Award details

Defining the mechanisms controlling mucus function

Reference	BB/W006456/1
Principal Investigator / Supervisor	Professor David Thornton
Co-Investigators / Co-Supervisors	Professor Richard Grencis, Professor Ian Roberts
Institution	The University of Manchester
Department	School of Biological Sciences
Funding type	Research
Value (£)	512,337
Status	Current
Type	Research Grant
Start date	01/02/2022
End date	31/01/2025
Duration	36 months

Abstract

Our research will address critical gaps in knowledge concerning the molecular mechanisms controlling the function of protective mucin-based mucus matrices found throughout the animal kingdom. Mucus is a biological hydrogel that controls access of microbes and harmful substances to the underlying epithelial cells and is thus critical for host defence. This specialised matrix is essential for health and recent discoveries of important new functional aspects of its biology have revealed remarkable complexity and overturned the view that mucus only acts as an inert physical barrier. The gel-forming mucins are the key components that underpin the structural integrity of mucus. The composition, structure and properties of mucus determine mucosal hydration, lubrication, provide the niche for commensal microbes and protection against pathogens and toxins. Currently, we lack complete understanding of how mucus composition and properties underpin its multiple roles in maintaining health. We will use an in vivo X. tropicalis tadpole model that we have developed and validated as an important tool to study mucus biology. Critically, the X. tropicalis tadpole produces mucins with structural and functional similarity to mammalian mucins. The unique combination of conserved mucin types, genetic tractability, fast generation time and ease of access to mucin producing tissues makes the tadpole model ideally suited for the research proposed. We will define, in vivo, the composition, structural organisation and functional properties of mucus produced under normal conditions and after infection. Also, after manipulating the mucins, we will define specific roles for their different domains in protection. Thus, we aim to exploit the X. tropicalis model system to define the temporal and molecular details of mucus matrix assembly and how this specifies its protective function. Our research will provide a step-change in understanding the principles that control the mucus matrix function.

Summary

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 ofmammals 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.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Immunology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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