Investigation of a novel supramolecular organisation of the oligomeric mucins MUC5AC MUC5B and MUC2

寡聚粘蛋白 MUC5AC MUC5B 和 MUC2 的新型超分子组织的研究

• 批准号: BB/D522389/1
• 负责人: David Thornton
• 金额: $ 31.92万
• 依托单位: University of Manchester
• 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%2FD522389%2F1
• 关键词: Investigation; novel; supramolecular; organisation; oligomeric

A layer of mucus is a common means of protecting the delicate exposed epithelial surfaces of an organism against its environment and a range of biological, chemical and physical insults. We have discovered that the gel-like characteristics of mucus in saliva and now potentially in other mucus gels (e.g. the respiratory, gastrointestinal and reproductive tracts) are caused by calcium binding in the large structural glycoproteins (mucins). Our evidence shows that this involves protein parts of the mucin linking mucin molecules together. Therefore we will identify the part(s) of the mucin responsible for calcium-binding by testing different parts of the molecule prepared separately and also in fragments of mucin purified from saliva. The details of how it functions and where it occurs in the structure of the mucin will be determined. We will also investigate whether mucins can be modified to remove or inactivate their calcium binding properties. This calcium dependent cross-link activity that we have detected in mucin is newly discovered and it is a potentially important mechanism contributing to the function of this vital protective barrier. Furthermore, an improved understanding of the organisation of this barrier has important implications for treatment of common diseases involving mucus overproduction (e.g. asthma and cystic fibrosis) and improved strategies for the delivery to and across epithelial surfaces of pharmaceuticals and gene therapy agents.

粘液层是保护生物体脆弱的暴露的上皮表面免受其环境和一系列生物、化学和物理损伤的常见手段。我们已经发现，唾液中粘液的凝胶状特征以及现在可能在其他粘液凝胶（例如呼吸道、胃肠道和生殖道）中的粘液的凝胶状特征是由大结构糖蛋白（粘蛋白）中的钙结合引起的。我们的证据表明，这涉及粘蛋白的蛋白质部分连接粘蛋白分子在一起。因此，我们将通过测试分别制备的分子的不同部分以及从唾液中纯化的粘蛋白片段来鉴定负责钙结合的粘蛋白部分。它如何发挥作用以及它在粘蛋白结构中的位置的细节将被确定。我们还将研究粘蛋白是否可以被修饰以去除或抑制其钙结合特性。我们在粘蛋白中检测到的这种钙依赖性交联活性是新发现的，它是有助于这种重要保护屏障功能的潜在重要机制。此外，对这种屏障的组织的更好理解对于治疗涉及粘液过度产生的常见疾病（例如哮喘和囊性纤维化）和改进药物和基因治疗剂递送至上皮表面和穿过上皮表面的策略具有重要意义。

项目成果

Assembly of the respiratory mucin MUC5B: a new model for a gel-forming mucin.

• DOI: 10.1074/jbc.m114.566679
• 发表时间: 2014-06-06
• 期刊: The Journal of biological chemistry
• 作者: Ridley C;Kouvatsos N;Raynal BD;Howard M;Collins RF;Desseyn JL;Jowitt TA;Baldock C;Davis CW;Hardingham TE;Thornton DJ
• 通讯作者: Thornton DJ