Project No. 2328

PRIORITY PROJECT

Primary Supervisor

Dr Sassan Hafizi – University of Portsmouth

Co-Supervisor(s)

Prof Mark Smales – University of Kent

Summary

Neuroinflammation is a major challenge as a therapeutic target for alleviating CNS damage and facilitating repair in neurodegenerative diseases such as multiple sclerosis and Alzheimer’s.

The protein Gas6 is widely expressed in the brain and is implicated as a negative regulator of CNS inflammation and immunity, and promoter of tissue repair. Gas6 becomes functional through a vitamin K-dependent carboxylation of multiple glutamic acid residues. However, it is not currently known whether endogenous vitamin K in the brain is sufficient to ensure sufficient carboxylation, and consequently activation, of Gas6 to enable it to exert its beneficial functions. Thus, we propose a new strategy to dampen neuroinflammation and promote repair in the brain, using vitamin K to enhance the functionality of endogenous brain Gas6.
In the project, we will screen a diverse array of synthesised vitamin K derivatives for their ability to stimulate Gas6 γ-carboxylation in mouse brain glial cell cultures and tissue explants. We will use a combination of specific immunoassays (Portsmouth) and LC-mass spectrometry (Kent) to determine the level of expression, as well as the extent of γ-carboxylation, of endogenous brain Gas6 protein. The project will also involve a similar approach in mice, which will be administered vitamin K orally in vivo, with subsequent analysis of vitamin K and Gas6 levels in the brain. There will also be a translational component to the project, where human brain tissues from the brain bank featuring neurodegenerative pathologies will be similarly analysed.

These different approaches to the PhD project will elucidate the value of elucidating Gas6 as a novel biomarker of brain vitamin K status, in turn revealing the extent of Gas6 dysfunction (and its potential as a therapeutic target) in CNS pathology. The data may also lead to new approaches aimed at delaying disease onset and progression through e.g. vitamin K supplementation.

Candidates graduating in a molecular life science subject (biochemical, biomedical, pharmacology, cell biology) and desirably with A level chemistry would be particularly suitable for this project.