# Inhibition of TNF-alpha Signaling to Reduce Intervertebral Disc Inflammation

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $172,501

## Abstract

Abstract
 Chronic back pain related to intervertebral disc (IVD) degeneration is a significant problem, costing
billions in the U.S. alone. Our proposal will explore new aspects of the factors that lead to disc degeneration
and inflammation, thus accelerating research on IVD degeneration and related back pain.
 The TNF-α-induced protein-8 (TNFAIP8, known as TIPE) family consists of four members (TNFAIP8 and
TIPE1-3). They are novel cytoplasmic proteins recently found to be key factors regulating inflammation. Our
preliminary data have shown that TNFAIP8 family proteins regulate macrophage infiltration into the injured IVD.
The premise of our proposal is that TNFAIP8 family members may be key regulators in IVD inflammation, and
that a novel small molecule inhibitor of tumor necrosis factor receptor (TNFR)-1 could represent a therapeutic
tool to reduce inflammation.
 In Aim 1, we hypothesize that genetic inactivation of TNFAIP8/TIPE2 results in reduced inflammation in
the injured mouse tail IVD. We will determine if genetic inactivation of TNFAIP8/TIPE2 will ameliorate IVD
inflammation and degeneration. We have acquired and are currently maintaining colonies of mutant mice lacking
two members of the TNFAIP8 family (TNFAIP8-/-, TIPE2-/-, and TNFAIP8/TIPE2 double knockout). Mouse tail
IVDs will be challenged with a needle puncture injury. Changes in macrophage infiltration and cytokine gene
expression post-injury will be compared among the mutant mice and with their wild type littermate controls.
 In Aim 2, we further hypothesize that a novel small molecule inhibitor of TNFR1 (SGT11) could
represent a therapeutic tool to reduce inflammation. Small molecules are especially attractive since they could
be modified for oral drug delivery. SGT11 has been shown to inhibit inflammation by changing the conformation
of TNFR1. Unlike current anti-TNF therapy that inhibits both TNFR1 and TNFR2 activation, SGT11 inhibits
TNFR1 but not TNFR2. If successful, this will be the first small molecule to modulate IVD inflammation. We will
determine if SGT11 could ameliorate IVD inflammation and reduce TNFAIP8/TIPE2 expression in the wild-type
mouse. Mouse tail IVDs will be punctured with a needle, with or without SGT11 treatment. Changes in
macrophage infiltration, cytokine and TNFAIP8 family gene expression in the IVD will be compared between
SGT11-treated and control groups.
 The proposed exploratory study breaks ground toward a novel direction since modulating TNF-TNFAIP8
axia with genetic methods and small molecule inhibitors has not been previously studied in the IVD. Discovery
of drugs that modulate IVD inflammation would result in a paradigm shift from current invasive surgeries on late
stage disease to early noninvasive therapies, thus benefiting patients.

## Key facts

- **NIH application ID:** 10448429
- **Project number:** 5R21AR078386-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** YEJIA ZHANG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $172,501
- **Award type:** 5
- **Project period:** 2021-07-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448429

## Citation

> US National Institutes of Health, RePORTER application 10448429, Inhibition of TNF-alpha Signaling to Reduce Intervertebral Disc Inflammation (5R21AR078386-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10448429. Licensed CC0.

---

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