Each year, millions of Americans suffer from chronic nerve compression (CNC) injuries such as carpal tunnel syndrome, cubital tunnel syndrome, and spinal nerve root stenosis. These peripheral neuropathies produce substantial morbidity secondary to symptoms of pain, altered sensation, and muscle atrophy because treatment options are very limited. As an orthopaedic surgeon specializing in peripheral nerve dysfunction, my goals as a physician-scientist are to improve our basic knowledge of the underlying pathophysiology and to identify approaches for translating these scientific discoveries into clinical care. As such, this project builds upon our prior work in defining the underlying molecular pathways involved in the pathogenesis of CNC injury. Previously, we established an experimental model for CNC injuries that demonstrated massive Schwann cell proliferation accompanied by demyelination without axonal degeneration in the early injury phase. Interestingly, this appears to occur in the absence of inflammatory cell activation. Additional work is needed to specify the signals triggering this cascade of events. In this project, we will test our primary hypothesis that CNC injury is an acquired basal lamina-associated disease. We will examine whether Schwann cells mediate the mechanical and ischemic effects of CNC injury by activating secondary messenger systems via alteration of the extracellular matrix (ECM) CM). A secondary hypothesis is that integrins serve as the critical intermediaries for the transduction of extracellular signals from CNC injury into intracellular molecular pathways;possible signals include mechanical stress and ischemia contributing independently or synergistically.
The specific aims of this project are (1) to determine if CNC injury induces the fibroproliferative response by altering Schwann cell basal lamina constituents (2) to test if Schwann cell integrins are key regulators of mechanotransduction after CNC injury via functional linkage to the ECM, and (3) to determine whether ischemia modulates Schwann cell mechanotransduction by lowering the threshold for mechanically induced demyelination. The present application seeks to define the signals that alter the ECM and trigger the injury-related responses, using our experimental models of CNC injury. In accomplishing these goals, we will have the potential to design novel new therapies by targeting these specific pathways.

Public Health Relevance

Millions of Americans suffer from chronic nerve compression (CNC) injuries such as carpal tunnel syndrome, cubital tunnel syndrome and spinal nerve root stenosis. Over the past eight years our research described for the first time that CNC injuries are a distinct entity characterized by the loss of myelin without axonal injury, the proliferation of Schwann cells and a lack of inflammation. The goal of this application is to build upon our previous research in the hopes of identifying the key molecular pathways involved in the disease process so that we will have the potential to design novel new therapies by targeting these specific pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049203-10
Application #
8599492
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jakeman, Lyn B
Project Start
2010-01-19
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2014
Total Cost
$295,195
Indirect Cost
$102,257
Name
University of California Irvine
Department
Orthopedics
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Woolley, Susan; Goetz, Ray; Factor-Litvak, Pam et al. (2018) Longitudinal Screening Detects Cognitive Stability and Behavioral Deterioration in ALS Patients. Behav Neurol 2018:5969137
Goyal, N A; Cash, T M; Alam, U et al. (2016) Seropositivity for NT5c1A antibody in sporadic inclusion body myositis predicts more severe motor, bulbar and respiratory involvement. J Neurol Neurosurg Psychiatry 87:373-8
Kurimoto, S; Jung, J; Tapadia, M et al. (2015) Activation of the Wnt/?-catenin signaling cascade after traumatic nerve injury. Neuroscience 294:101-8
Jung, James; Frump, Derek; Su, Jared et al. (2015) Desert hedgehog is a mediator of demyelination in compression neuropathies. Exp Neurol 271:84-94
Lin, Michael Y; Frieboes, Laura S; Forootan, Maryam et al. (2012) Biophysical stimulation induces demyelination via an integrin-dependent mechanism. Ann Neurol 72:112-23
Gupta, Ranjan; Nassiri, Nima; Hazel, Antony et al. (2012) Chronic nerve compression alters Schwann cell myelin architecture in a murine model. Muscle Nerve 45:231-41
Tapadia, Minal; Mozaffar, Tahseen; Gupta, Ranjan (2010) Compressive neuropathies of the upper extremity: update on pathophysiology, classification, and electrodiagnostic findings. J Hand Surg Am 35:668-77
Burns, Ted M; Conaway, Mark; Sanders, Donald B et al. (2010) The MG Composite: A valid and reliable outcome measure for myasthenia gravis. Neurology 74:1434-40
Pham, Khoa; Nassiri, Nima; Gupta, Ranjan (2009) c-Jun, krox-20, and integrin beta4 expression following chronic nerve compression injury. Neurosci Lett 465:194-8
Rasouli, Alexandre; Bhatia, Nitin; Dinh, Paul et al. (2009) Resection of glial scar following spinal cord injury. J Orthop Res 27:931-6

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