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.

抽象的 在美国，大约有120万人和全世界约3700万人患有HIV-1。在 艾滋病毒/艾滋病研究取得了很大进展，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。虽然艺术在控制病毒并引起艾滋病毒感染方面非常有效 一种可管理的疾病，在艺术方案中使用的药物会导致不良副作用。最广泛的 规定的抗逆转录病毒（ARV）是整合酶链转移抑制剂（Instis），它阻止了临界步骤 HIV-1整合到宿主染色体中。不幸的是，最近的报告表明Insti使用是相关的 与限制治疗的神经精神不良反应。显然，PLHIV通常与可卡因使用合并 加剧神经元缺陷的疾病（cud）。因此，了解Insti-Art的综合效应 关于神经元功能障碍的CUD对于艺术的长期有效性至关重要。该建议将调查 基于研究所的艺术和慢性可卡因使用的神经元和神经精神效应的综合。 Instis均包含在所有初始艺术方案中，并被广泛处方以控制HIV-1感染 全世界。目前批准的Instis包括Raltegravir，Elvitegravir，Dolutegravir，Bictegravir和Cabotegravir。 尽管通常据报道是安全有效的，但人们对不良代谢和 与基于研究所的艺术相关的神经精神效应。但是，机制和路径 驱动Insti-Inst-Inst-Inst-Intrics副作用副作用尚不清楚。此外，还有钥匙 在我们对Insti-Art中CUD的任何添加剂或协同作用的理解中，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 受影响突触功能和神经元的谷氨酸和钙信号的改变驱动 特定的大脑电路中的通信。为了测试这一点，我们开发了一种多管齐的方法 结合了神经元功能的生化，遗传和药理学分析与电生理学 神经元电路的研究。使用这种新颖的方法，我们将通过三个特定目标来检验我们的假设。 在AIM 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。目标 2，我们将探测Insti-Art对神经精神病学回路的不利影响。在AIM 3中，我们将调查 Insti-Art和慢性可卡因使用对突触神经传递改变的合并影响 神经精神病学电路。为了实现这些目标，我们结合了HIV神经病发生方面的专业知识， 神经科学和神经精神疾病以及临床研究。这些研究将在一起 全面定义分子，细胞和神经元电路水平效应Insti-Art和CUD。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 在患有艾滋病毒的艺术支持者中。