# Role of dorsal root ganglion FTO, a RNA demethylase, in neuropathic pain

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $509,884

## Abstract

PROJECT SUMMARY:
RNA modifications were recently rediscovered as essential regulators of gene expression. N6-methyladenosine
(m6A) is identified as the most prevalent internal modification of eukaryotic RNA. The m6A modification controls
RNA metabolism including RNA degradation and has been linked to human diseases such as obesity and
cancer. However, its role in chronic pain including neuropathic pain is unknown. Our preliminary data suggest
that a nerve injury-induced increase in dorsal root ganglion (DRG) FTO (fat mass and obesity-associated
protein), a well-characterized RNA demethylase, may participate in neuropathic pain by reducing the level of
m6A on Ehmt2 mRNA (encoding G9a, a histone methyltransferase), stabilizing nerve injury-induced G9a
upregulation, and, consequently, silencing the expression of mu opioid receptor (MOR) in the injured DRG.
Given that the transcriptional and translational changes in DRG gene expression following peripheral nerve
injury participate in the development and maintenance of neuropathic pain and that G9a as a repressor of gene
expression is a key endogenous contributor to neuropathic pain genesis, we propose that the increased FTO in
the injured DRG contributes to neuropathic pain. In Aim 1, we will first determine whether pharmacological
inhibition or genetic knockdown of DRG FTO attenuates nerve injury-induced pain hypersensitivity during the
development and maintenance periods, and whether mimicking nerve injury-induced increase in DRG FTO
leads to major symptoms of neuropathic pain in naive rats. In Aim 2, we will examine whether and how
peripheral nerve injury upregulates the expression of FTO in the DRG. Time-dependent changes in the
expression of Fto and its transcriptional activator Runx1 mRNAs and their proteins and in the level of m6A on
specific RNAs in the DRG after peripheral nerve injury will be examined. We will also define whether nerve
injury-induced up-regulation of DRG FTO is attributed to an increase in Runx1 in the injured DRG. In Aim 3, we
will examine how DRG FTO participates in neuropathic pain. We will first observe whether FTO binds to Ehmt2
mRNA and whether this binding activity is increased in the injured DRG neurons after the fifth lumbar spinal
nerve ligation (SNL). We will then define whether FTO contributes to the SNL-induced upregulation of Ehmt1
mRNA/G9a and the G9a-controlled downregulation of MOR by stabilizing the increased G9a expression in
the injured DRG. Finally, we will determine whether blocking the SNL-induced increase in DRG FTO reduces
the MOR-controlled primary afferent neurotransmitter release, restores the decrease of opioid analgesia, and
attenuates opioid tolerance development. These studies will not only advance our understanding of
posttranscriptional mechanisms of neuropathic pain, but will also open a door to develop a new strategy for the
prevention and treatment of this disorder.

## Key facts

- **NIH application ID:** 9978158
- **Project number:** 5R01NS111553-02
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Yuan-Xiang Tao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,884
- **Award type:** 5
- **Project period:** 2019-07-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978158

## Citation

> US National Institutes of Health, RePORTER application 9978158, Role of dorsal root ganglion FTO, a RNA demethylase, in neuropathic pain (5R01NS111553-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9978158. Licensed CC0.

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