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Understanding and exploiting host glycan breakdown by the human gut microbiota


   Biosciences Institute

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  Dr D Bolam, Prof D Rigden, Dr Jon Marles-Wright  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

The human gut microbiota (HGM) has a mutualistic relationship with the host, creating a profound but poorly understood impact on health, development, and disease. Complex carbohydrates (glycans) are the main nutrient source for the HGM and come from both dietary and host sources. Little is known known about how host glycans, found on many secreted proteins including intestinal mucins, are targeted by microbiota, despite the importance of these glycans to host health and their role in protection from pathogens. 

Here we seek to further our understanding of how the normal gut microbiota are able to degrade a range of host glycan structures from mucins and other glycoproteins in the gut and characterise the enzymes (glycanases) involved. The novel enzymes discovered will then be advanced to Ludger for testing in a range of glycobiology applications relevant to their business. Glycanases are often used to identify specific glycan structures (glycoprofiling), but there is a growing need for new or improved glycanase activities to provide novel and/or enhanced biomarker discovery and detection and to aid in the analysis of biopharmaceuticals which are often heavily glycosylated.

This CASE studentship is a collaboration between labs at Newcastle and Liverpool Universities and the glycobiology company Ludger Ltd (Oxford) to exploit the huge untapped resource of potential novel human-glycan active enzymes encoded by the human gut microbiota for use in personalised medicine and other glycobiology applications.

The project will involve use advanced bioinformatics techniques, including next generation deep learning-based methods such as AlphaFold 2, to identify novel glycanases for biochemical and structural characterisation, whilst working closely with Ludger to prioritise target enzymes activities most relevant for glycobiology applications. The student will gain extensive industrially relevant experience in glycoanalytics, as well expertise in the latest glycobiology, bioinformatics and structural techniques.

This exciting project aims to both provide a deeper understanding of how the human gut microbiota are able use diverse host glycans as a nutrient source, while also providing a pipeline for exploitation of these discoveries directly into an industrial setting.

The studentship should be commenced before the end of 2022.

HOW TO APPLY

Applications should be made by emailing [Email Address Removed] with:

·      a CV (including contact details of at least two academic (or other relevant) referees);

·       a covering letter – clearly stating your first choice project, and optionally 2nd ranked project, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University;

·      copies of your relevant undergraduate degree transcripts and certificates;

·      a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.

In addition to the above items, please email a completed copy of the Additional Details Form (as a Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to [Email Address Removed]. The closing date for applications is Friday 8th July 2022 at 12noon (UK time).


Funding Notes

CASE studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Note that home (UK) candidates may also apply to this studentship.

References

Prominent members of the human gut microbiota express endo-acting O-glycanases to initiate mucin breakdown. Nat Commun (2020) 11:4017.
A novel glycosidase plate-based assay for the quantification of galactosylation and sialylation on human IgG. Glycoconj J (2020) 37:691-702.
Complex N-glycan breakdown by gut Bacteroides involves an extensive enzymatic apparatus encoded by multiple co-regulated genetic loci. Nat Microbiol (2019)
Structure- and context-based analysis of the GxGYxYP family reveals a new putative class of glycoside hydrolase. BMC Bioinformatics (2014) 15:196.
Introducing endo-xylanase activity into an exo-acting arabinofuranosidase that targets side chains. Proc Natl Acad Sci USA. (2012) 109:6537-42.
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