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 在针对 HIV 感染的联合抗逆转录病毒疗法 (cART) 时代，临床和科学的主要焦点 调查发现，心血管疾病、神经认知障碍、肾病等疾病的风险很高。 艾滋病毒感染者（PWH）中的恶性肿瘤，同时正在制定识别和扭转这一趋势的战略。 潜在的病毒库，必须同时努力增强针对病毒的免疫防御 该机制建议的重点是确定免疫稳态。 调节 HIV 患者免疫保护的途径、分子靶点和小分子化合物， 其免疫功能因长期使用阿片类药物而受到损害。 来自阿片受体所有三种亚型的生化信号转导途径 人类 T 淋巴细胞将揭示影响免疫系统反应的特定分子靶标 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激活蛋白激酶 (MAPK) 信号 内源性、半合成和合成阿片类药物触发的转导途径是独特的 这个暑期实习生的项目将重点关注以下具体目标： NIDA 暑期本科生研究实习生的目标 1： 识别 CD8+ 和 CD4+ T 细胞中差异触发的分子信号转导途径 通过阿片受体激动剂，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份详细的治疗靶点清单，用于免疫药理学恢复 需要阿片类药物镇痛治疗的艾滋病毒感染者的功能。