Identification of immune protective pathways dysregulated by opioid use in HIV infection, using a systems biology-based approach, toward the goal of pharmacological restoration of immune function

使用基于系统生物学的方法，识别 HIV 感染中阿片类药物使用失调的免疫保护途径，以实现免疫功能药理学恢复的目标

• 批准号: 10398591
• 负责人: Alan David Levine
• 金额: $ 1.42万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398591
• 关键词: Absence of pain sensation; Affect; Analgesics; Anti-Retroviral Agents; Arrestins; Biochemical; CD4 Positive T Lymphocytes; CD8B1 gene; Chronic; Clinical; Coupled; Cyclic AMP; GTP-Binding Proteins; Gene Expression Profile; Goals; HIV; HIV Infections; Homeostasis; Human; Immune; Immune system; Internships; Investigation; Kidney Diseases; Life; Malignant Neoplasms; Minority; Mitogen-Activated Protein Kinases; Molecular; Molecular Target; National Institute of Drug Abuse; Opioid; Opioid Receptor; Opioid agonist; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Signal Transduction Pathway; Systems Biology; T-Lymphocyte; United States; Viral; Viral reservoir; Work; antiretroviral therapy; base; cardiovascular disorder risk; chronic pain; high risk; immune function; latent HIV reservoir; neurocognitive disorder; new therapeutic target; opioid therapy; opioid use; opioid use disorder; opioid user; restoration; small molecule; summer internship; synthetic opioid; therapeutic target; undergraduate research

Abstract In the era of combination antiretroviral therapy (cART) for HIV infection, a major focus of clinical and scientific investigation lies with the high risk of cardiovascular disease, neurocognitive disorders, nephropathy, and malignancy among persons with HIV (PWH). While strategies are being developed to identify and reverse the latent pool of viral reservoirs, a parallel effort must proceed to enhance immune defenses against viral persistence as well as re-establish immune homeostasis. The focus of this mechanistic proposal is to identify pathways, molecular targets, and small molecule compounds that regulate immune protection in the HIV patient, whose immune function is compromised by chronic opioid use. We hypothesize that defining the unique biochemical signal transduction pathways emanating from all three subtypes of opioid receptors in human T lymphocytes will reveal specific molecular targets that affect the responsiveness of the immune system in HIV+ and HIV- persons with Opioid Use Disorder. This work capitalizes on our recent findings that the G-protein coupled cAMP and the arrestin-associated Mitogen Activated Protein kinase (MAPK) signal transduction pathways triggered by endogenous, semi-synthetic, and synthetic opioids are distinctly and uniquely regulated in human T lymphocytes. This summer intern’s project will focus on the following Specific Aim: Aim 1 for the NIDA Summer Undergraduate Research Intern: Identify molecular signal transduction pathways in CD8+ and CD4+ T cells that are differentially triggered by opioid agonists, selective for each of the three opioid receptors. Our overall goal is to generate a refined list of therapeutic targets for pharmacologic restoration of immune function in persons with HIV that require opioid therapy for analgesia.

抽象的 在抗逆转录病毒疗法（CART）的时代，用于HIV感染，这是临床和科学的主要重点 调查在于心血管疾病，神经认知疾病，肾病和 艾滋病毒（PWH）患者的恶性肿瘤。正在制定策略来识别和扭转 潜在的病毒储存池，必须采取平行的努力来增强对病毒的免疫防御能力 持久性以及重新建立免疫稳态。该机理建议的重点是确定 调节HIV患者免疫保护的途径，分子靶标和小分子化合物， 慢性阿片类药物的使用损害其免疫功能。我们假设定义独特的 从阿片类药物接收器的所有三个亚型发出的生化信号转移途径 人T淋巴细胞将揭示影响免疫反应性的特定分子靶标 艾滋病毒+和艾滋病毒的系统患有阿片类药物使用障碍。这项工作利用了我们最近的发现， G蛋白耦合营地和逮捕蛋白相关的有丝分裂原激活蛋白激酶（MAPK）信号 由内源性，半合成和合成阿片类药物触发的转导途径明显且独特 在人类T淋巴细胞中调节。今年夏季实习生的项目将重点介绍以下特定目标： NIDA夏季本科研究实习生的目标1： 识别不同触发的CD8+和CD4+ T细胞中的分子信号转导途径 由Oopioid激动剂，对三个蛋黄酱接收器中的每个接收器中的每一个。 我们的总体目标是产生精致的治疗靶标，以恢复免疫的药物 在需要阿片类药物治疗的艾滋病毒的患者中起作用。