This peripheral nerve injury research program aims to provide mechanistic insights and targeted therapeutic strategies for neuronal damage. In the course of our VA Merit Award program we discovered matrix metalloproteinases (MMPs), a family of exracellular proteases, as key modulators of neuroimmune activation, demyelination, neuronal death and neuropathic pain after sciatic nerve injury, used as a successful mammalian model of neuronal regeneration. Individual MMP family members display differential functions during nerve damage, suggesting the importance of selective MMP inhibitor (MMPi) therapy for targeted intervention. For example, MMP-9 is an early-gene family member, that is expressed in nerve exclusively after injury by up to a 300-fold and only hours after insult. MMP-9 stimulates Schwann cell (SC) trophic (e.g. ErbB and IGF-1) signaling leading to sustained activation of extracellular signal-regulated kinase (ERK) and regulation of SC mitosis and myelin protein synthesis. MMP-9 gene deletion demonstrates remarkable neuroprotection, reduced immune cell infiltration into the injured nerve and notable changes to myelin protein turnover. Therapy with specific, broad- spectrum MMPi was highly effective in reducing painful tactile allodynia (i.e., pain from normally innocous stimuli), in protecting myelin from degradation and improving neuronal and glial survival. Our pilot data also demonstrates its promise in promoting the rate of nerve regrowth after rat sciatic nerve crush. The goal of this program is to establish the roles of individual MMPs in the processes of initiation and development of neurodegenerative cascades in peripheral nerve, utilizing a series of in vitro, ex vivo and in vivo approaches. It offers to develop therapeutic strategies for neurodegenerative diseases and sensory loss in VA patients. The most common causes of neurodegeneration and neuropathic pain are on the list of the VA patients most common health concerns, including diabetes, alcoholism, stroke and spinal cord injury. This porgram is designed to expedite the development and implementation of novel therapies to neurodegenerative diseases.

Public Health Relevance

The current demographic profile of the VA patients shows that almost one-third of the nation's population (over 60 million people) are veterans, dependents or survivors of deceased veterans who have privileges of the VA Healthcare System. The epidemiology of neurodegenerative diseases suggests that the VA patient population is at special risk of neuronal damage, loss of sensory function and debilitating neuropathic pain. The causes are on the list of the VA patients' most common health concerns, including trauma, spinal cord injury, diabetes and alcoholism and may be amenable to the molecular intervention by inhibition on matrix metalloproteainses (MMPs). Understanding the mechanisms of neuronal damage through preclinical studies is critical to expediteing the development and implementation of novel therapies to neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000638-02
Application #
7919439
Study Section
Neurobiology C (NURC)
Project Start
2009-10-01
Project End
2014-03-31
Budget Start
2010-10-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
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
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; 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
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