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Using complex glycans as drug delivery vectors

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  • Full or part time
    Dr A Cartmell
    Dr H Strahl von Schulten
    Dr Edwin Yates
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

The development of small molecules to treat human disease and enhance quality of life, is one of the most important areas in biotechnology. There are several key aspects of small molecules which need to be considered, including; (i) the efficacy against their target, (ii) establishing what the off target effects are, and (iii) determining how the molecule should best be delivered. Both efficacy and off-target effects can be optimised through effective, targeted, drug delivery. For instance, the ability to target a drug to a specific, localised area, will increase its effective concentration thus reducing off-target effects.

The colonic environment is one area where drug targeting would be of great benefit in treating such debilitating, localised diseases as ulcerative colitis, Crohn’s disease, irritable bowel syndrome, chronic pancreatitis and colon cancer. Furthermore, the colon could also be exploited as a site for systemic absorption to treat non-colonic conditions. There are, however, a number of challenges facing colonic drug delivery. The colon is at the distal part of the gastrointestinal (GI) tract and drugs must travel its full length in order to reach the target site. There are drastic changes in pH from the gastric environment to the colonic environment and the drug must survive both. The presence of food, metabolic enzymes and a vast microbial community, especially in the colon, further add to the complexity of the system.

Complex glycans (GAGs) already make it to the colon intact and the bacteria in the colon have the required enzymatic apparatus to metabolise them. This makes GAGs an ideal potential mechanism for colonic drug delivery. Two key parameters are needed to utilise GAGs for drug delivery: knowledge of the glycan’s composition and structure and detailed molecular insights into the proteins that metabolise them. It is with these key parameters in mind that the focus of this proposal will be to develop glycans for potential drug delivery. Furthermore, GAGs have been shown to be high priority substrates for gut bacteria. This means their metabolism is not repressed, or altered, by the presence of other glycans, including glucose. This is ideal for a drug delivery system as the GAG vehicle will be resistant to sudden dietary changes. This PhD will provide the student with unique multidisciplinary training in chemistry, biochemistry and high-resolution microscopy providing them with a wide breadth of skills that will render them highly employable to both the industry and academia.

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), and a covering letter – 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 and at the selected University. Applications not meeting these criteria will be rejected.

In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (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 Monday 18th May at 12noon.

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

The metabolism of multiple glycosaminoglycans by the human gut symbiont bacteroides thetaiotaomicron is orchestrated by a versatile core genetic locus. Nat. commun. under revision

The human gut microbe Bacteroides thetaiotaomicron encodes the founding member of a novel glycosaminoglycan-degrading polysaccharide lyase family PL29.

J Biol Chem. 2018 Nov 16;293(46):17906-17916. doi: 10.1074/jbc.RA118.004510. Epub 2018 Sep 27. PMID: 30262663

How members of the human gut microbiota overcome the sulfation problem posed by glycosaminoglycans.
Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7037-7042. doi: 10.1073/pnas.1704367114. Epub 2017 Jun 19. PMID:28630303

Extreme slow growth as alternative strategy to survive deep starvation in bacteria. Nat Commun. 2019 Feb 21;10(1):890. doi: 10.1038/s41467-019-08719-8. PMID:30792386

The type VI secretion system deploys antifungal effectors against microbial competitors. Nat Microbiol. 2018 Aug;3(8):920-931. doi: 10.1038/s41564-018-0191-x. Epub 2018 Jul 23. PMID:30038307

The Gram-positive model organism Bacillus subtilis does not form microscopically detectable cardiolipin-specific lipid domains.
Microbiology. 2018 Apr;164(4):475-482. doi: 10.1099/mic.0.000639. Epub 2018 Mar 5. PMID:29504925

19F labelled glycosaminoglycan probes for solution NMR and non-linear (CARS) microscopy. Glycoconj J. 2017 Jun;34(3):405-410. doi: 10.1007/s10719-016-9723-x. Epub 2016 Aug 15. PMID:27523650

Glycosaminoglycan origin and structure revealed by multivariate analysis of NMR and CD spectra. Glycobiology. 2009 Jan;19(1):52-67. doi: 10.1093/glycob/cwn103. Epub 2008 Oct 2. PMID:18832453

Protein-GAG interactions: new surface-based techniques, spectroscopies and nanotechnology probes. Biochem Soc Trans. 2006 Jun;34(Pt 3):427-30. Review. PMID:1670917



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