# PERK dependent mechanisms of neuroinflammation

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $468,890

## Abstract

Abstract:
 Ischemic stroke affects a substantial number of people leading to long-term disability or death. Despite
the prevalence of stroke, few treatment options are available. During an ischemic stroke, blood flow to a region
of the brain is restricted preventing delivery of oxygen and essential nutrients. This leads to a complex
environment within and around the infarcted tissue. This includes rapid cell death, inflammation, and
endoplasmic reticulum (ER) stress in the surviving cells. The impact of ER stress on astrocytes and microglia
and the resulting functional outcomes are unknown. ER stress activates the serine/threonine kinase protein
kinase R-like ER kinase (PERK) which phosphorylates the eukaryotic initiation factor 2α (eIF2α) to attenuate
protein translation. Our previous work has shown that PERK also activates the tyrosine kinase Janus kinase 1
(JAK1) to drive inflammatory gene expression. Additionally, our preliminary data show that PERK-dependent
attenuation of protein translation enhances cytokine-induced inflammation in astrocytes and enhances neuronal
death. Based on these findings, we hypothesize that PERK and JAK1 signaling contribute to worse stroke
outcome and that targeting translational repression may provide therapeutic benefit. In this cycle, we will test
this directly by deleting PERK in astrocytes and microglia to examine how PERK contributes to outcome in the
stroke model of middle cerebral artery occlusion (MCAO). We will examine how translational suppression and
JAK1 contribute to neuronal death and inflammation. Additionally, we will use the small molecule ISRIB to restore
protein translation following MCAO to examine effects on functional outcome. We anticipate that deletion of
PERK or restoration of protein translation will improve outcome following MCAO. Thus, identifying this signaling
axis as a potential therapeutic target and furthering our understanding of glial biology.

## Key facts

- **NIH application ID:** 10868554
- **Project number:** 5R01NS099304-09
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Gordon P. Meares
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,890
- **Award type:** 5
- **Project period:** 2017-07-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868554

## Citation

> US National Institutes of Health, RePORTER application 10868554, PERK dependent mechanisms of neuroinflammation (5R01NS099304-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10868554. Licensed CC0.

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