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 西方世界中艾滋病毒（PWH）的人在一般人群附近的预期寿命 他们仍然处于发展认知障碍的风险大大升高。这样的障碍最多 艾滋病毒疾病的常见神经系统并发症以及针对这些合并症的研究是四种 艾滋病研究办公室确定的总体优先级（NOT-OD-20-018）。最近的人类神经影像学 研究广泛地表明，在病毒抑制的PWH中，米勒损伤更频繁地观察到 由多个皮质圆引起，这是从假定的皮层构造的主要范式转变 在流行病早期观察到的严重认知障碍。但是，要求这一进展，我们仍然有一个 对这些皮质回路中功能障碍的分子前体和途径的了解有限 几乎没有可行的治疗选择，只有有限的潜在途径（例如大麻）。 此提案对RFA-DA-22-012的响应，该提案要求“定义与HIV相关的持续存在的申请 炎症及其与HIV相关的合并症（例如……神经系统疾病）的因果关系，” HIV免疫激活与大麻素使用与神经系统疾病有关的相互作用，” “表征并验证了大麻的潜在抗炎，免疫稳定（有益）特性 拟议的项目以创新的大规模，大规模的，拟议的项目对这个电话做出了反应。 动态神经影像学和分子标志物研究，该研究利用了最近发现的多个发现 大麻使用对与HIV相关的持续注射的机制和途径的影响 几乎抑制的PWH的认知和大脑功能下降。我们的每个目标都建立在一个重大发现的基础上 在2021年。特别是AIM 1检查大麻的使用是否调节超氧化物敏感的线粒体 PWH中的氧化还原环境和神经炎症，紧随其后的是线粒体 与对照组相比 炎症和认知功能。 AIM 2识别注意力与运动相关的神经振荡是否 由PWH中的相同的超氧化物敏感途径直接调节，这是基于我们的主要发现的 在PNA中表明，超氧化物敏感的线粒体氧化还原环境预测认知性能 以及对照中的潜在神经振荡。最后，AIM 3建立在我们最近的大麻的突破之上 抑制在PWH中观察到的病理赞助皮质活性，并进一步强调 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。这些最近的主要科学进步提供了理想 通过一个利用最先进的创新项目直接解决此RFA的关键目标的基础 ART神经影像学和系统生物学方法，并建立在既定的神经炎症模型上 在健康成年人中与认知和神经功能有关的PWH和PWH的认知下降有关。