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(BBSRC DTP) From mucin biochemistry to pulmonary immunity: How do mucins promote antimicrobial lung defences?


Project Description

Respiratory mucus plays multiple essential roles in mammalian lung function, from hydrating the epithelium and supporting gaseous exchange, to expelling inhaled particles and microbes and providing a conduit for innate and adaptive immune signaling. Throughout evolution the composite polymeric glycoproteins, called mucins, have underpinned the structural and functional integrity of mucus barriers however, the mechanistic basis of mucin-mediated lung defence remains poorly understood. In particular, the distinct and synergistic contributions made by biochemically- (structural integrity, viscosity) versus physiologically-mediated (immune signalling and microbicidal) effects of mucins remain largely unknown. In this project we will first apply a reductionist approach, using immortalised mucin-deficient cell lines and a genetically tractable inhaled fungal pathogen (Aspergillus fumigatus) to define the biochemical properties of mucin which support epithelial barrier integrity during pathogen challenge. The derived mechanistic model of mucin-mediated defence will then be transposed into a physiologically relevant immune context using healthy and mucin-deficient mice, and diseased and healthy human respiratory mucus, to establish a causal relationship between biochemical or physiological properties of mucins, or both, and effective defence against inhaled pathogens.

A suite of state-of-the-art biophysical, biochemical, genetic and in vivo methodologies including Light scattering, rheology, mass spectrometry, CRISPR-mediated genetic engineering of host and pathogen cells, human tissue culture, in vivo & in vitro modelling of host-pathogen interactions, imaging flow cytometry, microfluidics, confocal and light sheet microscopy approaches) will be taught during project rotations and then combined to address the research hypothesis. The project builds on work already carried out by a highly interdisciplinary team of three supervisors (Bignell, Thornton, Horsley) which has led to the discovery that a number of secreted Aspergillus proteins drive mucin and epithelial barrier degradation.

https://www.research.manchester.ac.uk/portal/elaine.bignell.html
https://www.research.manchester.ac.uk/portal/dave.thornton.html
https://www.research.manchester.ac.uk/portal/alexander.horsley.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

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