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 艾滋病毒相关的神经认知障碍（手）是艾滋病毒/患者的重要合并症 艾滋病（PLWH）。手与HIV诱导的神经毒性相关，导致损伤，严重损伤和 病例会导致调节神经认知的关键大脑区域中神经元死亡。抗逆转录病毒组合 治疗（CART）抑制活跃的HIV-1复制；但是它并没有降低手的患病率，因为它发生在 PLWH的30〜50％，预计将随着PLWH的年龄而增加。值得注意的是，可卡因（COC）使用疾病（CUD）是 在许多情况下，可以合并手，并严重恶化。具有讽刺意味的是，尽管购物车绝对必要 对于治疗艾滋病毒/艾滋病 神经毒性。这就提出了有关慢性推车是否有助于神经/神经认知的关键问题 与手相关的赤字；以及它如何在神经hiv和CUD的背景下改变脑神经元的活性；两者都是 该提议的重点。我们的研究表明，CART诱导内侧神经元CA2+失调 前额叶皮层（MPFC，神经认知和成瘾的关键调节剂），类似 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手，CUD和许多其他神经元有关 退化性疾病。因此，我们假设CART诱导的MPFC神经元CA2+失调恶化 神经hiv和COC引起的类似功能障碍； L-通道/ NMDAR过度活化。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。具体而言，我们将使用（i）购物车的三种组合大鼠模型 （慢性triumeq，一种一条一条车方案，该方案由3种抗逆转录病毒药物组成-Abacavir，Dolutegravir和 lamivudine），（ii）Neurohiv（HIV-1转基因大鼠）和（iii）COC滥用（COC自我给药，COC-SA） 阐明车体体体内对MPFC神经元活性及其机制的长期影响 Neurohiv和Cud（AIM1）；定义慢性推车对交互式星形胶质细胞/神经元功能障碍的影响 MPFC在Neurohiv和CUD条件下（AIM2）；并确定联合拮抗的影响 过度Ca2+流入/ [Ca2+]在神经hiv的背景下减轻神经元活动和认知行为 CUD（AIM3）。此外，我们还将定义HIV/CART/COC诱导的神经元/星形胶质细胞功能障碍 艾滋病毒+人类大脑（探索性目的）为主要概念和假设提供额外的支持 这个建议。拟议的研究将共同​​阐明神经hiv的慢性推车的机制 体内和COC-SA单独和共同改变MPFC神经元活动，并在此过程中确定关键 在购物车时代，机械目标将为治疗干预提供治疗干预。