Inflammation associated with HIV infection: role of receptor cross-talk

与 HIV 感染相关的炎症：受体串扰的作用

基本信息

批准号：
10663176
负责人：
Yuri Persidsky
金额：
$ 65.71万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10663176
关键词：
Acquired Immunodeficiency Syndrome Acute Address Agonist Analgesics Animals Attenuated Axonal Neuropathy Bilateral Brain Bromides CCL2 gene CCL3 gene CCL4 gene CCR1 gene CCR5 gene Cell Separation Chemotaxis Chronic Development Disease Enkephalins Epidemic Event Exposure to Failure Fiber Foundations Generations Genetic HIV HIV Envelope Protein gp120 HIV Infections Headache Highly Active Antiretroviral Therapy In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Intravenous Intravenous Drug Abuse Ligands Link Morbidity - disease rate Morphine Mouse Strains Mus Neurologic Neuropathy Opioid Opioid Analgesics Opioid Antagonist Opioid Receptor Opioid abuser Organ Pain Pain Measurement Pain management Pathologic Patients Phosphorylation Play Population Process Production Proteins Receptor Activation Receptor Cross-Talk Recurrent pain Reporting Role Signal Pathway Stimulus Syndrome Testing Transgenic Mice antagonist antiretroviral therapy chemokine chemokine receptor chronic pain clinically significant cytokine desensitization drug abuser humanized mouse in vivo morphine administration mortality mouse model mu opioid receptors neuroinflammation neuropathology novel opiate tolerance opioid abuse pain sensitivity painful neuropathy release of sequestered calcium ion into cytoplasm response

项目摘要

Abstract: Opiate drug abuse is a critical contributor to the global AIDS epidemic, and over a third of HIV infections in the U.S. can be linked to intravenous drug abuse. Recent estimates suggest that almost 20% of intravenous drug abusers are infected with HIV. HIV-associated neuropathy remains a clinically significant issue for patients infected with HIV, even in the current era of anti-retroviral therapy. In addition, HIV-infected opiate abusers demonstrate a more severe neuropathy than non-opiate abusers, and the basis for the greater neuropathy remains uncertain. In this application, we propose that HIV infection in the brain results in an inflammatory response, which promotes the production of inflammatory chemokines, leading to the activation of the respective chemokine receptors, resulting in the cross-desensitization of opioid receptors. The consequence of this set of events is an elevated sensitivity to pain stimuli. We propose to test these processes using mouse models to evaluate the influence of HIV gp120 in the induction of neuroinflammation, including the associated neuropathic pain. Our proposed studies will also attempt to address the ability of morphine to attenuate the development of this pain response. We also propose to confirm these studies through the analysis of an authentic HIV infection using a humanized mouse model. We believe the results from these studies will greatly enhance our understanding of the mechanisms which contribute to the development of neuroinflammation in HIV-infected subjects, including those who are opiate abusers.

抽象的：阿片类药物滥用是全球艾滋病流行的关键因素，超过三分之一的艾滋病毒美国的感染可能与静脉滥用药物有关。最近的估计表明几乎20％的静脉滥用药物感染了HIV。 HIV相关的神经病对于感染HIV的患者，即使在当前的时代抗逆转录病毒疗法。此外，艾滋病毒感染的鸦片滥用者表现出更严重的神经病比非运动施虐者，而较大的神经病的基础仍然存在不确定。在此应用中，我们建议大脑中的艾滋病毒感染导致炎症反应，促进炎症趋化因子的产生，导致各个趋化因子受体的激活，导致跨脱敏化阿片受体。这组事件的结果是对疼痛刺激的敏感性提高。我们建议使用小鼠模型测试这些过程以评估HIV的影响 GP120在诱导神经炎症的诱导中，包括相关的神经性疼痛。我们的拟议的研究还将试图解决吗啡衰减的能力这种疼痛反应的发展。我们还建议通过使用人源化小鼠模型分析真实的HIV感染。我们相信结果从这些研究中，将大大增强我们对贡献机制的理解在受HIV感染受试者中的神经炎症的发展，包括那些鸦片滥用者。