Pathogenic mechanisms of HIV-associated pain

项目摘要 疼痛是HIV-1/AIDS患者中最常见和最昂贵的神经系统疾病， 治疗仅提供通常无效的症状管理。缺乏深刻的、机械的 对HIV相关疼痛的潜在机制的理解显著阻碍了 需要有效的，合理的方法来控制艾滋病患者的疼痛。新出现的证据表明 脊髓背角（SDH;疼痛处理中心）中神经元-星形胶质细胞相互作用的关键作用， 脊髓）在HIV相关疼痛的发病机制中的作用。然而，介导这些的机制 细胞间的相互作用在很大程度上是未知的。我们的前期工作和初步研究表明，gp 120基因的表达可能是一个重要的调控因子。 外泌体信号介导SDH中的双向神经元-星形胶质细胞通讯。重要的是 外泌体通路在病理性疼痛的HIV患者的SDH中上调。药理 SDH中外来体分泌的抑制阻断了gp 120诱导的疼痛的表达。我们建议 外泌体介导的神经元-星形胶质细胞相互作用在GP 120诱导的疼痛发病机制中起关键作用。 具体地说，我们假设gp 120刺激Wnt信号蛋白的基于外泌体的分泌， SDH神经元，然后刺激星形胶质细胞释放外泌体，以反馈SDH疼痛 处理神经元以促进中枢敏感化。我们将使用跨学科的方法， 敲除、嵌合体分析、膜片钳记录和行为分析来验证这一假设。的 从该项目中获得的机制见解将促进艾滋病毒新疗法的开发， 靶向这种潜在的外泌体介导的致病过程的相关疼痛。

PROJECT SUMMARY Pain is the most common and most costly neurological disorder in HIV-1/AIDS patients, yet current pain treatment provides only symptomatic management that is often ineffective. Lack of deep, mechanistic understanding of the underlying mechanism of HIV-associated pain has significantly impeded the development of needed effective, rationale-based approaches for pain control in HIV patients. Emerging evidence suggests a crucial role for neuron-astrocyte interactions in the spinal dorsal horn (SDH; the pain processing center in the spinal cord) in the pathogenesis of HIV-associated pain. However, the mechanism that mediates these intercellular interactions is largely unknown. Our work prior and preliminary studies suggest that gp120 elicits exosome-based signals to mediate bidirectional neuron-astrocyte communication in the SDH. Importantly, the exosome pathway is up-regulated in the SDH of the HIV patients with pathological pain. Pharmacological inhibition of exosome secretion in the SDH blocks the expression of gp120-induced pain. We propose that exosome-mediated neuron-astrocyte interactions play a critical role in gp120-induced pain pathogenesis. Specifically, we hypothesize that gp120 stimulates exosome-based secretion of Wnt signaling protein from SDH neurons, which then stimulates astrocytes to release exosomes that in return feedback to SDH pain processing neurons to promote central sensitization. We will use an interdisciplinary approach of conditional knockout, mosaic analysis, patch clamp recording and behavioral analysis to test this hypothesis. The mechanistic insights gained from this project will facilitate the development of novel therapies for HIV- associated pain targeting this underlying exosome-mediated pathogenic process.