Suppression of Pathological Spontaneous Cortical Dynamics and Inflammation in NeuroHIV

NeuroHIV 病理性自发皮质动力学和炎症的抑制

• 批准号: 10590619
• 负责人: Tony W Wilson
• 金额: $ 67.38万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590619
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Agreement; Anti-Inflammatory Agents; Area; Attention; Automobile Driving; Behavior; Behavioral; Brain; Brain Mapping; Brain region; Cannabinoids; Cannabis; Chronic; Cognitive; Complication; Data Analyses; Disease; Economics; Environment; Epidemic; Equation; Exhibits; Foundations; Functional disorder; General Population; Goals; HIV; HIV Infections; HIV/AIDS; Heel; Human; Immune; Impaired cognition; Impairment; Inflammation; Knowledge; Life Expectancy; Link; Mediating; Methods; Mitochondria; Modeling; Molecular; Motor; Neurologic; Neurophysiology - biologic function; Neuropsychological Tests; Oxidation-Reduction; Participant; Pathologic; Pathway interactions; Performance; Persons; Property; Publishing; Quality of life; Reporting; Request for Proposals; Research; Risk; Sampling; Scientific Advances and Accomplishments; Seminal; Superoxides; System; Systems Biology; Targeted Research; Task Performances; Therapeutic; Unemployment; Viral; Western World; Work; behavior prediction; cognitive function; cognitive performance; comorbidity; comparison control; immune activation; improved; innovation; instrumentation; marijuana use; medication compliance; mild cognitive impairment; molecular marker; nervous system disorder; neural; neuroAIDS; neuroimaging; neuroimaging marker; neuroinflammation; virtual

Project Summary/Abstract Persons with HIV (PWH) in the western world have a life expectancy near that of the general population, yet they remain at a significantly elevated risk of developing cognitive impairments. Such impairments are the most common neurological complication of HIV disease, and research targeting these comorbidities is one of four overarching priorities identified by the Office of AIDS Research (NOT-OD-20-018). Recent human neuroimaging studies have broadly shown that the milder impairments more frequently observed in virally-suppressed PWH arise from multiple cortical circuits, which is a major paradigm shift from the putative subcortical origins of the severe cognitive impairments observed earlier in the epidemic. However, despite this progress, we still have a limited understanding of the molecular precursors and pathways that lead to dysfunction in these cortical circuits, and virtually no viable therapeutic options, with only limited potential avenues (e.g., cannabis) on the horizon. This proposal responds to RFA-DA-22-012, which calls for applications that “define HIV-associated persistent inflammation and its causal link to HIV-related comorbidities such as … neurological disorders,” “explore the interaction between HIV immune activation and cannabinoid use as it pertains to neurological disorders,” and “characterize and validate the potential anti-inflammatory, immune stabilizing (beneficial) properties of canna- binoids in chronic HIV infection.” The proposed project responds to this call with an innovative, large-scale, dynamic neuroimaging and molecular markers study that leverages multiple recent discoveries to identify the impact of cannabis use on the mechanisms and pathways underlying HIV-related persistent inflammation and decline in cognitive and brain function in virally-suppressed PWH. Each of our aims builds on a major discovery in 2021. Specifically, Aim 1 examines whether cannabis use modulates the superoxide-sensitive mitochondrial redox environment and neuroinflammation in PWH, which follows on the heels of our finding that mitochondrial function differentially modulates superoxide in PWH compared to controls, and that the latter predicts neuro- inflammation and cognitive function. Aim 2 identifies whether attention- and motor-related neural oscillations are directly modulated by the same superoxide-sensitive pathway in PWH, which builds on our major discovery featured in PNAS that the superoxide-sensitive mitochondrial redox environment predicts cognitive performance and the underlying neural oscillations in controls. Finally, Aim 3 builds on our recent breakthrough that cannabis suppresses the pathological spontaneous cortical activity that is observed in PWH, and further accentuated in cognitively impaired PWH, by examining whether these cannabis-induced alterations are mediated by the superoxide-sensitive mitochondrial redox environment. These recent, major scientific advances provide an ideal foundation to directly address the key objectives of this RFA through an innovative project that utilizes state-of- the-art neuroimaging and systems biology methods, and builds on an established model of neuroinflammation in PWH that has been linked to cognitive and neural function in healthy adults and cognitive decline in PWH.

项目摘要/摘要 在西方世界，艾滋病毒携带者(PWH)的预期寿命接近普通人群，但 他们患认知障碍的风险仍然显著增加。这种损伤是最严重的 HIV疾病常见的神经系统并发症，针对这些共病的研究是四个之一 艾滋病研究办公室确定的首要优先事项(NOT-OD-20-018)。最新人类神经成像 研究广泛表明，在病毒抑制的PWH中观察到的较轻微的损害更常见 起源于多个皮质环路，这是一个重大的范式转变，从假设的皮质下起源 早些时候在疫情中观察到严重的认知障碍。然而，尽管取得了这些进展，我们仍然有一个 对导致这些皮质回路功能障碍的分子前体和通路的了解有限， 而且几乎没有可行的治疗选择，仅有有限的潜在途径(例如大麻)。 该提案响应了RFA-DA-22-012标准，该标准要求应用程序定义与HIV相关的持久性 炎症及其与…等艾滋病毒相关共病的因果联系神经紊乱，“”探索 艾滋病毒免疫激活和大麻素使用之间的相互作用，因为它与神经疾病有关 “鉴定和验证美人掌潜在的抗炎、免疫稳定(有益)特性-- 慢性艾滋病毒感染中的双核类固醇。“拟议的项目以创新的、大规模的、 动态神经成像和分子标志物研究，利用多项最新发现来识别 大麻使用对艾滋病毒相关持续性炎症和感染的机制和途径的影响 病毒抑制的PWH患者认知和脑功能下降。我们的每个目标都建立在一个重大发现的基础上 在2021年。具体地说，目标1检查了大麻的使用是否调节了超氧化物敏感的线粒体 氧化还原环境和PWH的神经炎症，这紧随我们发现线粒体 与对照组相比，PWH患者的功能对超氧化物歧化有不同的调节作用，而后者预测神经- 炎症和认知功能。目标2确定注意力和运动相关的神经振荡 直接受到PWH中相同的超氧化物敏感途径的调节，这一途径建立在我们重大发现的基础上 PNAS的特点是超氧化物敏感的线粒体氧化还原环境预测认知能力 以及控制组中潜在的神经振荡。最后，目标3建立在我们最近的突破，即大麻 抑制PWH中观察到的病理性自发皮质活动，并在 认知受损的PWH，通过检查这些大麻诱导的改变是否由 超氧化物敏感的线粒体氧化还原环境。这些最新的重大科学进展提供了一种理想的 基金会通过一个创新项目直接解决该RFA的关键目标，该项目利用 最先进的神经成像和系统生物学方法，并建立在已建立的神经炎症模型基础上 在PWH患者中，这与健康成年人的认知和神经功能以及PWH患者的认知功能下降有关。