# Pathogenic Astrocyte Populations in EAE and MS

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $426,848

## Abstract

PROJECT SUMMARY
 Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that constitutes
the leading cause of neurologic disability in young adults. Astrocytes, microglia and monocytes play important
roles in MS and its model, experimental autoimmune encephalomyelitis (EAE), but the mechanisms that regulate
their activity are poorly understood. The study of astrocyte and microglia regulation may identify mechanisms of
pathogenesis and therapeutic targets in MS, particularly for the progressive phase of the disease.
 Our long-term goal is to develop therapies to limit astrocyte pathogenic activities in MS. During the course
of our studies we made the following preliminary observations: 1) SigmaR1-IRE1a signaling activates the
transcription factor XBP1 in astrocytes, promoting microglial activation, monocyte recruitment to the CNS and
disease pathology during EAE; 2) Astrocyte-specific XBP1 knockdown ameliorates EAE; 3) XBP1 is activated in
an astrocyte subset in EAE and MS; 4) XBP1 activation in astrocytes is associated to increased VEGF-B
signaling 5) Microglia and CNS-recruited monocytes produce VEGF-B during EAE; and 6) VEGF-B produced by
microglia boost astrocyte pro-inflammatory activities. We hypothesize that active XBP1 (XBP1s) drives a
pathogenic astrocyte subset (XBP1s+ astrocytes) in MS and EAE, which is controlled by microglia- and
monocyte-produced VEGF-B. Thus, we propose to study the role of SigmaR1-IRE1a-XBP1 signaling in
astrocytes in EAE and MS, and its potential as a therapeutic target. Our specific aims are:
SPECIFIC AIM 1: Does XBP1 activation define a subset of pathogenic astrocytes?
We propose to: 1) Characterize XBP1s+ astrocytes in EAE using Focused Interrogation of cells by Nucleic acid
Detection and Sequencing (FIND-seq) a method, which we developed to study cell subsets in-depth, and 2)
Generate a spatiotemporal map of the localization, regulation and cell interactions of XBP1s+ astrocytes and
other cell subsets in EAE and MS using MERFISH (Multiplexed error robust fluorescence in situ hybridization).
SPECIFIC AIM 2: How do microglia and monocytes control XBP1s+ astrocytes?
We propose to: 1) Define the role of VEGF-B produced by microglia and monocytes on the control of XBP1s+
and other astrocyte subsets during EAE, and 2) Identify by NICHE-seq additional pathways involved in the control
of XBP1s+ and other astrocyte subsets by microglia and monocytes during EAE.
SPECIFIC AIM 3: Is SigmaR1 a therapeutic target to modulate CNS inflammation?
We propose to: 1) Evaluate the therapeutic value of the clinical-grade CNS penetrant SigmaR1 antagonist S1RA
on EAE, and 2) Define the effects of S1RA on XBP1s+ astrocytes, and other cell subsets in the CNS in EAE.
 IN SUMMARY, this project studies a novel astrocyte subset, the molecular and cellular mechanisms that
control it, its distribution and cell interactions throughout the CNS, and its potential as a therapeutic target in MS.

## Key facts

- **NIH application ID:** 10881928
- **Project number:** 5R01NS129778-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Francisco J. Quintana
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $426,848
- **Award type:** 5
- **Project period:** 2023-07-06 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881928

## Citation

> US National Institutes of Health, RePORTER application 10881928, Pathogenic Astrocyte Populations in EAE and MS (5R01NS129778-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10881928. Licensed CC0.

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