Grant: Project Grant

Multiple sclerosis (MS) is a debilitating neuroinflammatory disease of the central nervous system (CNS) with high prevalence in young adults. MS activity is the result of self-targeting immune cells migrating across the brain and spinal cord blood vessels into the CNS; a process that does not occur in healthy individuals. Once inside the CNS, these immune cells attack and damage the myelin insulation surrounding the nerves, leading to a variety of clinical symptoms. Cell adhesion molecules (CAMs) on immune cells are essential mediators of immune cell migration across blood vessels. Whilst current MS therapies are able to decrease the number of relapses, none are able to completely prevent or halt disease progression, and many carry severe risks resulting from immunosuppression. Thus, identifying novel targets to prevent harmful immune cells from entering the CNS is a major therapeutic goal to prevent MS activity and progression. Our lab has identified a novel CAM, integrin alpha8 (alpha8), on a harmful subset of immune cells in MS. The binding partner of alpha8, nephronectin (NPNT), is found on the CNS blood vessels, suggesting that it might assist immune cells bearing alpha8 to enter the brain and spinal cord. The goals of our research are (1) to study the presence of alpha8 on various harmful immune cells and its binding partner NPNT on the CNS blood vessels; (2) investigate which stage(s) of immune cell migration alpha8 is critical for; (3) study whether alpha8 blockade prevents the pathogenic immune cells from crossing the CNS blood vessels, thereby preventing disease activity and progression in various animal models of MS and (4) identify novel binding partners of alpha8 which could be targeted therapeutically. A better understanding of the mechanisms by which harmful immune cells enter the CNS in MS is critical for the development of new therapeutics that prevent CNS damage and therefore ward off or inhibit disease progression.