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, and utilised our knowledge of NAMPT ligands to develop a novel class of NAMPT activators. 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support by our finding that enzymatic activity and dimerisation can be independently manipulated by synthetic ligands (unpublished).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 design, synthesis and evaluate the binding of novel and putative NAMPT ligands using a range of biophysical techniques including Tm shift and SPR/BLI.
2) To develop a quantitative model of ligand binding at the NAMPT active site (theoceptor) and use this to evaluate the binding of known active compounds, natural (phospho)lipids and related compounds.
3) To evaluate the effects of validated (endogenous) ligands on the enzymatic and immunological functions of NAMPT using a range of enzymatic and cellular assays.
4) 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 (medicinal/synthetic) chemistry, biochemistry or related disciplines who wish to expand their understanding of medicinal and computational chemistry, chemical biology and/or biophysics/enzymology.
Eligibility
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/bbsrc-dtp/
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]
Equality, Diversity and Inclusion
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 https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
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