# The role of the astrocyte immunoproteasome during chronic CNS autoimmunity

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $402,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10304869
- **Project number:** 5R01NS119178-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Jessica L Williams
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304869

## Citation

> US National Institutes of Health, RePORTER application 10304869, The role of the astrocyte immunoproteasome during chronic CNS autoimmunity (5R01NS119178-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10304869. Licensed CC0.

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