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.

摘要 在艾滋病毒感染的联合抗逆转录病毒治疗（cART）时代，临床和科学研究的主要焦点是 研究表明，高风险的心血管疾病，神经认知障碍，肾病， 艾滋病毒感染者中的恶性肿瘤（PWH）。虽然正在制定战略，以查明和扭转 潜在的病毒库，必须进行平行的努力，以增强免疫防御病毒 持久性以及重建免疫稳态。这一机制性建议的重点是确定 调节HIV患者免疫保护的途径、分子靶点和小分子化合物， 他们的免疫功能因长期使用阿片类药物而受损我们假设，定义独特的 阿片受体的所有三种亚型发出的生化信号转导途径， 人类T淋巴细胞将揭示影响免疫应答的特异性分子靶点， 艾滋病毒阳性和艾滋病毒阴性的阿片类药物使用障碍患者的系统。这项工作利用了我们最近的发现， G蛋白偶联的cAMP和抑制蛋白相关的丝裂原活化蛋白激酶（MAPK）信号 由内源性、半合成和合成阿片样物质触发的转导途径是独特的， 在人T淋巴细胞中调节。今年暑期实习生的项目将集中在以下具体目标： NIDA暑期本科研究实习生目标1： 识别CD8+和CD4+ T细胞中差异触发的分子信号转导途径 通过阿片激动剂，对三种阿片受体中的每一种都有选择性。 我们的总体目标是生成一个精细的治疗靶点列表，用于免疫系统的药理学恢复。 在需要阿片类药物治疗镇痛的艾滋病毒感染者中发挥作用。