Extremity trauma, accounting for the majority (>60%) of combat wounds, results in peripheral nerve injury (PNI). Despite the propensity of peripheral nerve for regeneration, PNI patients commonly achieve no useful degree of sensorimotor recovery and suffer severe neuropathic pain (NP). New therapeutic approaches to facilitate recovery after PNI aim to provide (1) adequate Schwann cell (SC) numbers and SC-released factors required for repair and/or artificial bridging of a severed nerve, and (2) extracellular matrix milieu that inhibits fibrous sar formation and promotes axonal growth. In the course of this VA Merit Review program, we pioneered studies implicating matrix metalloproteinase-9 (MMP-9) as a protease uniquely expressed in adult nerve only after PNI involved in suppression of SC division via activation of NRG1/ErbB-ERK mediated cell cycle arrest. Our exciting new data implicates catalytic MMP-9 activity within the first days of PNI as determinant to SC-mediated remyelination, and the development of NP. Pharmacological MMP inhibition (MMPi) immediately after PNI facilitates sensory nerve regrowth by enhancing the rate of SC mitosis and preventing the development of a fibrous scar. Purification of MMP-9 from the PNI site using gelatin-sepharose beads identified multiple MMP-9 isoforms, which may be targeted by selective and unique anti-MMP-9 inhibitors. We provide novel data implicating an endogenous MMP-9 inhibitor, TIMP-1, as mediator of cAMP- induced pro-regenerative program in DRG after PNI, able to promote outgrowth of DRG neurons. Our groundbreaking data implies the existence of TIMP-1/CD63 signaling in SCs, independent of MMPs. We also offer the first studies implicating MMP-14 in PNI, using a new, highly selective MMP-14 inhibitor. Our data suggests that MMP-14 regulates peripheral nerve regeneration by proteolysis of laminin, neuron-glial antigen 2 (NG2) proteoglycan and MMP-2. Using state-of-the-art and specialized molecular and cell biological tools, as well as neuropathological and behavioral techniques, we will characterize the mechanisms and therapeutic value of MMP-9 (Aim 1) and MMP-14 (Aim 2) regulation of SC and DRG neuronal function, and MMP- dependent and MMP-independent TIMP actions in PNI. With cutting-edge, selective MMPi reagents and strong Preliminary Studies supporting their use, we anticipate this program will provide novel mechanistic insights and targeted therapeutic strategies to improve PNI related to combat and other prevalent conditions amongst VA patients.

Public Health Relevance

Peripheral nerve damage accounts for the majority of all combat injuries and results in poor recovery of motor and sensory function. Generation of support cells (Schwann cells) is necessary to promote nerve growth necessary for full recovery of function. Our program has discovered the enzymes (matrix metalloproteinases, MMPs) responsible for poor nerve regrowth and severe pain arising from innocuous touch, which we aim to target.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000638-05A1
Application #
8818976
Study Section
Special Emphasis Panel (NURB)
Project Start
2009-10-01
Project End
2018-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
5
Fiscal Year
2015
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
Remacle, Albert G; Dolkas, Jennifer; Angert, Mila et al. (2018) A sensitive and selective ELISA methodology quantifies a demyelination marker in experimental and clinical samples. J Immunol Methods 455:80-87
Chernov, Andrei V; Remacle, Albert G; Hullugundi, Swathi K et al. (2018) Amino acid sequence conservation of the algesic fragment of myelin basic protein is required for its interaction with CDK5 and function in pain. FEBS J 285:3485-3502
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
Ko, Justin S; Eddinger, Kelly A; Angert, Mila et al. (2016) Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia. Brain Behav Immun 56:378-89
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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