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My laboratory studies peripheral nerve injury and Schwann cell biology as it relates to chronic neuropathic pain. Specifically, we study receptors and cell-signaling pathways that regulate the response to peripheral nerve injury. Using molecular, cellular and animal model studies, we have identified low-density lipoprotein receptor-related protein (LRP1) as a receptor that functions as a major orchestrator of changes that occur in Schwann cells after nerve injury. LRP1 appears to be a novel regulator of phenotypic modulation of Schwann cells during injury. LRP1 is an endocytic and a cell-signaling receptor that controls the phosphatidylinositol 3-kinase-Akt pathways, the Ras-ERK/MAP kinase pathway, and the IKK-NFκB pathway. LRP1 also functions as a regulator of neuroinflammation. We have shown that diverse proteins implicated in PNS injury bind to LRP1 and robustly activate Schwann cell-signaling. A major goal of my laboratory is to determine the mechanisms by which LRP1 regulates the response to PNS injury and chronic neuropathic pain. We feel it is possible to exploit the activities of LRP1 in the development of novel therapeutics that target chronic pain. A second receptor of great interest to this laboratory is the erythropoietin receptor (EpoR). My laboratory initially discovered that EpoR is located in peripheral nerve. We have demonstrated that activation of EpoR protects both sensory neurons and Schwann cells from apoptosis and facilitates recovery from neuropathic pain after peripheral nerve injury. We are actively investigating the role of EpoR in models of low back pain. Again, there is excellent potential to exploit our growing knowledge of the function of EpoR for therapeutics development in neuropathic pain. My laboratory is a member of the Neurosciences Imaging Center. We have ongoing collaborations with faculty in the Departments of Pathology and Neurosciences at UCSD, Chiba University in Japan and the University Vita-Salute San Raffaele in Milan, Italy. My lab is funded by NIH NINDS.
References (Selected From 56 Publications)
Gorovoy M, Gaultier A, Campana WM, Firestein GS, Gonias SL. Inflammatory mediators promote production of shed LRP1/CD91, which regulates cell signaling and cytokine expression by macrophages.J Leukoc Biol. 2010 Jul 7.
Mantuano E, Jo M, Gonias SL, Campana WM.Low density lipoprotein receptor-related protein (LRP1) regulates Rac1 and RhoA reciprocally to control Schwann cell adhesion and migration. J Biol Chem. 2010 May 7;285(19):14259-66.
Inoue G, Gaultier A, Li X, Mantuano E, Richardson G, Takahashi K, Campana WM.Erythropoietin promotes Schwann cell migration and assembly of the provisional extracellular matrix by recruiting beta1 integrin to the cell surface.Glia. 2010 Mar;58(4):399-409.
Shi Y, Mantuano E, Inoue G, Campana WM, Gonias SL. Ligand binding to LRP1 transactivates Trk receptors by a Src family kinase-dependent pathway.Sci Signal. 2009 Apr 28;2(68):ra18.
Gaultier A, Wu X, Le Moan N, Takimoto S, Mukandala G, Akassoglou K, Campana WM, Gonias SL.Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis.J Cell Sci. 2009 Apr 15;122(Pt 8):1155-62. Epub 2009 Mar 19.
Mantuano E, Inoue G, Li X, Takahashi K, Gaultier A, Gonias SL, Campana WM.The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to low-density lipoprotein receptor-related protein. J Neurosci. 2008 Nov 5;28(45):11571-82.
Mantuano E, Mukandala G, Li X, Campana WM, Gonias SL. Molecular dissection of the human alpha2-macroglobulin subunit reveals domains with antagonistic activities in cell signaling.J Biol Chem. 2008 Jul 18;283(29):19904-11.