Award details

Nampt/PBEF/Visfatin: a new molecular target for blocking axon degeneration

Reference	BBS/E/B/0000C246
Principal Investigator / Supervisor	Professor Michael Philip Coleman
Co-Investigators / Co-Supervisors
Institution	Babraham Institute
Department	Babraham Institute Department
Funding type	Research
Value (£)	84,164
Status	Completed
Type	Institute Project
Start date	01/11/2010
End date	30/06/2013
Duration	32 months

Abstract

We aim here to clarify the target of a drug that delays axon degeneration in primary culture. We have range of tools available including a conditional null allele, a second drug that inhibits a strong candidate enzyme and a mutation that confers drug resistance on this enzyme. Resolving this question will strongly support an external application to fund in vivo studies and disease and to identify more potent molecules. It will also help exploit the translational and commercial potential in collaboration with BBT, who are keen to provide additional support. First however, the target needs to be clear. Treating axon degeneration is a major unmet need. One in two of us will suffer its painful or disabling consequences through Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, glaucoma, diabetic neuropathy or other disorders. We find that FK866, a pro- apoptotic cancer drug in Phase II trials (Holen et al., 2008), consistently protects injured axons in culture thus mimicking the slow Wallerian degeneration (WldS) phenotype. Unlike WldS, which substitutes for the labile NAD+ synthesising enzyme Nmnat2 (Gilley and Coleman, 2010), FK866 inhibits the previous enzyme in the NAD+ synthetic pathway, Nampt, depleting cells of NAD+. This is the basis of its anti-cancer action but whether Nampt also underlies the neuroprotective effect is not yet clear. This development is critically important for understanding the degenerative mechanism and the neuroprotective action of WldS. It is also an exciting basis for drug development in axonal disorders. For both purposes, the molecular target of FK866 has to be identified conclusively. Therefore, using pharmacological and genetic methods we will test the hypothesis that Nampt activity is necessary for Wallerian degeneration in vitro.

Summary

unavailable

Committee	Not funded via Committee
Research Topics	Ageing, Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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