# Functional interrogation of region-specific reactive astrocyte factors in neuroinflammation

> **NIH NIH F31** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $41,906

## Abstract

Project Summary
Once thought to be immunologically privileged except in disease, the central nervous system (CNS) is now
understood to interact closely with the immune system even in the absence of pathology. Astrocytes, the most
abundant CNS glial cell, are key mediators of brain-immune cross-talk, interacting closely with microglia, forming
the glial limitans interfacing with and regulating the blood-brain barrier, and recruiting peripheral immune cells
into the CNS via the secretion of chemokines in disease. In response to CNS inflammation, astrocytes undergo
dramatic transcriptional and functional changes – a response termed ‘astrocyte reactivity’. Reactive astrocytes
are a common feature of nearly all injury and disease in the nervous system, yet our understanding of the role
of these cells in the pathogenesis of disease remains limited. Continually emerging evidence has shown that
astrocytes consist of heterogeneous subpopulations that vary greatly across different regions of the brain;
however, inflammatory astrocyte reactivity is still widely viewed as a homogeneous response. To explore
heterogeneity in reactive astrocyte responses to inflammation, I have performed paired single-nucleus RNA and
ATAC sequencing of astrocytes from mice injected with the bacterial endotoxin lipopolysaccharide (LPS),
producing acute neuroinflammation and astrocyte reactivity. By profiling astrocytes across the whole forebrain,
I identified that, in the early phase of the inflammatory response, telencephalic reactive astrocytes highly express
hepatocyte growth factor (HGF), a secreted factor with anti-inflammatory properties in peripheral tissues. In
contrast, diencephalic reactive astrocytes produced 15-hydroxyprostaglandin dehydrogenase (HPGD), the
enzyme responsible for degradation of the inflammatory eicosanoid prostaglandin E2 (PGE2). The goal of this
proposal is to investigate the role of region-specific reactive astrocyte expression of HGF and HPGD in
the progression of neuroinflammation. Given HGF expression has been previously described as attenuating
inflammatory cytokine production by peripheral immune cells, I hypothesize that telencephalic reactive astrocyte
HGF inhibits microglial reactivity, reducing the production of inflammatory cytokines and suppressing
neuroinflammation. To test this hypothesis, experiments in Aim 1 will assess the effect of HGF on microglial
reactivity in vitro and in vivo using astrocyte-specific Hgf conditional knockout mice following LPS injection. As
hypothalamic PGE2-responsive neurons have been implicated in altered body temperature and anorexia during
neuroinflammation, Aim 2 will explore the effects of reactive astrocyte HPGD expression on the abundance of
PGE2 in the diencephalon, body temperature, and sickness behaviors following LPS injection in astrocyte-
specific Hpgd conditional knockout mice. Together, these experiments will provide novel characterization of the
functional roles of two region-specific reactiv...

## Key facts

- **NIH application ID:** 10997906
- **Project number:** 1F31NS135948-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Michael Ryan O'Dea
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,906
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997906

## Citation

> US National Institutes of Health, RePORTER application 10997906, Functional interrogation of region-specific reactive astrocyte factors in neuroinflammation (1F31NS135948-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997906. Licensed CC0.

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