A live model to study mucociliary clearance in health and disease

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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.