# Binding NF-κB essential modulator (NEMO) to Treat Surgical Pain

> **NIH NIH R21** · STANFORD UNIVERSITY · 2024 · $427,187

## Abstract

PROJECT SUMMARY:
Surgical pain is caused by tissue injury and inflammation. To treat surgical pain, people are given opioids
which is leading to secondary health problems after surgery including opioid abuse, dependence, and
overdose that is driving the United States opioid epidemic. This is particularly important for older adults as
treating pain with opioids also present challenges with age-related changes in drug metabolism in addition to
drug-drug interactions due to polypharmacy. Therefore, discovering new non-opioid targets and developing
non-opioid treatments that are as effective in the young and elderly populations to alleviate surgical pain are
urgently needed.
For this HEAL proposal, the goal of the research is to develop a peptidomimetic to block the interaction of
NF-κB essential modulator (IKGKB, UniProt #Q9Y6K9) with IKKβ and further determine whether a peptide
targeting NF-κB essential modulator (NEMO) reduces surgical pain in young and old rodents. NEMO is a
promising non-opioid target to develop drugs to treat pain since NEMO is a critical protein regulating the
canonical pathway of NF-κB-mediated inflammation. Here we will leverage new key findings regarding the
NEMO interaction site with IKKβ based upon the crystal structure to develop a peptidomimetic to block the
NEMO interaction with IKKβ. In order to carry out this work, we developed an assay to screen NEMO peptide
modifications by using a mouse skin fibroblast NIH-3T3 cell line that contains a stable NF-κB luciferase
reporter. Further, we will determine whether a NEMO binding peptide will limit pain and inflammation after
injury using a surgical incision model. To carry out these studies, we developed a rodent paw surgical incision
model that increases phosphorylated NF-κB 3-fold in addition to a 10-fold increase in NF-κB-regulated pro-
inflammatory cytokines including IL-6 and IL-1β. Taken together, this proposal can advance the field by
developing a potential non-opioid therapeutic to treat pain and test whether a peptide binding NEMO is
effective in reducing surgical pain in young and old rodents.
Additionally, since the studies performed for this proposal will determine whether binding NEMO limits NF-κB
activation and production of NF-κB-mediated proinflammatory genes, these studies also have a broad
importance to aging. This is because inflammation is a hallmark of aging and the cellular senescence-
associated secretory phenotype described in aging cells is driven by increases in IL-6 and IL-1β; where IL-6 is
the major driver of this phenotype. Therefore, developing a peptidomimetic that binds NEMO may potentially
have broader implications besides treating surgical pain and useful in limiting inflammatory pain for the elderly.

## Key facts

- **NIH application ID:** 10846174
- **Project number:** 1R21AG086147-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Eric Richard Gross
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $427,187
- **Award type:** 1
- **Project period:** 2024-05-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846174

## Citation

> US National Institutes of Health, RePORTER application 10846174, Binding NF-κB essential modulator (NEMO) to Treat Surgical Pain (1R21AG086147-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10846174. Licensed CC0.

---

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