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：
10434706
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/10434706
关键词：
Ache Acquired Immunodeficiency Syndrome Acute Address Agonist Analgesics Animals Attenuated Axonal Neuropathy Bilateral Blood - brain barrier anatomy Brain Bromides CCL2 gene CCL3 gene CCL4 gene CCR1 gene CCR5 gene Cells 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 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 base chemokine chemokine receptor chronic pain clinically significant cytokine desensitization drug abuser humanized mouse in vivo morphine administration mortality mouse model mu opioid receptors neuroinflammation 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一个重要因素，超过三分之一的艾滋病毒美国的感染可能与静脉注射药物滥用有关。最近的估计表明近 20% 的静脉注射吸毒者感染了艾滋病毒。 HIV相关神经病即使在当今时代，对于感染艾滋病毒的患者来说，这仍然是一个具有临床意义的问题。抗逆转录病毒治疗。此外，感染艾滋病毒的阿片类药物滥用者表现出更严重的症状神经病变比非阿片类药物滥用者更严重，并且更大的神经病变的基础仍然存在不确定。在此应用中，我们提出大脑中的 HIV 感染会导致炎症反应，促进炎症趋化因子的产生，导致各自趋化因子受体的激活，导致交叉脱敏阿片受体。这组事件的结果是对疼痛刺激的敏感性升高。我们建议使用小鼠模型来测试这些过程，以评估艾滋病毒的影响 gp120 诱导神经炎症，包括相关的神经性疼痛。我们的拟议的研究还将尝试解决吗啡减弱吗啡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。我们相信结果这些研究将极大地增强我们对促进机制的理解 HIV 感染者（包括那些患有 HIV 的人）神经炎症的发展阿片类药物滥用者。