Neuropathic pain (NP) is 'pain arising as a direct consequence of a lesion or disease affecting the somatosensory nervous system'that has certain features of a neuroimmune disorder. In response to peripheral nerve damage, T helper (Th) lymphocyte trafficking and induction of major histocompatibility complex (MHC) II (essential to the capture and antigen presentation for Th cell recognition) in the injured nerve and the segmental spinal cord are 'necessary and sufficient'for the development of NP. MHCII has been implicated in differential induction of NP but not inflammatory pain, but the antigens and the processes of their formation remain elusive. Our groundbreaking program centers on the organizing thesis that immunodominant antigens, formed in damaged myelinated nerves, are at the source of low-threshold mechanical hyperpathia. Touch is signaled by non-nociceptive large myelinated (Ab) afferents, which after injury begin interpreting light touch as devastating pain (mechanical allodynia). Our cutting-edge preliminary data have determined a fundamentally novel mechanism explaining this phenomenon: selective proteolysis of myelin basic protein (MBP) by matrix metalloproteinases (MMPs) releases the cryptic immunodominant epitopes, MBP84-104 and MBP69-86, normally sheltered from immunosurveillance. We clearly demonstrate that immunodominant MBP peptides produce robust allodynia upon injection into intact nerve. An intriguing finding is that endogenous immunodominant MBP69-86 epitope co-localizes with MHCII in antigen-presenting Schwann cells of the injured nerve, in close proximity to the action potential-generating nodes of Ranvier. Using state-of-the-art biochemical and molecular tools (e.g. Illumina BeadChip gene arrays, MALDI-TOF mass spectrometry, Ingenuity, NextBio, GeneGo and proprietary MMP substrate database) and fundamental (neuropathological, behavioral, systems) approaches, we will characterize the T cell-dependent and -independent actions of MBP residues in nociception (Aim 1). The molecular domains of myelinated fibers responsible for MBP action in T cell homing and locomotion, and also, the receptors for MBP residues in nerve will be determined (Aim 2). Importantly, we determined that voltage gated sodium channel expression and the spinal release of a glutamate receptor subunit depend on MMP activity. The concluding focus of the proposal are the novel catalytic and non- catalytic MMP targets in regulating T cell trafficking and integration into the spinal neuro-glial signaling network, facilitating maladaptive central plasticity and aberrant neuroimmune synaptogenesis (Aim 3). This multi- disciplinary program merges the leading expertise and utmost resources in biochemistry of metalloproteolysis (Alex Strongin, Ph.D., Sanford-Burnham Medical Research Inst.), neurobiology of MMPs in peripheral myelination and neuroinflammation (Veronica Shubayev, M.D., UCSD), and pain pathways (Tony Yaksh, Ph.D., UCSD) with innovative study designs, which we believe are bound to transform our mechanistic understanding diagnostic and therapeutic practices predicting and preventing the transition to the NP state.

Public Health Relevance

Neuropathic pain arises from damage to the sensory nervous system and responds poorly to standard analgesics. Typically, immune response promotes neuronal repair and full recovery of sensory function, such as touch. This program will identify the unique molecular events of immune response that lead to chronic inflammation and aberrant repair of sensory nerves that result in severe chronic pain.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Wan, Jason
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Ratnikov, Boris I; Cieplak, Piotr; Gramatikoff, Kosi et al. (2014) Basis for substrate recognition and distinction by matrix metalloproteinases. Proc Natl Acad Sci U S A 111:E4148-55
Shiryaev, Sergey A; Aleshin, Alexander E; Muranaka, Norihito et al. (2014) Structural and functional diversity of metalloproteinases encoded by the Bacteroides fragilis pathogenicity island. FEBS J 281:2487-502
Golubkov, Vladislav S; Prigozhina, Natalie L; Zhang, Yong et al. (2014) Protein-tyrosine pseudokinase 7 (PTK7) directs cancer cell motility and metastasis. J Biol Chem 289:24238-49
Remacle, Albert G; Shiryaev, Sergey A; Golubkov, Vladislav S et al. (2013) Non-destructive and selective imaging of the functionally active, pro-invasive membrane type-1 matrix metalloproteinase (MT1-MMP) enzyme in cancer cells. J Biol Chem 288:20568-80
Takeuchi, Kimio; Morizane, Yuki; Kamami-Levy, Cynthia et al. (2013) AMP-dependent kinase inhibits oxidative stress-induced caveolin-1 phosphorylation and endocytosis by suppressing the dissociation between c-Abl and Prdx1 proteins in endothelial cells. J Biol Chem 288:20581-91