HIV and NRTI's-induced painful pathogenic mechanisms and gene therapy

描述（由申请人提供）：HIV患者通常会出现疼痛性神经病变，并在高效抗逆转录病毒疗法（HAART）治疗后加重。最近开发的动物模型，通过应用gp 120的坐骨神经沿着核苷逆转录酶抑制剂（NRTI）的全身管理，允许研究的发病机制的HIV/HAART神经性疼痛。我们和其他人已经描述了在神经病理性疼痛中背根神经节（DRG）中肿瘤坏死因子（TNFa）的增加和脊髓小胶质细胞的激活。在神经性疼痛的其他模型中，已经描述了背角中活性氧（ROS）的增加和GABA能张力的降低。背角抑制性和易化性冲动之间的平衡失调是疼痛超敏反应的主要机制。提出的研究将检验以下假设：HIV/HAART神经病中的疼痛是由促炎细胞因子的产生引起的，促炎细胞因子导致ROS的释放，导致脊髓背角中GABA能张力降低。我们提出了一系列的实验与模型的HIV/HAART神经病变：1）确定的TNF α，活性氧，谷氨酸脱羧酶（GAD）和GABA的变化在DRG和脊髓中的HIV相关的疼痛; 2）严格测试之间的关系，TNF α和活性氧升高; 3）检查活性氧和GABA能紧张的关系;和4）确定是否可以通过单纯疱疹病毒载体介导的基因转移来减少HIV相关的疼痛，以增加抗炎性细胞因子和抑制性氨基酸对DRG及其神经化学机制。这些研究的结果将为HIV/AIDS患者神经病理性疼痛的发病机制提供重要的见解，并可能为新的治疗提供临床前证据。 公共卫生相关性：HIV感染最严重的神经系统并发症之一是与核苷逆转录酶抑制剂（NRTI）相关的疼痛性神经病。这项研究可能有助于我们更好地了解疼痛的机制，从而找到减轻疼痛的新方法。

DESCRIPTION (provided by applicant): Patients with HIV often develop a painful neuropathy that is exacerbated by treatment with highly active anti-retroviral therapy (HAART). The recent development of animal models, created by application of gp120 to the sciatic nerve along with systemic administration of nucleoside reverse transcriptase inhibitors (NRTIs), have allowed studies of the pathogenesis of HIV/HAART neuropathic pain. We and others have described an increase in tumor necrosis factor (TNFa) in dorsal root ganglia (DRG) and activation of spinal microglia in the neuropathic pain. In other models of neuropathic pain, increases in reactive oxygen species (ROS) and decreases in GABAergic tone in the dorsal horn have been described. A disturbed balance between inhibitory and facilitatory impulses in the dorsal horn is the main mechanisms for pain hypersensitivity. The studies proposed will test the hypothesis that: pain in HIV/HAART neuropathy results from the production of proinflammatory cytokines that result in the release of ROS leading to a reduction in GABAergic tone in the dorsal horn of spinal cord. We propose a series of experiments with models of HIV/HAART neuropathy to: 1) define the changes of TNFa, ROS, glutamic acid decarboxylase (GAD) and GABA in DRG and spinal cord in HIV-associated pain; 2) critically test the relationship between elevations in TNFa and ROS; 3) examine the relationship between ROS and GABAergic tone; and 4) determine whether HIV-associated pain can be reduced by herpes simplex virus vector-mediated gene transfer to increase anti-inflammatory cytokine and inhibitory amino acid to DRG and their neurochemical mechanisms. The results of these studies will provide important insights into the pathogenesis of neuropathic pain in patients with HIV/AIDS, and may provide preclinical evidence for a novel therapy. PUBLIC HEALTH RELEVANCE: One of the most debilitating neurological complications of HIV infection is painful neuropathy associated with nucleoside reverse transcriptase inhibitors (NRTIs). This study may help us understand the mechanism of pain better so that we can find a novel way to reduce pain.