# Pathogenesis of Nerve Injury: Role of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1)

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## Abstract

Extremity trauma causing peripheral nervous system (PNS) injury accounts for the majority of combat wounds.
Despite high regenerative capacity of the PNS, patients develop severe neuropathic pain, not amenable to
analgesic therapies. The congressional Opioids and STOP Initiative Act of 2017 calls to “expand, intensify, and
coordinate fundamental, translational, and clinical research”
on pain and develop new non-addictive pain
treatments.
In addition to physical and emotional disability, chronic pain costs the U.S. over $
600 billion every
year. Over 65% of American Veterans report pain, with severe pain 40% greater in Veterans than non-
Veterans.
Our unbiased transcriptomics study identified Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) among the
top-10 induced (out of thousands regulated) genes in painful PNS injury. The main function of TIMP-1 is
inhibition of the matrix metalloproteinase (MMP) family of extracellular proteases. In the framework of this VA
Merit program, we have pioneered the study of the MMP/TIMP axis in PNS injury and pain regulation. This
renewal application centers on our second unbiased finding: TIMP-1 is an X-chromosome-linked gene,
exhibiting polymorphic, aberrant and sex-dependent transcript isoforms in painful PNS injury.
Our data strongly suggest that TIMP-1 is an analgesic, pro-survival and regenerative factor induced in the PNS
in response to injury. However, expression of polymorphic, aberrant TIMP-1 transcript variants, potentially
resulting in dysfunctional gene or protein products, predisposes to chronic pain development. With our
innovative tools and concepts, groundbreaking data and strong track record in MMP/TIMP and PNS research,
we aim to study cellular and subcellular, including nuclear patterns of TIMP-1 distribution, interactors and
functions in PNS injury (Aim 1). We will then identify sex-specific, aberrant, transcript variants of TIMP-1 gene
arising due to sexually dimorphic (X chromosome inactivation in females) and monomorphic (universal in both
sexes) epigenetic abnormalities (Aim 2). As polymorphic TIMP-1 variants occur in humans, we expect our
findings will swiftly translate into medical epigenetic diagnostics of pain states in a clinical setting. Finally we
aim to develop targeted TIMP-1 gene therapy in PNS injury and pain (Aim 3).
This program employs multidisciplinary state-of-the-art (e.g. RNA-seq, SMRT-BS, BioID, ChiP) technologies
and fundamental neuropathological and behavioral approaches to study PNS injury and pain. We anticipate
our program will make a major impact on pain diagnostics and development of non-addictive analgesics.

## Key facts

- **NIH application ID:** 10620196
- **Project number:** 5I01BX000638-12
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** VERONICA SHUBAYEV
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-10-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620196

## Citation

> US National Institutes of Health, RePORTER application 10620196, Pathogenesis of Nerve Injury: Role of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) (5I01BX000638-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10620196. Licensed CC0.

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