Grant: Project Grant

Multiple Sclerosis (MS) lesions have a loss of myelin, a fatty substance surrounding nerve fibres. Myelin speeds communication and provides nutrients to the underlying nerve fibre. Myelin is essential for the survival of the nerve fibres; when myelin is destroyed, often, the fibre dies as well. Several medications are available for people with MS. Despite this, people still have some ongoing myelin injury. An alternative is to promote myelin repair or remyelination. Often, remyelination is inefficient for people with MS, and no available drugs boost remyelination. Remyelination is also known to decline with age, which must be considered during remyelination drug discovery because MS is a decades-long disease. In this project, we hope to address a critical obstacle for remyelination: age-related remyelination decline. New therapies that are being tested in clinical trials to boost remyelination work poorly in promoting benefits when myelinating cells are subjected to a known obstacle for repair. These obstacles are found inside the MS lesion and prevent remyelination. We believe the best way to make the lesion environment more favourable for remyelination is to target the cells that serve as the lesion's custodians: the microglia. Microglia's essential function is to clear the lesion of debris. With age, these cells become less efficient in removing debris, causing an age-dependent decline in remyelination. We will use a strategy to renew microglia and test whether this recovers the capacity of microglia to clear debris. We will also examine how microglia respond to myelin injury, what defines their ability to remove debris, and how they change throughout remyelination. Finally, we will develop a strategy to model human microglial aging in a dish so that we can use this to find new microglia-boosting medications. We believe these studies will identify new pathways to boost microglial function to improve remyelination.