromfield, Stephen M.;Posocco, Paola;Smith, David K.
通讯作者：
Smith, David K.

Novel ex vivo transgenic mouse brain tissue assay for screening BACE1 inhibitors

用于筛选 BACE1 抑制剂的新型离体转基因小鼠脑组织测定法

DOI：
发表时间：
期刊：
Nature Methods
影响因子：
48
作者：
Guimond, SE
通讯作者：
Guimond, SE

Rapid purification and high sensitivity analysis of heparan sulfate from cells and tissues: toward glycomics profiling.

DOI：
10.1074/jbc.m109.032755
发表时间：
2009-09-18
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Guimond SE;Puvirajesinghe TM;Skidmore MA;Kalus I;Dierks T;Yates EA;Turnbull JE
通讯作者：
Turnbull JE

Influence of substitution pattern and cation binding on conformation and activity in heparin derivatives.

取代模式和阳离子结合对肝素衍生物构象和活性的影响。