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120万人感染HIV-1，全球约有3700万人感染。在……里面 尽管艾滋病毒/艾滋病研究取得了长足的进步，但抗逆转录病毒疗法仍然是唯一的治疗方法。 HIV-1感染的选择。虽然抗逆转录病毒疗法在控制病毒和使艾滋病毒感染方面非常有效 作为一种可控制的疾病，ART方案中使用的药物会产生不良副作用。其中最广泛的 处方的抗逆转录病毒药物(ARV)是整合酶链转移抑制剂(INSTI)，它可以阻断关键的 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 有治疗限制的神经精神不良反应。显然，PLHIV经常与可卡因使用并存 加剧神经元缺陷的紊乱(CUD)。因此，了解INSTI-ART的综合影响 而对神经元功能障碍的CUD对于ART的长期有效性至关重要。这项提案将探讨 基于INSTI的抗逆转录病毒药物和慢性可卡因使用对神经元和神经精神的联合影响。 INSTI被包括在所有最初的ART方案中，并被广泛开出用于控制HIV-1感染的抗逆转录病毒药物 全世界。目前批准的INSTI包括raltegravir、elvitegravir、dolutegravir、bitegravir和Cabotegravir。 虽然普遍报道是安全有效的，但人们越来越关注不良代谢和 与INSTI为基础的抗逆转录病毒治疗相关的神经精神影响。然而，其机制和途径 驱动INSTI相关的神经元和神经精神病学副作用的原因尚不清楚。此外，还有关键 在INSTI-ART中，我们对CUD的任何相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 由影响突触功能和神经元的谷氨酸和钙信号的变化驱动 在特定的大脑回路中进行交流。为了测试这一点，我们开发了一种多管齐下的方法 将神经功能的生化、遗传学和药理学分析与电生理学相结合 神经回路的研究。使用这种新的方法，我们将通过三个具体的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。在AIM 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与慢性可卡因联合应用对脑内突触神经递质改变的影响 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方面的专业知识， 神经科学和神经精神障碍，以及临床研究。总而言之，这些研究将 全面定义分子、细胞和神经元电路水平效应INSTI-ART和CUD。这是一项新的 知识将促进新的和改进的治疗策略，以降低神经元缺陷的严重程度 在艾滋病病毒携带者中。