Project description
Remyelination and its contribution to neurodegeneration
Chronic multiple sclerosis lesions leave axons denuded of myelin as a result of the endogenous remyelination process failure, contributing to the neurodegeneration and progressive disability associated with the disease. Stimulating effective remyelination is a key goal for regenerative medicine. Studies in human and animal models have shown that remyelination results in short and thin myelin sheaths with poor conduction acceleration and axonal metabolic support. The EU-funded ReMyelin project will study changes in the intrinsic and extrinsic mechanisms that lead to the short and thin myelin sheaths. This research will identify the causes of altered sheath characteristics in remyelination and enable future studies targeting these pathways so as to enhance remyelination.
Objective
The failure of the endogenous regenerative process – remyelination - in chronic Multiple Sclerosis (MS) lesions leaves axons denuded of myelin and contributes to the neurodegeneration that underlies the progressive disability associated with the disease. Stimulating effective remyelination is therefore a key goal for regenerative medicine. Neuropathological studies in humans and animal models have shown that remyelination results in short, thin myelin sheaths. predicted to be less efficient at accelerating conduction and providing axonal metabolic support - two key functions of the myelin sheath. To this end, this project (ReMyelin) examines intrinsic and extrinsic mechanisms that might explain these short, thin sheaths. We propose that they result from a combination of altered intrinsic and extrinsic pathways affecting the myelination process. Intrinsic pathways will be revealed by an innovative three-dimensional culture system using artificial axons developed in the laboratory of the host investigator, enabling changes associating with ageing to be revealed, whilst extrinsic pathways will be revealed using a genetic approach that allows the visualization of newly-generated myelin-forming cells (oligodendrocytes) and their myelin sheaths in demyelinated lesions of mice. These studies on the extrinsic pathway will focus on the role of axonal activity, using chemogenetics to activate or inhibit axonal activity focally and rehabilitation to activate the system more globally. Together these experimental approaches will identify the causes for altered sheath geometry in remyelination, with these new discoveries then underpinning future studies targeting these pathways so as to enhance remyelination.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
EH8 9YL Edinburgh
United Kingdom