# Initial Development of AEG-1 inactivation as a possible strategy for pain treatment

> **NIH NIH R61** · VIRGINIA COMMONWEALTH UNIVERSITY · 2022 · $1,179,675

## Abstract

Summary
Adequate management of pain is an unmet medical need. Opioids remain an important class of pain
medications but their use in chronic, non-malignant pain has contributed to what is now referred to as the
“opioid epidemic”. There is clearly an urgent need to identify and validate novel targets allowing development
of novel non-opioid analgesics that are effective and safe. This proposal focuses on a new molecule,
Astrocyte elevated gene-1 (AEG-1), as a possible target for pain. AEG-1, also known as metadherin (MTDH),
is a scaffold protein which mediates its function by protein-protein interaction. AEG-1 functions as a scaffold
protein in multiple intermediary signaling complexes in NF-kB signaling pathway, thereby functioning as a
fundamental molecule in NF-kB activation. NF-kB is a key transcription factor regulating pro-inflammatory
cytokines and AEG-1 is a major regulator of inflammation. AEG-1 KO mice show a profound inhibition of
inflammation and AEG-1 KO macrophages show profound inhibition of lipopolysaccharide (LPS)-induced
NF-kB activity and inflammatory gene expression. NF-kB plays a major regulatory role in chronic
inflammatory pain. Since AEG-1 regulates NF-kB it may be hypothesized that AEG-1 might function as a key
molecule regulating pain mechanisms. Our preliminary studies demonstrate that nociceptive behaviors and
inflammation in both the complete Freund adjuvant (CFA) chronic inflammatory pain were significantly
reduced in AEG-1 KO mice compared to AEG-1 WT mice, without affecting motor activity and coordination
of the animals. These findings identify a key role of AEG-1 in regulating chronic pain and a potential target
for ameliorating chronic pain. We hypothesize that AEG-1 is a valid target regulating pain behaviors and
AEG-1 inhibition might be developed as a potential strategy for developing new analgesics for chronic pain.
We will test our hypothesis in Aim 1 by analyzing pain behaviors in two chronic neuropathic pain models in
AEG-1 KO and WT mice. Aim 2 will investigate the role of macrophage/microglia AEG-1 cells by using
myeloid cell-specific conditional AEG-1 KO mouse. In Aim 3 we will evaluate efficacy of macrophage-targeted
nanoparticles delivering AEG-1 siRNA to ameliorate chronic inflammatory pain. Our studies will identify AEG-
1 as a novel and crucial regulatory molecule modulating pain response and will pave the way for developing
RNAi strategy for pain. Multiple clinical trials are ongoing to test siRNAs targeting diverse genes in a variety
of diseases thereby establishing potential application of this strategy to manage pain in the clinics.

## Key facts

- **NIH application ID:** 10454012
- **Project number:** 1R61NS127287-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** M. Imad Damaj
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,179,675
- **Award type:** 1
- **Project period:** 2022-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454012

## Citation

> US National Institutes of Health, RePORTER application 10454012, Initial Development of AEG-1 inactivation as a possible strategy for pain treatment (1R61NS127287-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10454012. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*