# Development and Validation of a Mouse Model of Intervertebral Disc Degeneration-Induced Low Back Pain to Facilitate Non-Addictive Analgesic Discovery

> **NIH NIH R61** · UNIVERSITY OF MINNESOTA · 2024 · $774,930

## Abstract

PROJECT SUMMARY / ABSTRACT
Low back pain (LBP) is a leading cause of disability worldwide with an estimated 40% of LBP attributed to
degenerating intervertebral discs (IVD), frequently referred to as discogenic LBP. Many of the current
preclinical models of discogenic LBP impose focal injury with rapid onset and are typically limited to 1 or 2
IVDs. In contrast, in clinical discogenic LBP, IVDs degenerate over a long period of time creating pain-
generating tissue states during this progressive process. The overall objective for this application is to develop
a clinically representative preclinical model of discogenic LBP that recapitulates the human discogenic LBP
biological processes, making it more likely to aid in the development of novel therapies to reduce or stop the
pain. In our prior work with a mouse lacking the SPARC gene (a structural protein in IVDs and other tissues),
we demonstrated that this preclinical model leads to IVD degeneration replicating human discogenic LBP.
While these mice demonstrate healthy behavior, removing the SPARC gene from the entire body leads to off-
target effects. As an example, the eyes and brains have atypical features. We therefore propose to develop
and validate an inducible, disc-specific SPARC deletion model using Cre/LoxP which would retain the clinical
discogenic LBP phenotype while also ensuring normal development of all of the other tissues in the body.
Aim 1 (R61, Year 1&2): Optimize the crossbreeding protocol(s) and induction timing to reproduce the
behavioral, radiographic, and cellular/molecular facets of clinical discogenic LBP. Our working
hypothesis is that crossing SPARC-floxed mice with tamoxifen‐inducible cytokeratin 19 mice (Krt19-CreERT;
targets nucleus pulposus (NP) cells) and/or with tamoxifen-inducible aggrecan mice (Agc1-CreERT2; targets
all components of IVDs) will lead to a clinically representative discogenic LBP model. We will induce
recombination in utero and at skeletal maturity to initiate IVD degeneration and test for signs of low back pain.
Milestones: Demonstration of IVD degeneration and pain phenotype. If multiple models meet the criteria, the
model with the latest induction time and the most favorable off-site recombination profile will be selected.
Aim 2 (R33, Year 3): Validate the behavioral phenotype and determine responsiveness to
pharmacological intervention. Our working hypothesis is that axial pain will be sensitive to morphine,
pregabalin and ibuprofen while radiating pain will only respond to pregabalin.
Aim 3 (R33, Year 3): Independent replication. Concurrent to Aim 2, an independent lab at University of New
England will perform the same procedures as described in Aim 2.
These results will have an important positive impact because there is a need for a clinically representative
discogenic LBP preclinical model for the discovery and validation of novel non-addictive therapeutics.

## Key facts

- **NIH application ID:** 11040422
- **Project number:** 1R61NS136569-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** LAURA S STONE
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $774,930
- **Award type:** 1
- **Project period:** 2024-09-18 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11040422

## Citation

> US National Institutes of Health, RePORTER application 11040422, Development and Validation of a Mouse Model of Intervertebral Disc Degeneration-Induced Low Back Pain to Facilitate Non-Addictive Analgesic Discovery (1R61NS136569-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11040422. Licensed CC0.

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