A live model to study mucociliary clearance in health and disease

研究健康和疾病中粘液纤毛清除的实时模型

• 批准号: NC/S001034/1
• 负责人: David Thornton
• 金额: $ 62.96万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FS001034%2F1
• 关键词: live; model; study; mucociliary; clearance

The human lungs are the sites of gaseous exchange where air, containing oxygen, is breathed in and carbon dioxide is breathed out. This direct interaction with the outside world makes the lungs particularly vulnerable to the entry of harmful foreign agents such as pollutants and bacteria, viruses and fungi. In order to prevent their entry into the body, a protective barrier shields the exposed surfaces of the lungs. This barrier is composed of mucus, a gel-like material that acts like a 'molecular sieve' to trap inhaled infectious agents and pollutants. Once trapped, these foreign bodies need to be removed from the lung before they cause damage. Specific lung cells, called ciliated cells, project tiny hair-like structures (cilia) into the overlying mucus layer. The cilia move together in a coordinated manner so as to generate a directional flow that takes the mucus, and any trapped material, away from the lungs. This process is known as mucociliary clearance and if it is defective this can lead to disease. Examples of diseases with defective mucociliary clearance includes cystic fibrosis, where mucus is thick and sticky and cannot be moved; asthma, where an overproduction of mucus can cause airway obstruction; and primary ciliary dyskinesia where cilia movement is impaired and so mucus cannot be cleared. These diseases, particularly cystic fibrosis and primary ciliary dyskinesia, lead to increase vulnerability to infection, which can prove fatal.In order to effectively treat these diseases, we need to understand precisely how mucociliary clearance works so that we can design drugs to improve outcomes for patients. Scientists often employ model organisms to understand the details of a biological process that is difficult, or ethically improper, to study in humans. With mucociliary clearance, mammalian models, particularly mice, are commonly used to either mimic diseases or to understand the role of particular genes in the process. However, the anatomical location of the lungs within the body means that it is difficult to study the dynamics of mucociliary clearance and often involves invasive techniques that can be harmful to the mice. In this research proposal, we introduce an alternative model, the tadpole of the frog species, Xenopus tropicalis, to replace the use of mice in these studies. Importantly, their skin surface produces mucus and has ciliated cells that move the mucus, just like in the human lungs. Details about the function of particular genes in mucociliary clearance and how mucus interacts with cilia and with other agents (e.g. bacteria) can be elucidated with this model, extending our understanding of mucociliary clearance in humans. Crucially, the tadpoles that we use are at an early developmental stage and are considered to be non-sentient. Our aim for this project is to develop and validate this live model of mucociliary clearance using the tadpole skin in order to gain new scientific insight at the same time as replacing, and reducing the reliance on, mice.

人体的肺部是气体交换的场所，吸入含有氧气的空气并呼出二氧化碳。这种与外界的直接相互作用使肺部特别容易受到污染物、细菌、病毒和真菌等有害外来物质的影响。为了防止它们进入体内，保护屏障保护了肺部的暴露表面。该屏障由粘液组成，粘液是一种凝胶状材料，其作用类似于“分子筛”，可捕获吸入的传染源和污染物。一旦被困，这些异物需要在造成损害之前从肺部清除。特定的肺细胞（称为纤毛细胞）将微小的毛发状结构（纤毛）投射到上面的粘液层中。纤毛以协调的方式一起移动，从而产生定向流动，将粘液和任何截留的物质带离肺部。这个过程被称为粘膜纤毛清除，如果它有缺陷，就会导致疾病。粘液纤毛清除有缺陷的疾病的例子包括囊性纤维化，其中粘液浓稠且粘稠且无法移动；哮喘，粘液分泌过多会导致气道阻塞；原发性纤毛运动障碍，纤毛运动受损，因此粘液无法清除。这些疾病，特别是囊性纤维化和原发性纤毛运动障碍，会导致感染的可能性增加，这可能是致命的。为了有效治疗这些疾病，我们需要准确了解粘膜纤毛清除的工作原理，以便我们可以设计药物来改善患者的治疗结果。科学家经常利用模型生物来了解生物过程的细节，而这些生物过程在人类身上进行研究是困难的，或者在伦理上是不恰当的。通过粘液纤毛清除，哺乳动物模型，特别是小鼠，通常用于模拟疾病或了解特定基因在此过程中的作用。然而，肺部在体内的解剖位置意味着很难研究粘膜纤毛清除的动态，并且通常涉及可能对小鼠有害的侵入性技术。在本研究提案中，我们引入了另一种模型，即青蛙物种热带爪蟾的蝌蚪，以取代这些研究中使用的小鼠。重要的是，它们的皮肤表面会产生粘液，并具有移动粘液的纤毛细胞，就像人类的肺部一样。通过该模型可以阐明特定基因在粘液纤毛清除中的功能以及粘液如何与纤毛和其他物质（例如细菌）相互作用的细节，从而扩展我们对人类粘液纤毛清除的理解。至关重要的是，我们使用的蝌蚪正处于早期发育阶段，被认为是没有知觉的。我们该项目的目标是开发和验证这种使用蝌蚪皮肤进行粘膜纤毛清除的活体模型，以便在替代小鼠并减少对小鼠的依赖的同时获得新的科学见解。