The role of heparin mimetics in promoting myelination

Previously, we demonstrated that low sulphated modified heparin mimetics (mHeps) appear to reduce characteristics of astrocytosis, suggesting they may be a potential new therapeutic for CNS repair. mHeps are a class of glycomolecules with structural similarities to resident heparan sulfates (HS) and are made up of repeating disaccharide units with variable sulphation groups. They are thought to modulate cell signalling by both sequestering ligands (chemokine/cytokines in the extracellular matrix) and acting as a cofactor in the formation of ligand-receptor complexes. To explore whether these compounds would affect remyelination, a necessary feature for repair in multiple sclerosis (MS), we treated antibody/complement demyelinated mixed neural cell myelinating cultures with low sulphated mHeps. In this model, we found that the mHeps significantly promoted remyelination. To identify factors that might be bound to the mHeps we bound the supernatant collected from the demyelinated cultures to pull down binding factors. We eluted potential candidates and analysed them by mass spec. Over 100 candidates were identified in which the most abundant candidate belonged to the RAGE signalling pathway. This project aims to continue to validate potential HS regulated/binding molecules that might be active in remyelination. Molecules will be validated by ELISA and in remyelination assays in vitro and using myelination mutants zebrafish in vivo. The ultimate aim is to determine if low sulphated mHeps may be novel therapeutic for remyelination and a novel therapeutic for MS.

Prerequisites
The background of a student suitable for this project would a basic science-based graduate (neuroscience/cell biology/biochemistry) with a degree of 2i and above.
Essential skills are some lab experience in cell biology techniques; however we will select the student we regard has the necessary intellectual, technical and motivational attributes to undertake the work.

The project is a part of SPRINT-MND/MS, a new Scotland-wide PhD scheme for research into motor neurone disease and multiple sclerosis. Projects, encompassing a wide range of topics including laboratory, clinical, and social sciences, are available at Aberdeen, Dundee, Edinburgh, Glasgow and St Andrews Universities. This exciting initiative provides a great opportunity for budding researchers in any field related to MND or MS to join Scotland’s network of world-leading scientists and health professionals. Find more information here: www.edneurophd.ed.ac.uk/sprint-mndms-phd-programme