PROJECT SUMMARY/ABSTRACT The purpose of this project is to identify a novel pathway of neuroprotection in the chronic progressive phases of the immune-mediated disease multiple sclerosis (MS). Chronic progressive MS is largely neurodegenerative as opposed to inflammatory; thus, it is not surprising that approved treatments, all of which are immunomodulatory, have limited efficacy in treating progressive MS patients. Therefore, a paramount necessity in MS research is to understand the mechanisms underlying progression in order to identify novel therapeutic targets for the treatment of progressive MS. Our previous studies revealed that immune cytokines act on regionally heterogenous astrocytes to yield beneficial effects during protection and repair of the adult central nervous system (CNS) following injury. Since astrocytes are abundant in MS lesions and have a critical regulatory role in CNS function and homeostasis during inflammation, we hypothesized that astrocytes act as a pivotal regulator of immune-mediated processes during chronic neuroinflammation. Towards this hypothesis, we identified a novel, interferon (IFN)γ-regulated pathway active in chronic white-matter lesion astrocytes within progressive, postmortem MS patient tissue. We went on to discover that IFNγ preferentially mediates upregulation of the immunoproteasome (iP) in primary astrocytes, which leads to a reduction in damaging oxidative stress and protection from exacerbated chronic disease in an in vivo murine model of MS, experimental autoimmune encephalomyelitis (EAE). Guided by strong preliminary data, we propose to pursue three Specific Aims to elucidate how IFNγ mediates CNS protection via the astrocyte iP during chronic neuroinflammation: 1) Determine the expression kinetics of the IFNγ-iP axis in astrocytes during MS and EAE. 2) Identify the mechanisms responsible for IFNγ-mediated survival and reactive oxygen species (ROS) clearance in astrocytes. 3) Examine the role of astrocytic iP in modulating neurodegeneration. Collectively, our proposed research strategy will broadly impact the field by dissecting previously unknown kinetics and mechanisms underlying an undescribed pathway that is active in astrocytes during neuroinflammation and it will reveal a paradigm-shifting protective role for immune cytokines and the iP during chronic MS. Long-term, these studies may reveal novel therapeutic strategies for progressive MS patients and have the potential to be extrapolated to other neurodegenerative diseases with known iP dysfunction.