Defining the mechanisms controlling mucus function

定义控制粘液功能的机制

• 批准号: BB/W006456/1
• 负责人: David Thornton
• 金额: $ 65.28万
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW006456%2F1
• 关键词: Defining; mechanisms; controlling; mucus; function

Mucus is essential for health and this gel-like substance controls access of disease-causing microbes and harmful substances to cells and tissues at exposed mucosal surfaces of animals (for example, the linings of the lung and gut). It is therefore the critical first line of defence against infection, chemical challenges and physical injury. Far from being just a simple physical barrier, new evidence has revealed that mucus is complex and dynamic, and responsive to environmental challenges, such as those induced by disease-causing microbes. While great progress has been made towards understanding mucus function, we currently still lack the precise details of how mucus performs its vital protective role in maintaining healthy mucosal surfaces. Here, we will take a multi-pronged approach to discover how mucus properties are controlled to optimise its defensive role and how these properties evolve when fighting bacteria. The structural integrity and many of the known functional properties of mucus are due to a family of very large sugar-rich molecules called gel-forming mucins. These molecules underpin protective mucus barriers found throughout the animal kingdom, and of particular relevance to this project, the mucus barrier on the surface of amphibians. In the research, we will use the Western clawed frog tadpole (species name Xenopus tropicalis) as a tool to address critical gaps in our knowledge concerning the precise details of mucus protection that will be of relevance to animals and humans. The research team have already developed and validated the tadpole as a new and important tool to study mucus biology. Critically, these tadpoles produce gel-forming mucins with structural and functional similarity to gel-forming mucins produced by mammals. Importantly, the specialised mucin producing cells are on the external surface of the tadpole thereby allowing easy access and ready manipulation. This is in stark contrast to the comparable internal mucosal surfaces of mammals which are difficult to access involving extensive tissue damage. Moreover, this simple non-mammalian organism is easy to genetically manipulate and reproduces quickly. This unique combination of features makes the tadpole model ideally suited for the research proposed in this application and will provide valuable insight into evolutionarily conserved mechanisms of mucin and mucus function. In this research project, we will use the tadpole model to define the make-up, formation, organisation and function of mucus produced under normal conditions and how these change after infection with a disease-causing bacterium found in their native environment. Moreover, after genetically changing the gel-forming mucins to alter their nature, we will define specific roles for the different parts of these complex molecules in mucosal protection. Thus, the overall aim of the proposal is to exploit the tadpole model system we have developed to define how mucus changes over-time and how this specifies its protective function. Our program of work will provide a step-change in understanding how mucus performs its protective functions at mucosal sites that will be relevant across the animal kingdom. In particular, providing new insight into how mucus protects against infection.

粘液对健康至关重要，这种凝胶状物质控制致病微生物和有害物质进入暴露在动物黏膜表面的细胞和组织(例如，肺和肠道的衬里)。因此，它是抵御感染、化学挑战和身体伤害的关键第一道防线。新的证据表明，粘液不仅是一种简单的物理屏障，而且是复杂和动态的，对环境挑战(如致病微生物引起的挑战)具有响应性。虽然对粘液功能的了解已经取得了很大的进展，但目前我们仍然缺乏关于粘液如何在维持健康的粘膜表面发挥重要保护作用的确切细节。在这里，我们将采取多管齐下的方法来发现如何控制粘液属性以优化其防御作用，以及在与细菌作战时这些属性是如何演变的。粘液的结构完整性和许多已知的功能特性归功于一种被称为凝胶形成粘蛋白的非常大的富含糖的分子家族。这些分子支撑着在整个动物界发现的保护性粘液屏障，特别是与这个项目相关的两栖动物表面的粘液屏障。在这项研究中，我们将使用西方爪蛙蝌蚪(物种名称热带非洲爪蛙)作为工具，解决我们在粘液保护的确切细节方面的关键知识空白，这些细节将与动物和人类相关。研究小组已经开发并验证了蝌蚪是研究粘液生物学的一种新的重要工具。关键的是，这些蝌蚪产生的凝胶粘蛋白在结构和功能上与哺乳动物产生的凝胶粘蛋白相似。重要的是，专门生产粘蛋白的细胞位于蝌蚪的外表面，因此便于接触和操作。这与哺乳动物的内部粘膜表面形成了鲜明的对比，哺乳动物的内部粘膜表面很难接触到，涉及广泛的组织损伤。此外，这种简单的非哺乳动物生物很容易进行基因操作，繁殖速度很快。这种独特的特征组合使蝌蚪模型非常适合于本应用中提出的研究，并将为粘蛋白和粘液功能的进化保守机制提供有价值的见解。在这项研究项目中，我们将使用蝌蚪模型来定义正常条件下产生的粘液的组成、形成、组织和功能，以及这些粘液在感染了在其自然环境中发现的致病细菌后如何变化。此外，在对形成凝胶的粘蛋白进行遗传改变以改变它们的性质之后，我们将定义这些复杂分子的不同部分在粘膜保护中的具体作用。因此，该提案的总体目标是利用我们开发的蝌蚪模型系统来定义粘液如何随时间变化以及如何指定其保护功能。我们的工作计划将在理解粘液如何在整个动物界相关的粘膜部位发挥其保护功能方面提供一个阶段性的改变。特别是，为粘液如何预防感染提供了新的见解。