Role of GRIN2 in ART and SUD associated neurological deficits.

GRIN2 在 ART 和 SUD 相关神经功能缺损中的作用。

• 批准号: 10561195
• 负责人: Chandravanu Dash
• 金额: $ 75.47万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561195
• 关键词: AIDS/HIV problem; Adherence; Adverse effects; Affect; Anti-Retroviral Agents; Biochemical; Biochemical Genetics; Biochemistry; Biology; Brain; Calcium; Calcium Channel; Calcium Signaling; Chromosomes; Chronic; Clinical; Clinical Research; Cocaine; Cocaine use disorder; Communication; Data; Disease Management; Drug abuse; Drug usage; Effectiveness; Electrophysiology (science); Equilibrium; Functional disorder; Genetic; Genetic study; Glutamate Receptor; Glutamates; Goals; HIV; HIV Infections; HIV-1; HIV-1 integrase; Individual; Infection; Integrase; Integrase Inhibitors; Knowledge; Length; Life; Measures; Mediating; Metabolic; Molecular; Molecular Target; Mus; N-Methylaspartate; Neurites; Neurocognitive Deficit; Neurologic; Neurologic Deficit; Neuronal Dysfunction; Neurons; Neuropathogenesis; Neurosciences; Nucleus Accumbens; Pathway interactions; Persons; Pharmacology; Pharmacology Study; Play; Regimen; Reporting; Research; Role; Severities; Signal Pathway; Signal Transduction; Synapses; Testing; Therapeutic; Viral Load result; Virus; antiretroviral therapy; base; cocaine exposure; cocaine use; comorbidity; density; excitotoxicity; glutamatergic signaling; improved; in vivo; inhibitor; neuronal circuitry; neuropsychiatric disorder; neuropsychiatry; neurotransmission; novel strategies; response; reward circuitry; side effect; synaptic function; voltage

ABSTRACT Approximately 1.2 million people in the US and ~ 37 million people worldwide are living with HIV-1. In spite of considerable progress in HIV/AIDS research, anti-retroviral therapy (ART) remains the only treatment option for HIV-1 infection. While ART has been highly effective in controlling the virus and making HIV infection a manageable disease, the drugs used in the ART regimens cause adverse side effects. Among the most widely prescribed antiretrovirals (ARVs) are integrase strand transfer inhibitors (INSTIs) which block the critical step of HIV-1 integration into host chromosomes. Unfortunately, recent reports suggest that INSTI use is associated with treatment-limiting neuropsychiatric adverse effects. Evidently, PLHIV are often comorbid with cocaine use disorders (CUD) that exacerbates neuronal deficits. Thus, understanding the combined effects of INSTI-ART and CUD on neuronal dysfunction is critical for the long-term effectiveness of the ART. This proposal will probe the combined neuronal and neuropsychiatric effects of INSTI-based ART and chronic cocaine use. INSTIs are included in all initial ART regimens and are widely prescribed ARVs to control HIV-1 infection worldwide. Currently approved INSTIs include raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. Although generally reported to be safe and effective there is a growing concern about the adverse metabolic and neuropsychiatric effects associated with the INSTI-based ART. However, the mechanisms and the pathways that drive INSTI-associated neuronal and neuropsychiatric side effects are unknown. Furthermore, there are key knowledge gaps in our understanding of any additive or synergistic effects of CUD in INSTI-ART associated neurological deficits. We hypothesize that INSTI-ART and cocaine-associated neurocognitive deficits are driven by alterations in glutamate and calcium signaling that affect synaptic function and neuronal communication in specific brain circuits. To test this, we have developed a multi-pronged approach that combines biochemical, genetic, and pharmacologic analysis of neuronal function with electrophysiological studies of neuronal circuits. Using this novel approach, we will test our hypothesis through three specific aims. In Aim 1, we will assess the effects of INSTI-ART regimens on excitatory glutamate neurotransmission. In Aim 2, we will probe the adverse effects of INSTI-ART on neuropsychiatric circuitry. In Aim 3, we will probe the combined effects of INSTI-ART and chronic cocaine use on alterations in synaptic neurotransmission within neuropsychiatric circuitry. To achieve these goals, we have combined the expertise in HIV neuropathogenesis, to that of neuroscience and neuropsychiatric disorders, and clinical research. Together, these studies will comprehensively define the molecular, cellular, and neuronal circuit level effects INSTI-ART and CUD. This new knowledge will promote new and improved therapeutic strategies to reduce the severity of neuronal deficits among ART-adherent people living with HIV.

抽象的 美国大约有 120 万人，全世界大约有 3700 万人感染 HIV-1。在 尽管艾滋病毒/艾滋病研究取得了相当大的进展，抗逆转录病毒疗法（ART）仍然是唯一的治疗方法 HIV-1 感染的选择。虽然ART在控制病毒和使HIV感染方面非常有效 虽然这是一种可以控制的疾病，但 ART 治疗方案中使用的药物会引起不良副作用。其中应用最为广泛的 处方抗逆转录病毒药物 (ARV) 是整合酶链转移抑制剂 (INSTI)，可阻断 HIV-1 整合到宿主染色体中。不幸的是，最近的报告表明 INSTI 的使用与 具有限制治疗的神经精神不良反应。显然，艾滋病毒携带者经常与可卡因使用共存 加剧神经元缺陷的疾病（CUD）。因此，了解 INSTI-ART 的综合效果 CUD 对神经元功能障碍的影响对于 ART 的长期有效性至关重要。该提案将探讨 基于 INSTI 的 ART 和长期使用可卡因的综合神经元和神经精神效应。 INSTI 包含在所有初始 ART 治疗方案中，并被广泛用于控制 HIV-1 感染的抗逆转录病毒药物 (ARV) 全世界。目前批准的 INSTI 包括拉替拉韦、埃替拉韦、多替拉韦、比克替拉韦和卡博特拉韦。 尽管普遍报道其安全有效，但人们越来越担心不良代谢和 与基于 INSTI 的 ART 相关的神经精神效应。但其机制和途径 导致 INSTI 相关神经元和神经精神副作用的原因尚不清楚。此外，还有关键 我们对 INSTI-ART 相关 CUD 的任何附加或协同效应的理解存在知识差距 神经功能缺陷。我们假设 INSTI-ART 和可卡因相关的神经认知缺陷是 由谷氨酸和钙信号的改变驱动，影响突触功能和神经元 特定大脑回路中的通讯。为了测试这一点，我们开发了一种多管齐下的方法 将神经元功能的生化、遗传和药理学分析与电生理学相结合 神经元回路的研究。使用这种新颖的方法，我们将通过三个具体目标来检验我们的假设。 在目标 1 中，我们将评估 INSTI-ART 方案对兴奋性谷氨酸神经传递的影响。瞄准 2、我们将探讨INSTI-ART对神经精神回路的不良影响。在目标 3 中，我们将探讨 INSTI-ART 和长期使用可卡因对体内突触神经传递改变的综合影响 神经精神回路。为了实现这些目标，我们结合了艾滋病毒神经发病机制的专业知识， 神经科学和神经精神疾病以及临床研究。这些研究共同将 全面定义了 INSTI-ART 和 CUD 的分子、细胞和神经元回路水平效应。这个新的 知识将促进新的和改进的治疗策略，以减轻神经元缺陷的严重程度 接受 ART 的艾滋病毒感染者。