Department of Anesthesiology
Division of Neuroanesthesia
Peripheral
Nerve Research Group
Overview
The Peripheral Nerve Research Group is part of the larger Neuroanesthesia Research Group in the Department of Anesthesiology at the University of California, San Diego School of Medicine. The Neuroanesthesia group consists of clinicians, researchers and students interested in mechanisms of inflammation and ischemia, and who share space, resources and common academic interests. Investigators include:
Hemal H. Patel, Ph.D.
Piyush M. Patel, MD., F.R.C.P.C.
David M. Roth, M.D., Ph.D.
Gerard Schulteis, Ph.D.
Veronica Shubayev, M.D.The Peripheral Nerve Research Group is involved in basic research studies of the peripheral nervous system, especially the pathogenesis of traumatic, toxic, and metabolic neuropathies that are painful. The research emphasis is focused on defining the initial neural-immune mechanisms linking injury to the peripheral nervous system with structural and chemical alterations in the central nervous system causing neuropathic pain. These investigations relate directly to rationale for new therapy. See details of research program for more information.
The Laboratory provides training for post-graduate scholars and for medical, graduate, and selected undergraduate students at UCSD. It also hosts the Editorial Office for the Journal of the Peripheral Nervous System, and the administrative offices of the Peripheral Nerve Society.
Investigators in the Peripheral Nerve Research Group
Robert R. Myers, Ph.D.
Curriculum Vitae (short Web version)
Publications (MEDLINE Database)
Professor Emeritus of Anesthesiology
Professor Emeritus of Pathology (Division of Neuropathology)
Emeritus Editor-in-Chief, Journal of the Peripheral Nervous System
Interests: Neuropathology; neurotoxicity; neuropathic pain; models of neuropathy
Veronica I. Shubayev, M.D.
Publications (MEDLINE Database)
Assistant Professor of Anesthesiology
Interests: Matrix metalloproteinases; MMP and TNF neurobiology
axonal transport; neural regeneration; nanoparticlesResearch 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
Abbreviations: MMP – matrix metalloproteinase, Sc - Schwann cell, MBP - myelin basic protein, mf – macrophage, DRG - dorsal root ganglia
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).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
Recent and current lab members
Senior Technician: Jennifer Dolkas
Postdoctoral trainees:
Hideo Kobayashi, M.D., Ph.D.
Sharmila Chattopadhyay, Ph.D.
Kinshi Kato, M.D., Ph.D.
Huaqing Liu, Ph.D.
Maria Kim, M.D.Undegraduate students:
Elena ZIninberg, UCSD, Molecular and Cellular biology
Renata Ferreira, UCSD, Bioengineering
Research Facilities
The research space occupies a suite of laboratories and offices at the Medical Teaching Facility in the School of Medicine at UCSD, and additional laboratory space in the adjacent VA Medical Center. The UCSD laboratories are devoted to tissue processing, immunohistochemistry, molecular biology, physical chemistry, and quantitative histology and image analysis of tissue from the nervous system. Complete histological facilities for light and electron microscopy include embedding of tissue in plastic, paraffin, or frozen blocks for sectioning. Both thick, semi-thin, and thin sections can be cut on cryotomes, Leitz microtomes, Leitz ultramicrotome, or Reichart cryoultramicrotome. Leica microscopes are available for phase, darkfield, fluorescent, and brightfield photographic microscopy. Zeiss and Seimens electron microscopes are a shared resourcey. A cell culture facility is maintained in the laboratory. Complete facilities are available for immunohistochemistry and in situ hybridization using non-radioactive techniques. Real-time, quantitative PCR (Strategene) and other molecular biology tools including ELISA and zymography are contained within the laboratory. Physiologic techniques include measurement of nerve blood flow. Behavioral tests of nociception and hyperalgesia are available for several experimental neuropathology models that are well established. Computer facilities in the image analysis section of the laboratory are devoted to quantitative neuropathology using primarily ImagePro software. Facilities include Unix servers, a Silicon Graphics imaging workstation, and Macintosh computers hard-wired to the campus ethernet/internet. Kodak and Leica high-resolution digital cameras are used to capture microscopic images for computer analysis. Shared facilities used by the research group include HPLC, GC, RIA, spectrophotometry, ABS protein separator, Beckman amino acid analyzer, and confocal microscope.
GLP Facility. The laboratory has adopted GLP procedures to support drug company investigations of neurotoxicity in preclinical studies of new compounds. Please contact Dr. Myers directly (rmyers@ucsd.edu) for more information.
Teaching Files - Powerpoint Lectures or Lecture notes in pdf format
Review of Neuropathic Pain - ISSLS Harry Farfan Presidential Lecture
Primer on the Neurological Basis of Pain and Disc-Related Diseases
Information for Patients
The laboratory staff is not able to respond directly to inquiries from individual patients with nerve disease. We strongly recommend that you contact your own physician for information specific to your complaint. However, we realize that you may also want to gather information from the internet (that's why you are here), in which case we recommend that you consult the patient-related web pages of the Peripheral Nerve Society. We highly recommend the clinical care provided by our colleagues in the UCSD Pain Management Program.
Contact Information
Amber Millen
Administrative Assistant / PNS Executive Secretary
Peripheral Nerve Research Group
Department of Anesthesiology (0629)
University of California, San Diego
9500 Gilman Drive
La Jolla, CA 92093-0629 USA
(858) 534-3865 Telephone
(858) 534-1445 Telefax
pns@ucsd.edu Email
Orthopaedic Osseointegration (VA
/ Walter Reed Army Hospital Symposium on Amputation Care)
View
lecture on web or Download pdf file
View
Branemark.mov (Dedication of a statue in honor of P-I Branemark)
University
of California, San Diego (UCSD)
UCSD School of Medicine
UCSD Department of Anesthesiology
UCSD Department of Pathology
Peripheral Nerve Society
Journal
of the Peripheral Nervous System
