Pathogenic mechanisms of HIV-associated pain

HIV相关疼痛的发病机制

基本信息

批准号：
9768586
负责人：
SHAO-JUN TANG
金额：
$ 57.76万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768586
关键词：
AIDS/HIV problem Abbreviations Acquired Immunodeficiency Syndrome Astrocytes Autopsy Back Behavioral Biopsy Communication Data Development Disease Enterobacteria phage P1 Cre recombinase Feedback Funding Glial Fibrillary Acidic Protein Glycoproteins HIV HIV Envelope Protein gp120 HIV therapy HIV-1 HIV-associated neurocognitive disorder Healthcare Impairment Intrathecal Injections Knock-out Knockout Mice LDL-Receptor Related Proteins Ligands Mediating Monitor Mosaicism Multivesicular Body Neurons Pain Pain management Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacology Play Process Quality of life Role Signal Transduction Signaling Protein Sphingomyelinase Spinal Spinal Cord Testing Treatment Cost Up-Regulation WNT Signaling Pathway Wnt proteins Work antiretroviral therapy base central sensitization chronic pain cost design dorsal horn effective therapy exosome feeding in vivo inhibitor/antagonist insight interdisciplinary approach mouse model nervous system disorder neuroAIDS novel novel therapeutics pain processing patch clamp receptor

项目摘要

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.

项目概要疼痛是 HIV-1/AIDS 患者中最常见和最昂贵的神经系统疾病，但目前的疼痛治疗仅提供通常无效的症状管理。缺乏深度、机械性对艾滋病毒相关疼痛的潜在机制的了解极大地阻碍了发展 HIV 患者疼痛控制所需的有效、基于原理的方法。新出现的证据表明脊髓背角（SDH；疼痛处理中心）中神经元与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。然而，调节这些的机制细胞间的相互作用很大程度上是未知的。我们的前期工作和初步研究表明 gp120 引发基于外泌体的信号介导 SDH 中双向神经元-星形胶质细胞通讯。重要的是，患有病理性疼痛的 HIV 患者的 SDH 中外泌体途径上调。药理作用抑制 SDH 中的外泌体分泌可阻断 gp120 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 gp120 诱导的疼痛发病机制中发挥着关键作用。具体来说，我们假设 gp120 刺激 Wnt 信号蛋白的外泌体分泌 SDH 神经元，然后刺激星形胶质细胞释放外泌体，从而反馈 SDH 疼痛处理神经元以促进中枢敏化。我们将使用有条件的跨学科方法基因敲除、镶嵌分析、膜片钳记录和行为分析来检验这一假设。这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针对这种潜在的外泌体介导的致病过程的相关疼痛。