Veronica I. Shubayev, M.D.

Research of my group is focused on identifying the mechanisms of neuronal damage, particularly related to the extracellular protease family of matrix metalloproteinases (MMPs). We are interested in elucidating the role of MMPs in survival and phenotypic remodeling of glia and neurons through proteolysis of extracellular and cell surface factors resulting in altered cell signaling events. A dedicated NIH program centers on validating MMPs as early biomarkers of neuronal degeneration. We utilize peripheral (i.e., sciatic) nerve injury as a model neuronal regeneration system in identifying MMP-dependent cytokine and trophic pathways leading glial activation, neuroimmune response and myelin protein regulation during nerve repair. The second focus of our research is on the mechanisms of localized and central neuroinflammation leading to persistent nerve-injury related (i.e., neuropathic) pain. Our discovery of the cytokine axonal transport provided a unique mechanism of axonal-glial crosstalk and central glial activation. Through ISSLS prize (Volvo Award)-winning work, we identified TNF-a as a matrix-bound component of nucleus pulposus of lumbar disc and a therapeutic target for radiculopathy. Other interests in the laboratory include a collaborative research with the Department of Mechanical and Aerospace Engineering at UCSD assessing therapeutic and diagnostic modalities of magnetic nanoparticles in clinical and basic neurosciences.

Mechanisms of MMP action in neuropathic nociception
1. Early-gene MMPs (e.g., MMP-9) are induced in myelinated Schwann cells (Sc) within 1 day after nerve injury by the action of proinflammatory cytokines and trophic factors (Shubayev et al., 2006, Chattopadhyay et al., 2007). MMPs selectively degrade myelin basic protein (MBP) contributing to demyelination (Kobayashi et al., in press). This myelin damage of mechanosensory (myelinated) Ab fibers results in ectopic hyperexcitability of axonal plasma membrane and neuropathic pain (Devor, 2006).
2. MMPs promote macrophage infiltration into the site of nerve injury (Shubayev et al., 2006). This advances demyelination, axonal degeneration and neuroinflammation, while sustains pro-nociceptive milieu (Myers et al., 2006).
3. In the spinal cord, MMP inhibitor (MMPi) therapy reduces activation of central glia, such as GFAP (+) astrocytes, required for both the development and maintenance of neuropathic pain. MMPi shows effective in the attenuation of acute and persistent pain from non-painful tactile stimuli, i.e. mechanical allodynia and promotes cell survival (Kobayashi et al., in press).

Abbreviations: MMP – matrix metalloproteinase, Sc - Schwann cell, MBP - myelin basic protein, mf – macrophage, DRG - dorsal root ganglia

Selected References

Chattopadhyay S and Shubayev VI: MMP-9 controls Schwann cell proliferation and phenotypic remodeling via IGF-1 and ErbB receptor-mediated activation of MEK/ERK pathway. Glia, 2008, in press

Shubayev VI, Pisanic T and Jin S: Magnetic iron oxide nanoparticles for theragnostics, Advanced Drug Delivery Reviews, 2008, in press

Kobayashi H, Chattopadhyay S, Dolkas J, Kikuchi S, Myers RR, Shubayev VI: MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage, Molec. Cell Neurosci, 2008, 39: 619–627, 2008

Shubayev VI, Angert M, Dolkas J, Campana WM, Palenscar K, Myers RR. TNF-a-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve. Mol Cell Neurosci. 31:407-415, 2006.

Myers RR, Campana WC, Shubayev VI: The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets, Drug Discovery Today, 11 (1/2): 8-20, 2006

Shubayev VI and Myers RR: Axonal transport of TNF-a in painful neuropathy: Distribution of ligand tracer and TNF receptors. J. Neuroimmunol. 114 (1-2): 48-56, 2001

Igarashi T, Kikuchi S, Shubayev V, Myers RR. 2000 Volvo Award Winner in Basic Science Studies: Exogenous TNF-a mimics nucleus pulposus-induced neuropathology - molecular, histologic, and behavioral comparisons in rats. Spine, 25 (23): 2975-80, 2000