Grant: Project Grant

In multiple sclerosis (MS), a brain cell type called oligodendrocyte that makes sheaths (myelin) around nerve fibers is lost. Moreover, nerve cells are also killed. There are spontaneous attempts at repair within lesions, taking the form of new oligodendrocytes that then remake myelin (remyelination). There are many advantages to remyelination, including the potential to restore lost deficits. Thus, we aim to enhance remyelination in people living with MS (PwMS). Remyelination research has met with the realization that there are inhibitors to repair within lesions, particularly scar-forming substances that are called extracellular matrix (ECM) molecules. We have described that one such class of ECM molecules, the chondroitin sulfate proteoglycans (CSPGs), prevents oligodendrocyte maturation and myelin repair. We have now obtained preliminary data that CSPGs confer microglia (an immune cell type in the brain) the capacity to kill nerve cells. Thus, CSPGs are highly undesirable within MS plaques and we seek to overcome them and other scar-forming ECM members in lesions. While there are over 300 ECM molecules known to exist in the body, only a handful have been analysed in MS. Here, by using a novel technique to extract recalcitrant molecules from the scar of MS lesions, we seek to uncover the entire spectrum of ECM members that exists in MS plaques to determine if particular members inhibit remyelination. While these experiments are ongoing, we focus on CSPGs and a new identified ECM, lumican, and ask if they subvert microglia to kill neurons and oligodendrocytes to exacerbate repair failure. Finally, we will synthesize novel drugs to reduce CSPG production, test them after myelin loss in an animal model of MS, and evaluate whether these medications that overcome scars promote remyelination and facilitate recovery.