cART, neuroHIV, cocaine abuse and the mPFC neuron/astrocyte dysfunction

cART、神经艾滋病毒、可卡因滥用和 mPFC 神经元/星形胶质细胞功能障碍

• 批准号: 10560050
• 负责人: XIU-TI HU
• 金额: $ 78.63万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 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/10560050
• 关键词: AIDS/HIV problem; Address; Adult; Age; Animal Model; Anti-HIV Agents; Anti-HIV Therapy; Anti-Retroviral Agents; Astrocytes; Automobile Driving; Autopsy; Behavior; Brain; Brain region; Cause of Death; Cell Communication; Cells; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine use disorder; Cognition; Cognitive; Connexin 43; Connexins; Corpus striatum structure; Data; Development; Disease; Electrophysiology (science); FDA approved; Functional disorder; Glutamates; HIV; HIV-1; HIV-associated neurocognitive disorder; Hippocampus (Brain); Homeostasis; Human; Hyperactivity; Immune System Diseases; Immune system; Individual; Injury; Knowledge; Lamivudine; Learning; Link; Long-Term Effects; Medial; Mediating; Medicine; Memantine; Membrane Potentials; Memory; Messenger RNA; Modeling; Molecular; Molecular Biology; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; National NeuroAids Tissue Consortium; Neurocognition; Neurocognitive Deficit; Neurodegenerative Disorders; Neurologic; Neuronal Dysfunction; Neurons; Nifedipine; Persons; Pharmaceutical Preparations; Pharmacology; Play; Prefrontal Cortex; Prevalence; Process; Proteins; Quantitative Reverse Transcriptase PCR; Rattus; Regimen; Reporting; Research; Role; Saline; Sampling; Therapeutic; Therapeutic Intervention; Transgenic Organisms; abacavir; addiction; antagonist; antiretroviral therapy; astrogliosis; brain dysfunction; channel blockers; chemokine; cocaine self-administration; comorbidity; cytokine; excitotoxicity; experience; extracellular; hippocampal pyramidal neuron; improved; in vivo; innovation; interest; neuroAIDS; neuron loss; neurotoxicity; novel therapeutic intervention; novel therapeutics; overexpression; patch clamp; protein expression; success; voltage

ABSTRACT HIV-Associated Neurocognitive Disorders (HAND) is a significant comorbid condition for people living with HIV/ AIDS (PLWH). HAND is associated with HIV-induced neurotoxicity that dysregulates, injures, and in severe cases, causes death of neurons in the key brain regions that regulate neurocognition. Combined antiretroviral therapy (cART) inhibits active HIV-1 replication; but it has not reduced the prevalence of HAND, as it occurs in 30~50% of PLWH and is expected to increase as PLWH age. Notably, Cocaine (Coc) Use Disorders (CUD) are comorbid with HAND in many cases and worsen it severely. Ironically, although cART is absolutely necessary for treating HIV/AIDS, emerging data point to cART as a potential contributor to HAND through cART-induced neurotoxicity. This raises key questions regarding if chronic cART contributes to neurological/neurocognitive deficits linked to HAND; and how it alters brain neuron activity in the context of neuroHIV and CUD; both are the focus of this proposal. Our studies suggest that cART induces neuronal Ca2+ dysregulation in the medial prefrontal cortex (mPFC, a key regulator of neurocognition and addiction), similar to that well-described in neuroHIV and CUD mediated by overactive voltage-gated L-type Ca2+ channels (L-channels) and NMDA receptors (NMDARs). Dysfunction of mPFC pyramidal neurons is linked to HAND, CUD and many other neuro- degenerative diseases. Thus, we hypothesize that cART-induced mPFC neuronal Ca2+ dysregulation worsens similar dysfunction caused by neuroHIV and Coc; and that is reduced by combined antagonism of L -channel/ NMDAR overactivation. We will determine the effects of cART, neuroHIV and Coc on mPFC pyramidal neurons, and elucidate their underlying mechanism. Specifically, we will use three combined rat models of (i) cART (chronic Triumeq, a 1st-line cART regimen consisting of 3 antiretroviral drugs - abacavir, dolutegravir and lamivudine), (ii) neuroHIV (HIV-1 transgenic rats), and (iii) Coc abuse (Coc self-administration, Coc-SA), to elucidate the long-term effects of cART in vivo on mPFC neuronal activity and their mechanism in the context of neuroHIV and CUD (Aim1); define the effects of chronic cART on interactive astrocyte/neuron dysfunction in the mPFC under neuroHIV and CUD conditions (Aim2); and identify the effects of combined antagonism of excessive Ca2+ influx/ [Ca2+]in that alleviate neuronal activity and cognitive behavior in the context of neuroHIV/ CUD (Aim3). Further, we will also define HIV/cART/Coc-induced neuron/astrocyte dysfunction in post-mortem HIV+ human brains (Exploratory Aim) to provide additional support for the principal concept and hypothesis of this proposal. Together, the proposed research will elucidate the mechanism by which neuroHIV, chronic cART in vivo and Coc-SA, individually and jointly, alter mPFC neuronal activity, and in such process identify the key mechanistic targets that will inform therapeutic intervention for HAND and CUD in the era of cART.

抽象的 HIV 相关神经认知障碍 (HAND) 是 HIV 感染者/患者的一种重要合并症。 艾滋病（PLWH）。 HAND 与 HIV 引起的神经毒性有关，这种神经毒性会导致失调、损伤，严重时会导致神经毒性。 在某些情况下，会导致调节神经认知的关键大脑区域的神经元死亡。联合抗逆转录病毒药物 疗法 (cART) 抑制活跃的 HIV-1 复制；但它并没有降低 HAND 的患病率，因为它发生在 占 PLWH 的 30~50%，预计随着 PLWH 年龄的增长而增加。值得注意的是，可卡因 (Coc) 使用障碍 (CUD) 是 在许多情况下与 HAND 共存并使其严重恶化。讽刺的是，尽管 cART 是绝对必要的 对于治疗 HIV/AIDS，新出现的数据表明 cART 通过 cART 诱导成为 HAND 的潜在贡献者 神经毒性。这就提出了关于慢性 cART 是否会导致神经/神经认知障碍的关键问题。 与 HAND 有关的赤字；以及它如何在神经艾滋病毒和 CUD 的背景下改变大脑神经元活动；两者都是 本提案的重点。我们的研究表明，cART 会导致内侧神经元 Ca2+ 失调 前额皮质（mPFC，神经认知和成瘾的关键调节器），类似于 由过度活跃的电压门控 L 型 Ca2+ 通道（L 通道）和 NMDA 介导的 NeuroHIV 和 CUD 受体（NMDAR）。 mPFC 锥体神经元的功能障碍与 HAND、CUD 和许多其他神经元有关 退行性疾病。因此，我们假设 cART 诱导的 mPFC 神经元 Ca2+ 失调恶化 由neuroHIV和Coc引起的类似功能障碍；并且通过 L 通道/的联合拮抗作用来减少 NMDAR 过度激活。我们将确定 cART、neuroHIV 和 Coc 对 mPFC 锥体神经元的影响， 并阐明其潜在机制。具体来说，我们将使用 (i) cART 的三种组合大鼠模型 （慢性 Triumeq，一种一线 cART 治疗方案，由 3 种抗逆转录病毒药物组成 - 阿巴卡韦、多替拉韦和 拉米夫定），（ii）neuroHIV（HIV-1转基因大鼠），以及（iii）Coc滥用（Coc自我给药，Coc-SA），以 阐明体内 cART 对 mPFC 神经元活动的长期影响及其机制 神经 HIV 和 CUD（目标 1）；定义慢性 cART 对星形胶质细胞/神经元相互作用功能障碍的影响 神经 HIV 和 CUD 条件下的 mPFC（目标 2）；并确定联合拮抗作用的效果 过量的 Ca2+ 流入/[Ca2+]in 会减轻神经 HIV 背景下的神经元活动和认知行为/ CUD（目标 3）。此外，我们还将在死后定义 HIV/cART/Coc 诱导的神经元/星形胶质细胞功能障碍 HIV+ 人类大脑（探索性目标）为主要概念和假设提供额外支持 这个建议。总之，拟议的研究将阐明神经艾滋病毒、慢性 cART 体内和 Coc-SA 单独或联合改变 mPFC 神经元活动，并在此过程中确定关键 机制目标将为 cART 时代的 HAND 和 CUD 治疗干预提供信息。