Direct injury to the sciatic nerve and other major nerves in the peripheral nervous system (PNS) may cause chronic neuropathic pain. Multiple mechanisms are involved in the development and maintenance of neuropathic pain. These mechanisms involve neurons and glia at the site of injury, in the dorsal root ganglia, and in the spinal dorsal horn. At the injury site, diverse extracellular mediators, including cytokines and proteases, provide communication between damaged axons, Schwann cells, and preserved C-fibers, which may be very important in pain processing. We hypothesize that receptors which regulate the extracellular microenviron- ment within the injured nerve may regulate neuropathic pain. The low-density lipoprotein receptor related pro- tein-1 (LRP-1) is a multifunctional receptor that binds numerous extracellular mediators implicated in the res- ponse to PNS injury. Ligand-binding to LRP-1 results in receptor-mediated endocytosis and also in cell-signaling. We have demonstrated for the first time that Schwann cells express LRP-1 and that LRP-1 expression is increased in Schwann cells by nerve injury. LRP-1 expresses activities that may be important in nerve in- jury, including regulation of Schwann cell activation and survival, regulation of the response to inflammatory cytokines, and management of myelin debris. LRP-1 also appears to regulate spontaneous and evoked pain- related behavior. The goal of this research program is to elucidate the function of membrane-anchored LRP-1 and the shed form of the receptor in peripheral nerve injury.
In Aim 1, we will apply a series of """"""""loss of function"""""""" and """"""""gain of function"""""""" approaches to study the activity of LRP-1 as a regulator of Schwann cell biology in vitro, in sciatic nerve injury in vivo, and in the development of neuropathic pain.
In Aim 2, we will study LRP-1 ligands, which may be essential in triggering LRP-1-dependent cell-signaling pathways that regulate the res- ponse to PNS injury. Finally, in Aim 3, we will elucidate the role of LRP-1 in the clearance of myelin debris in the injured sciatic nerve. Overall, these studies will offer insight into novel mechanisms that may control the progression of peripheral nerve injury and the development and maintenance of neuropathic pain. We hope to elucidate novel pathways by which Schwann cells regulate neuropathic pain. Furthermore, these studies offer the opportunity for developing novel strategies to treat or prevent neuropathic pain.7.

Public Health Relevance

Direct injury to nerves in the peripheral nervous system may cause chronic pain. Currently, most of the therapeutics for chronic pain treatment are not effective. This grant application seeks to understand the molecular mechanisms underlying peripheral nerve injury and with that understanding, build a foundation in which we can develop novel therapeutics for chronic pain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Kleitman, Naomi
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Lee-Kubli, Corinne A; Ingves, Martin; Henry, Kenneth W et al. (2016) Analysis of the behavioral, cellular and molecular characteristics of pain in severe rodent spinal cord injury. Exp Neurol 278:91-104
Flütsch, Andreas; Henry, Kenneth; Mantuano, Elisabetta et al. (2016) Evidence that LDL receptor-related protein 1 acts as an early injury detection receptor and activates c-Jun in Schwann cells. Neuroreport 27:1305-1311
Mantuano, Elisabetta; Lam, Michael S; Shibayama, Masataka et al. (2015) The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration. J Cell Sci 128:3478-88
Gonias, Steven L; Campana, W Marie (2014) LDL receptor-related protein-1: a regulator of inflammation in atherosclerosis, cancer, and injury to the nervous system. Am J Pathol 184:18-27
Orita, Sumihisa; Henry, Kenneth; Mantuano, Elisabetta et al. (2013) Schwann cell LRP1 regulates remak bundle ultrastructure and axonal interactions to prevent neuropathic pain. J Neurosci 33:5590-602
Yamauchi, Kazuyo; Yamauchi, Tomonori; Mantuano, Elisabetta et al. (2013) Low-density lipoprotein receptor related protein-1 (LRP1)-dependent cell signaling promotes neurotrophic activity in embryonic sensory neurons. PLoS One 8:e75497
Yoon, Choya; Van Niekerk, Erna A; Henry, Kenneth et al. (2013) Low-density lipoprotein receptor-related protein 1 (LRP1)-dependent cell signaling promotes axonal regeneration. J Biol Chem 288:26557-68
Mantuano, Elisabetta; Henry, Kenneth; Yamauchi, Tomonori et al. (2011) The unfolded protein response is a major mechanism by which LRP1 regulates Schwann cell survival after injury. J Neurosci 31:13376-85
Shi, Yang; Yamauchi, Tomonori; Gaultier, Alban et al. (2011) Regulation of cytokine expression by Schwann cells in response to α2-macroglobulin binding to LRP1. J Neurosci Res 89:544-51
Gorovoy, Matvey; Gaultier, Alban; Campana, W Marie et al. (2010) Inflammatory mediators promote production of shed LRP1/CD91, which regulates cell signaling and cytokine expression by macrophages. J Leukoc Biol 88:769-78

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