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.
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.
|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|
|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|
|Frieboes, Laura R; Gupta, Ranjan (2009) An in-vitro traumatic model to evaluate the response of myelinated cultures to sustained hydrostatic compression injury. J Neurotrauma 26:2245-56|
|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|
|Dinh, Paul; Hazel, Antony; Palispis, Winnie et al. (2009) Functional assessment after sciatic nerve injury in a rat model. Microsurgery 29:644-9|
|Mozaffar, Tahseen; Strandberg, Erika; Abe, Kazuko et al. (2009) Neuromuscular junction integrity after chronic nerve compression injury. J Orthop Res 27:114-9|
|Rasouli, Alexandre; Bhatia, Nitin; Dinh, Paul et al. (2009) Resection of glial scar following spinal cord injury. J Orthop Res 27:931-6|
|Chao, Tom; Pham, Khoa; Steward, Oswald et al. (2008) Chronic nerve compression injury induces a phenotypic switch of neurons within the dorsal root ganglia. J Comp Neurol 506:180-93|
|Gupta, Ranjan; Channual, Jennifer C (2006) Spatiotemporal pattern of macrophage recruitment after chronic nerve compression injury. J Neurotrauma 23:216-26|
|Berger, Brent L; Gupta, Ranjan (2006) Demyelination secondary to chronic nerve compression injury alters Schmidt-Lanterman incisures. J Anat 209:111-8|
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