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.

Public Health Relevance

Extremity trauma causing nerve injury accounts for the majority of combat wounds and results in chronic nerve (termed neuropathic) pain. Effective nerve repair is necessary to prevent the development of neuropathic pain. Tissue inhibitor of metalloproteinase (TIMP) proteins control nerve regrowth and pain development and this control point may be genetically and epigenetically linked to sex chromosomes.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000638-09A1
Application #
10000652
Study Section
Special Emphasis Panel (ZRD1)
Project Start
2009-10-01
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161
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Remacle, Albert G; Hullugundi, Swathi K; Dolkas, Jennifer et al. (2018) Acute- and late-phase matrix metalloproteinase (MMP)-9 activity is comparable in female and male rats after peripheral nerve injury. J Neuroinflammation 15:89
Hong, Sanghyun; Remacle, Albert G; Shiryaev, Sergei A et al. (2017) Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain. Brain Behav Immun 60:282-292
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Liu, Huaqing; Dolkas, Jennifer; Hoang, Khan et al. (2015) The alternatively spliced fibronectin CS1 isoform regulates IL-17A levels and mechanical allodynia after peripheral nerve injury. J Neuroinflammation 12:158
Remacle, Albert G; Kumar, Sonu; Motamedchaboki, Khatereh et al. (2015) Matrix Metalloproteinase (MMP) Proteolysis of the Extracellular Loop of Voltage-gated Sodium Channels and Potential Alterations in Pain Signaling. J Biol Chem 290:22939-44
Nishihara, Tasuku; Remacle, Albert G; Angert, Mila et al. (2015) Matrix metalloproteinase-14 both sheds cell surface neuronal glial antigen 2 (NG2) proteoglycan on macrophages and governs the response to peripheral nerve injury. J Biol Chem 290:3693-707
Liu, Huaqing; Angert, Mila; Nishihara, Tasuku et al. (2015) Spinal Glia Division Contributes to Conditioning Lesion-Induced Axon Regeneration Into the Injured Spinal Cord: Potential Role of Cyclic AMP-Induced Tissue Inhibitor of Metalloproteinase-1. J Neuropathol Exp Neurol 74:500-11
Chernov, Andrei V; Dolkas, Jennifer; Hoang, Khang et al. (2015) The calcium-binding proteins S100A8 and S100A9 initiate the early inflammatory program in injured peripheral nerves. J Biol Chem 290:11771-84

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