Unravelling the molecular mechanisms controlling respiratory tract mucus gel formation in health and disease

肺部产生胶状物质粘液，以保护身体免受环境挑战(污染或空气中存在的细菌和病毒)。这种粘液困住这些环境因子，它们被所谓的粘液纤毛自动扶梯移出肺外；这种自动扶梯是由许多排列在上呼吸道表面的细胞组成的，这些细胞有毛发状突起(纤毛)。纤毛拍打并将粘液向上移动到咽喉，在那里它被吞咽。患有哮喘、囊性纤维化和慢性复发性呼吸道阻塞等呼吸道疾病的患者面临的主要斗争之一是他们产生太多粘液，粘液比正常情况下更粘稠。其结果是，粘液不能被纤毛移动，并阻塞呼吸系统，从而导致感染和死亡风险。粘液的骨架被提供了称为粘蛋白的极大分子。与粘液中的许多其他分子不同，粘蛋白被制造出来，然后储存在细胞内的特殊结构中，等待适当的信号释放，并通过与自身和其他分子的相互作用形成粘液。在它们的释放过程中，粘蛋白的结构从高度浓缩的形式变化为扩张的绳状形式。在呼吸道粘液中发现两种类型的粘蛋白(MUC5AC和MUC5B)，我们知道在疾病中会产生更多的这些分子；尤其是其中一种具有异常结构形式(更浓缩和网状而不是更正常的绳状形式)的粘蛋白(MUC5B)的过度生产导致呼吸道阻塞。重要的是，最近的研究表明，MUC5B对于粘液的产生至关重要，这种粘液很容易被纤毛移动。因此，我们研究提案的主要问题是异常粘液是如何产生的；是主要凝胶形成分子MUC5B的有缺陷的凝结、有缺陷的膨胀或改变的相互作用性质(或这些因素的组合)。为了回答这个问题，我们使用了跨越生物学和物理学的最先进的方法。我们在这个项目中的目标是了解控制粘蛋白产生的机制，这些粘蛋白具有导致粘液无法保护肺的特性。这种肺部粘液生物学的新知识将有助于为患有呼吸道阻塞的人设计新的治疗方法。

The lungs produce the jelly-like substance mucus in order to defend the body from environmental challenges (pollution or bacteria and viruses present in the air). This mucus traps these environmental agents and they are moved out of the lung by what is called the 'mucociliary escalator'; this is made up from many cells lining the surface of the upper airways, which have hair-like protrusions (cilia). The cilia beat and move the mucus up to the throat where it is swallowed. One of the major struggles faced by individuals suffering from airway diseases such as asthma, cystic fibrosis and chronic recurrent obstruction of their airway is that they make too much mucus, and the mucus is stickier than normal. The consequence of this is that the mucus cannot be moved by cilia and it blocks the respiratory system, which leads to infection and risk of death. The framework of the mucus is provided extremely large molecules called mucins. Unlike many other molecules in mucus, mucins are made and then stored within special structures inside cells awaiting the appropriate signal to be released and, via interactions with themselves and other molecules, form mucus. During their release the structure of mucins changes from a highly condensed form to an expanded, rope-like form. There are two types of mucin (MUC5AC and MUC5B) found in airways mucus and we know that in disease larger amounts of these molecules are produced; in particular overproduction of one of these (MUC5B) with an abnormal structural form (more condensed and web-like rather than the more normal rope-like form) contributes to obstruction of the airways. Importantly, recent research suggests that MUC5B is crucial for the generation of mucus that is easily moved by cilia. Therefore, the principal question of our research proposal is how abnormal mucus is generated; is it defective condensation, defective expansion, or altered interactive properties (or a combination of these factors) of the main gel-forming molecule, MUC5B. To answer this question we are employing state-of-the-art methods spanning biology and physics. Our goal in this project is to understand the mechanisms that control the production of mucins with properties that cause the failure of mucus to protect the lung. This new knowledge of mucus biology in the lung will help design novel treatments for people suffering with obstruction of their airways.