Probing the mechanism of Programmed Axon death using Protein Design

Human genetics points to roles in polyneuropathies and motor neuron disease, while animal studies strongly suggest wider relevance also in peripheral neuropathies, glaucoma, viral encephalitis, traumatic brain injury, Parkinson's disease and possibly multiple sclerosis. With the recent success of a Phase I clinical trial for SARM1 inhibitors and others in development, it is an important time to develop new tools to study the pathway further.

Project Aims

SARM1 is a modular protein composed of ARM, SAM and TIR domains. CryoEM and crystal structures of each domain and the holoprotein are available, both in its inactive and activated forms. Against this background the aim of this project is to perform rational design of variant forms of SARM1, or hybrids with reporter molecules, to act as tools for studying SARM1 activation, stability, enzyme activity and post-translational modification.

The successful candidate will gain skills in molecular cloning, site directed mutagenesis, enzyme assays, primary and hiPSC-derived neuron cell cultures, transfection and structural analysis and will contribute to both basic biological knowledge and drug discovery efforts in this area.

Our research group has a strong collaborative and supportive culture with many opportunities for conference participation and personal and professional development.

How to Apply;

If you are interested in this project, please go to the University pages and apply via the online portal;

PhD https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcnpdpcn/apply

Research MPhil https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcnmpmds/apply

Funding Notes

For academic year October 27/28;

Gates US applications (round 1) close 14th October 26, further information available via Gates Website; View Website

Cambridge Trust, Gates Cambridge (round 2) deadline 8th December 26 to be eligible for funding. If you apply after the funding deadlines you will not be eligible for the Cambridge Funding competition, please indicate in your application all the funding you are eligible for. You can also check funding search Search - Postgraduate Funding Search

Funding is not available for Lent or Easter 27 places as the funding deadline for these has already passed, you will need to have other funding in place to support your studies

References

Suggested Reading
Coleman and Hoke, Nat Rev Neurosci 21: 183-196 (2020)
Gilley et al, eLife 10: e70905
Loreto et al, Neurobiol Dis 213: 106986
https://www.sciencewithoutanguish.com