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: 10701055
• 负责人: Chandravanu Dash
• 金额: $ 74.34万
• 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/10701055
• 关键词: Adherence; Adverse effects; Affect; Anti-Retroviral Agents; Biochemical; Biochemistry; Biology; Brain; Calcium; Calcium Channel; Calcium Signaling; Chromosomes; Chronic; Clinical; Clinical Research; Cocaine; Cocaine use disorder; Communication; Data; Disease; 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; HIV/AIDS; Individual; Infection; Integrase; Integrase Inhibitors; Knowledge; Length; 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 Study; Play; Qualifying; Regimen; Reporting; Research; Role; Severities; Signal Pathway; Signal Transduction; Synapses; Testing; Therapeutic; Viral Load result; Virus; antiretroviral therapy; cocaine exposure; cocaine use; comorbidity; excitatory neuron; excitotoxicity; extracellular; glutamatergic signaling; improved; in vivo; inhibitor; neuronal circuitry; neuropsychiatric disorder; neuropsychiatry; neurotransmission; novel strategies; pharmacologic; postsynaptic; 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.

摘要 美国约有120万人，全世界约有3700万人感染HIV-1。在 尽管艾滋病研究取得了相当大的进展，但抗逆转录病毒疗法（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， 作为一种可控制的疾病，ART疗法中使用的药物会引起不良副作用。其中最广泛的 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， 有限制治疗的神经精神副作用显然，艾滋病毒感染者经常与可卡因使用共病 疾病（CUD），其加剧神经元缺陷。因此，了解INSTI-ART的综合效果 和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和慢性可卡因使用的神经元和神经精神作用的组合。 INSTI包括在所有最初的抗逆转录病毒治疗方案中，并且是控制HIV-1感染的广泛处方抗逆转录病毒药物 国际吧目前批准的INSTI包括雷特格韦、埃替格韦、度鲁特韦、比替格韦和cabotegravir。 虽然一般报道是安全和有效的，但越来越多的人担心不良的代谢和 与基于INSTI的ART相关的神经精神效应。然而， 导致INSTI相关的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CUD在INSTI-ART相关治疗中的任何累加或协同效应的理解存在知识差距 神经缺陷我们假设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 在特定的大脑回路中进行交流。为了验证这一点，我们开发了一种多管齐下的方法， 将神经元功能的生物化学、遗传学和药理学分析与电生理学相结合， 神经回路的研究。使用这种新颖的方法，我们将通过三个具体目标来测试我们的假设。 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。在Aim中 2、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和慢性可卡因使用对突触神经传递改变的联合作用 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， 到神经科学和神经精神疾病以及临床研究。这些研究将 全面定义分子、细胞和神经元回路水平的INSTI-ART和CUD效应。这个新 知识将促进新的和改进的治疗策略，以减少神经元缺陷的严重性 艾滋病毒感染者中的抗逆转录病毒疗法依从者。