Neurodegenerative disorders affect over 50 millions of Americans and cost annually over 500 billion dollars. Considerable efforts have been put forth to identifying biomarkers of neurodegeneration, that will allow for early and specific diagnosis of neurodenerative conditions that correlate longitudinally with the course of the disease (type 0); for evaluation of the effectiveness of neuroprotective intervention (type 1), or for predicting the clinical outcome (type 2, or surrogate endpoint). Matrix Metalloproteinases (MMPs) are the family of extracellular proteases that have been associated with many neurodegenerative disorders as modulators of demyelination, immune cell migration and blood-brain permeability. A series of recent reports have implicated MMPs as biomarkers of multiple sclerosis, stroke and Alzheimer's disease. Our own preliminary studies in the peripheral nervous system demonstrate that MMPs, particularly MMP-9, display critical attributes of a highly sensitive, specific and early biomarker of peripheral neurodegeneration. Using MMP-9 gene knockout model of Wallerain degeneration, and MMP-9-neutralizing therapy, we have established a direct link between MMP-9 levels and macrophage influx, myelin degradation and glial activation after peripheral nerve injury. These features of neurodegeneration will allow us to comparatively assess the value of MMP-9 and other MMPs as biomarkers of peripheral (sciatic nerve and L5 spinal nerve) and central (L5 spinal cord) neurodegeneration in rat. The utility of MMPs as surrogate biomarkers for spinal cord injury will be evaluated using experimental neuroprotective therapy with agents of different drug classes (i.e. riluzole, dizocilpine, minocycline). The overall goal of this proposal is to systematically evaluate the value of MMPs as biomarkers of central and/or peripheral neurodegeneration potentially useful for diagnostic, preclinical or clinical assessments in neurodegenerative conditions. Matrix Metalloproteainses (MMPs) is a protease family that controls degradation of structural molecules, such as collagens, cell surface receptor, cell adhesion molecules and other proteins of the extracellular spaces. Our studies demonstrate the important role of MMPs in peripheral neurodegeneration, immune cell recruitment and neuropathic pain. MMP-9 displays a particularly important feature: its activity is specific to degenerative conditions and its robust and early increase is readily quantifiable in tissues and body fluids, before any visible manifestation of injury. This proposal aims to determine the value of MMPs as biomarkers of neurodegeneration that could be used for the early diagnosis of neurodegenerative disease and the efficacy of neuroprotective therapy to spinal cord injury. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS060307-02
Application #
7479659
Study Section
Special Emphasis Panel (ZNS1-SRB-B (01))
Program Officer
Tagle, Danilo A
Project Start
2007-08-15
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$193,125
Indirect Cost
Name
University of California San Diego
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
Kim, Youngsoon; Kong, Seong Deok; Chen, Li-Han et al. (2013) In vivo nanoneurotoxicity screening using oxidative stress and neuroinflammation paradigms. Nanomedicine 9:1057-66
Liu, Huaqing; Shiryaev, Sergey A; Chernov, Andrei V et al. (2012) Immunodominant fragments of myelin basic protein initiate T cell-dependent pain. J Neuroinflammation 9:119
Kim, Youngsoon; Remacle, Albert G; Chernov, Andrei V et al. (2012) The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration. PLoS One 7:e33664
Liu, Huaqing; Shubayev, Veronica I (2011) Matrix metalloproteinase-9 controls proliferation of NG2+ progenitor cells immediately after spinal cord injury. Exp Neurol 231:236-46
Liu, Huaqing; Kim, Youngsoon; Chattopadhyay, Sharmila et al. (2010) Matrix metalloproteinase inhibition enhances the rate of nerve regeneration in vivo by promoting dedifferentiation and mitosis of supporting schwann cells. J Neuropathol Exp Neurol 69:386-95
Kato, Kinshi; Liu, Huaqing; Kikuchi, Shin-ichi et al. (2010) Immediate anti-tumor necrosis factor-alpha (etanercept) therapy enhances axonal regeneration after sciatic nerve crush. J Neurosci Res 88:360-8
Kato, K; Kikuchi, S; Shubayev, V I et al. (2009) Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve. Neuroscience 160:492-500
Shubayev, Veronica I; Pisanic 2nd, Thomas R; Jin, Sungho (2009) Magnetic nanoparticles for theragnostics. Adv Drug Deliv Rev 61:467-77
Chattopadhyay, Sharmila; Shubayev, Veronica I (2009) MMP-9 controls Schwann cell proliferation and phenotypic remodeling via IGF-1 and ErbB receptor-mediated activation of MEK/ERK pathway. Glia 57:1316-25

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