# JAK1 Signaling in Neuroinflammation

> **NIH NIH F31** · WEST VIRGINIA UNIVERSITY · 2021 · $39,583

## Abstract

Project Summary:
Neurodegenerative diseases are a rising public health concern with limited treatment options.
Neurodegenerative diseases are associated with cell stress including the accumulation of misfolded proteins in
the endoplasmic reticulum (ER). When the protein folding capacity of the ER is overwhelmed, ER stress occurs,
resulting in the initiation of the unfolded protein response (UPR) to regain homeostasis. However, unresolved
UPR activation leads to cell death and aberrant inflammation. Astrocytes are the most populous cell in the central
nervous system (CNS) and are largely resistant to ER stress-induced cell death. Recent evidence indicates ER
stress and inflammation are linked. We have found that UPR activation in astrocytes activates JAK1-dependent
inflammatory gene expression. Canonical JAK1 signaling is initiated by ligand binding of a cytokine receptor that
results in Signal Transducers and Activators of Transcription (STAT)-dependent inflammatory gene expression.
Previously, using RNA sequencing of primary murine astrocytes, we have demonstrated that JAK1 regulates
approximately 10% of ER stress-induced gene expression. However, we found JAK1 initiates different gene
expression based on the activating stimulus. Our central hypothesis is that cell stress induces JAK1-dependent
inflammation in astrocytes that contributes to a neurotoxic environment in the CNS. In response to ER stress,
JAK1 regulates a distinct subset of gene expression that we hypothesize does not rely on JAK1-dependent
tyrosine kinase activity. First, we will generate and characterize astrocyte-specific JAK1 knockout mice. We
anticipate that these astrocytes will have reduced capacity to respond to cytokines and ER stress. Further, we
will use the mouse model Experimental Autoimmune Encephalomyelitis (EAE), a model of Multiple Sclerosis and
generalized neuroinflammation, to study the cell-specific contributions of JAK1 signaling in a pathological state.
To expand on the nature of noncanonical JAK1 signaling, we will use in vitro molecular biology and bioinformatics
techniques to gain mechanistic insight on the cell stress-induced molecular mechanisms of JAK1 signaling in
astrocytes. We anticipate that JAK1 signaling in astrocytes drives inflammatory gene expression in the CNS.
However, ER stress will drive distinct gene expression without utilizing the kinase activity of JAK1. The long-term
goal is to elucidate therapeutic targets for neurodegenerative conditions that attenuate damaging inflammation
while leaving the beneficial immune response intact and avoiding broad immunosuppression.

## Key facts

- **NIH application ID:** 10167667
- **Project number:** 5F31NS113482-02
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Savannah Graham Sims
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $39,583
- **Award type:** 5
- **Project period:** 2020-06-01 → 2021-10-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167667

## Citation

> US National Institutes of Health, RePORTER application 10167667, JAK1 Signaling in Neuroinflammation (5F31NS113482-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10167667. Licensed CC0.

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