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(BBSRC DTP) Developing computational, chemical and biophysical approaches to study the function and regulation of nicotinamide phosphoribosyltransferase (NAMPT)


Faculty of Biology, Medicine and Health

About the Project

NAMPT is a highly-conserved protein that plays a critical role in maintenance of intracellular NAD levels, while also acting as a potent stimulator of inflammatory signalling when released from cells, for example following cell death.

There is significant and ongoing interesting modulating the intracellular activity of NAMPT, as inhibition results in potent cytotoxicity that may be useful in treatment of cancer, while activation increases cellular NAD levels and may be useful in improving healthy aging. Targeting the inflammatory effect of extracellular NAMPT is also emerging as a promising therapeutic approach, however the contribution of NAMPT’s enzymatic activity to it’s inflammatory effects is only now being elucidated.

In collaboration with KCL we have demonstrated that the inflammatory effects of extracellular NAMPT are enzyme-independent and driven by an unexplained increase in monomeric NAMPT as circulating protein concentration increases. Previous studies have failed to demonstrate a role for classical post-translational modifications that could explain this change, however the role of ligand-induced changes in function are poorly understood. This has implications for both the enzymatic and inflammatory functions of NAMPT, support by our recent finding that enzymatic activity and dimerisation can be independently manipulated by synthetic ligands (unpublished).

The aim of the project is to further our understanding of the mechanisms that control the enzymatic and cytokine-like effects of NAMPT/visfatin.

The objectives to achieve this aim are:
1) To develop a quantitative model of ligand binding at the NAMPT active site (theoceptor) and use this to evaluate the binding of natural (phospho)lipids and related compounds.
2) To evaluate the binding of known, novel and putative NAMPT ligands using a range of biophysical techniques including Tm shift and SPR/BLI.
3) To optimise FRET/FP and FCS based on probe systems previously developed in house to allow determination of binding affinity and stoichiometry.
4) To evaluate the effects of validated (endogenous) ligands on the enzymatic and immunological functions of NAMPT using a range of enzymatic and cellular assays.
5) To use this data to drive refinement of binding and molecular dynamic models to explain the physical basis of these effects.

The project with be suitable for candidates with a background in chemistry, biochemistry or related disciplines who wishes to expand their understanding of computational chemistry, chemical biology and/or biophysics/enzymology.

https://www.research.manchester.ac.uk/portal/sam.butterworth.html

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We 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.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

1) Neumann, C. S.; Olivas, K. C.; Anderson, M. E.; Cochran, J. H.; Jin, S.; Li, F.; Loftus, L. V.; Meyer, D. W.; Neale, J.; Nix, J. C.; et al. Targeted Delivery of Cytotoxic NAMPT Inhibitors Using Antibody–Drug Conjugates. Mol. Cancer Ther. 2018, 17 (12), 2633–2642.
2) Gardell, S. J.; Hopf, M.; Khan, A.; Dispagna, M.; Hampton Sessions, E.; Falter, R.; Kapoor, N.; Brooks, J.; Culver, J.; Petucci, C.; et al. Boosting NAD+ with a Small Molecule That Activates NAMPT. Nat. Commun. 2019, 10 (1), 3241.
3) Colombo, G.; Clemente, N.; Zito, A.; Bracci, C.; Colombo, F. S.; Sangaletti, S.; Jachetti, E.; Ribaldone, D. G.; Caviglia, G. P.; Pastorelli, L.; et al. Neutralization of Extracellular NAMPT (Nicotinamide Phosphoribosyltransferase) Ameliorates Experimental Murine Colitis. J. Mol. Med. 2020, 98 (4), 595–612.
4) Sayers, S. R.; Beavil, R. L.; Fine, N. H. F.; Huang, G. C.; Choudhary, P.; Pacholarz, K. J.; Barran, P. E.; Butterworth, S.; Mills, C. E.; Cruickshank, J. K.; et al. Structure-Functional Changes in ENAMPT at High Concentrations Mediate Mouse and Human Beta- Cell Dysfunction in Type 2 Diabetes. Diabetologia 2020, 63, 313.

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