# Alternative polyadenylation(APA) mechanisms of comorbid mood disorders in chronic pain

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $427,327

## Abstract

PROJECT SUMMARY/ABSTRACT
The primary objective of this project is to determine the alternative polyadenylation (APA) mechanisms
underlying comorbid depressive and anxiety symptoms in chronic pain. Mood disorders such as depression and
anxiety are frequently observed in patients with chronic pain. These 'comorbid' mood disorders are clinically
difficult to treat, and they can significantly intensify patient suffering. Despite similar behavioral symptoms, the
mechanisms underlying chronic pain-induced mood disorders versus stress-induced mood disorders are distinct.
It has been known that the anterior cingulate cortex (ACC) is one such critical hub for comorbid
depressive/anxiety symptoms associated with chronic pain, and chronic pain induces marked gene expression
changes in the ACC, representing the fundamental mechanism of comorbid mood disorders. Despite these
compelling observations, the underlying gene expression changes within the ACC that drive comorbid mood
disorders in chronic pain remain unclear and represent a critical knowledge gap. Alternative polyadenylation
(APA) is a major mechanism that alters gene output within the brain. The process of APA generates mRNA
isoforms with varying untranslated region (3'UTR) lengths, which post-transcriptionally regulate mRNA stability,
localization, and translation rate. Abnormal regulation of the cleavage and polyadenylation machinery in the brain
has been associated with Parkinson's disease, oculopharyngeal muscular dystrophy, and Huntington's disease.
In this collaborative and multidisciplinary project, Dr. Lingyong Li, a neuroscientist with expertise in chronic pain
and comorbid mood disorders, and Dr. Eric Wagner, an expert in alternative polyadenylation field, will collaborate
and test the overall hypothesis that Nudt21-regulated APA in ACC neurons mediates chronic pain's
depressive/anxiety consequences. The specific aims of this application are to (1) Probe the role of ACC Nudt21
expression in chronic neuropathic pain-induced depressive/anxiety symptoms; (2) Identify specific genes subject
to Nudt21-regulated APA within ACC neurons important for chronic pain-induced mood disorders. Because the
critical role of dysregulated APA-mediated gene expression changes in comorbid mood disorders has not been
recognized previously, our use of APA machinery to answer these questions could transform our knowledge of
how APA dysregulation defines and contributes to comorbid mood disorders in chronic pain. We expect that new
findings from this proposal will provide a new landscape to understand the underlying molecular mechanisms of
the comorbid mood disorders in chronic pain and provide an entirely new layer of therapeutic possibility for
chronic pain management.

## Key facts

- **NIH application ID:** 10572902
- **Project number:** 1R21NS130325-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Lingyong Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $427,327
- **Award type:** 1
- **Project period:** 2022-09-19 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10572902

## Citation

> US National Institutes of Health, RePORTER application 10572902, Alternative polyadenylation(APA) mechanisms of comorbid mood disorders in chronic pain (1R21NS130325-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10572902. Licensed CC0.

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