This R21 proposal is resubmitted in response to Program Announcement---""""""""Preclinical Therapeutics Development for NeuroAIDS"""""""" """"""""to validate existing animal models of HIV pathogenesis for use in screening the therapeutic potential of compounds or treatment strategies''. Patients with HIV infection often suffer from a painful neuropathy that may be worsened by highly active anti-retroviral therapy (HAART). The pathogenesis of this very painful disorder is unknown, which presently has no effective treatment. Studies in vitro have shown that the coat glycoprotein gp120 of HIV, acting through the CXCR4 receptor can: 1) stimulate Schwann cells to release RANTES and then induce release of tumor necrosis factor alpha (TNF1) from dorsal root ganglion (DRG) neuron;and 2) activate glia to release TNF1. Studies in vivo have shown that: 1) intrathecal gp120 activates microglia and spinal meningeal cells to release proinflammatory cytokines (e.g.,TNF1);2) application of gp120 to sciatic nerve increases TNF1 in nerve and results in the activation of spinal glia and the pain-related behavior;3) systemic 2',3'-dideoxycytidine (ddC), a principal component of HAART increases CXCR4 and its cognate ligand (SDF-1) in DRG in vivo and induces mechanical allodynia;and 4) perineural application of gp120 combined with ddC results in greater pain than either treatment in isolation. Our preliminary data suggest that transgene-mediated p55 soluble tumor necrosis factor receptor (p55sTNFR) or interleukin 10 reduces pain-related behavior and downregulates the increases in the spinal TNF1 and phosphorylation of p38 (p-p38) in neuropathic or inflammatory pain model. Taken together these results we suggest the hypothesis that: Combination of gp120 and HAART, acting through the CXCR4 receptor activates a neuroimmune pathway involving proinflammatory cytokines to cause neuropathic pain. In order to test this hypothesis, we propose a series of experiments with 2 specific aims.
Specific Aim 1. To characterize the sequence of alterations in neurochemical changes in DRG and spinal dorsal horn in animals with neuropathic pain induced by treatment with gp120, ddC, and the combination of gp120 and ddC.
Specific Aim 2. To test the therapeutic role of HSV-mediated gene transfer of p55sTNFR or IL-10 to DRG neurons in the emergence of neuropathic pain induced by gp120, ddC, or the combination of gp120 and ddC. The results of these studies will provide important insights into the pathogenesis of neuropathic pain in patients with HIV treated with HAART, and may point towards novel therapeutic approaches to treat that pain. The studies will provide preliminary data for future long-term research career of the mechanisms and treatment of HIV-related pain.
proposal will investigate the mechanism of HIV-related neuropathic pain. The study may provide a new approach to treatment of HIV-related pain.
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