SIGNATURES OF CANNABIS ABUSE IN NEUROHIV (SCAN): AN INTEGRATED MOLECULAR AND IMAGING APPROACH

神经艾滋病毒中大麻滥用的特征（扫描）：一种综合的分子和成像方法

基本信息

批准号：
10430165
负责人：
JAMES T. BECKER
金额：
$ 77.56万
依托单位：
FATHER FLANAGAN'S BOYS' HOME
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10430165
关键词：
AIDS dementia AIDS/HIV problem Acquired Immunodeficiency Syndrome Adult Affect Architecture Area Attention B-Lymphocytes Behavioral Biological Assay Biological Markers Blood Brain Brain Mapping CD8-Positive T-Lymphocytes Cannabis Abuse Cells Chemicals Chronic Clinical Markers Clinical assessments Coagulation Process Cognition Disorders Cognitive Cognitive deficits Collection Color Complication Data Databases Deterioration Diagnostic tests Disease Disease Progression Early identification Economics Endothelium Enrollment Exhibits Flow Cytometry Fostering Frequencies Functional Magnetic Resonance Imaging Functional disorder Future General Population Genus Hippocampus Goals HIV HIV Infections HIV-1 HIV-associated neurocognitive disorder Host Defense Mechanism Immune Immunologic Markers Impaired cognition Impairment Individual Infection Inflammation Inflammatory Life Expectancy Magnetic Resonance Imaging Magnetoencephalography Maps Matched Group Medical center Methods Mitochondria Modality Molecular Molecular Analysis Monitor National NeuroAids Tissue Consortium Natural Killer Cells Nature Nebraska Neurocognitive Neurologic Neuropsychological Tests Neuropsychology Neurosecretory Systems Participant Pathogenesis Performance Persons Plasma Population Prevalence Preventive treatment Prognosis Quality of life Request for Applications Request for Proposals Research Resources Risk Source Substance Use Disorder Substance abuse problem Sum System Targeted Research Terminal Disease The Multicenter AIDS Cohort Study Unemployment Universities Visual Perception Visual attention Western World antiretroviral therapy biomarker identification biomarker signature cognitive function cognitive performance cognitive testing comorbidity comparative diagnostic biomarker gamma-Aminobutyric Acid hemodynamics imaging approach imaging modality immune activation indexing innovation marijuana use disorder medication compliance molecular imaging molecular marker monocyte multimodality neural circuit neuroAIDS neuroimaging neurophysiology non-invasive imaging predictive marker prevent prognosis biomarker quantitative imaging relating to nervous system resilience spectroscopic imaging treatment trial

项目摘要

Project Summary/Abstract HIV-infected adults in the western world have a life expectancy near that of the general population, but are at a significantly elevated risk of developing cognitive deficits. Such impairments are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected individuals, and research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (NOT-OD-15-137). Substance use disorders (SUD) are also more prevalent in the HIV-infected population, yet their relative contribution to the increased rate of cognitive impairment in this group remains poorly understood. A key barrier to progress in this area has been the historic lack of diagnostic tests and biomarkers that can precisely assess the neurological complications of HIV-infection, which has all but precluded quantification of the additive impact of SUD comorbidity. This barrier is central to RFA-DA-18-023, which requests applications that “foster biomarker and signature identification that could advance the clinical assessment of the degree of deterioration or damage, of functional reserve, and of resilience of host defense mechanisms, towards HIV- infection and comorbidity of HIV with SUDs.” Specifically, the RFA requests proposals that identify biomarkers derived from blood, plasma, noninvasive neuroimaging modalities, and/or other sources, with an emphasis on biomarkers that can be quantitated, with levels assessed for their ability to predict disease progression. The current project directly targets the scientific gaps identified in this RFA, Identification of Biomarkers of HIV Pathogenesis and Substance Abuse Comorbidity, using a multipronged approach that includes state-of-the-art neurophysiological, structural, and spectroscopic noninvasive imaging, cognitive assessment, and cellular and molecular analyses of blood/plasma in the context of cannabis use disorder (CUD). Specifically, the Signatures of Cannabis Abuse in NeuroHIV (SCAN) Consortium will utilize advanced magnetoencephalographic (MEG) imaging to quantify the neural dynamics serving cognitive processing, 3-Tesla MRI and multimodal parcellation methods to map brain architecture, functional MRI (fMRI) for hemodynamics and intrinsic networks, and 7-Tesla spectroscopic imaging to quantify local GABA levels across the brain. These data will be integrated with a comprehensive molecular screen that includes 35 plasma biomarkers covering the immune, inflammatory, coagulation, endothelial, and neurological systems, a 10-color flow cytometry panel delineating CD4 and CD8 T cells, B cells, NK cells, monocyte subsets, and activation markers, known clinical markers, and mitochondrial function in immune cells using the Seahorse Analyzer method. To enhance rigor, demographically-matched groups of uninfected controls with and without CUD will be enrolled, which will enable the interaction of HIV and CUD to be quantified. In sum, to truly meet the goals of this RFA, we will use a broad range of neuroimaging, molecular, and cellular functional assays to uncover biomarker signatures of HIV and CUD that will enable identification of early dysfunction, progression, and prognosis, enabling future preventative and treatment trials.

项目概要/摘要西方世界感染艾滋病毒的成年人的预期寿命接近普通人群，但仍处于发生认知缺陷的风险显着升高，此类损伤是最常见的神经系统损伤。 HIV 疾病的并发症，患病率估计为所有 HIV 感染者的 35-70%，针对此类合并症的研究已被艾滋病研究办公室确定为首要任务 (NOT-OD-15-137) 然而，药物滥用障碍 (SUD) 在 HIV 感染人群中也更为普遍。他们对这一群体认知障碍发生率增加的相对贡献仍知之甚少。该领域取得进展的一个主要障碍是历史上缺乏诊断测试和生物标志物精确评估 HIV 感染的神经系统并发症，这几乎无法量化 SUD 合并症的附加影响是 RFA-DA-18-023 的核心，它要求申请。 “促进生物标志物和特征识别，可以促进对疾病程度的临床评估恶化或损害，功能储备和宿主防御机制的恢复力，对艾滋病毒- 具体来说，RFA 要求提出识别生物标志物的提案。” 源自血液、血浆、无创神经影像方式和/或其他来源，重点是可以定量的生物标志物，并评估其水平以预测疾病进展的能力。当前的项目直接针对本 RFA《艾滋病毒生物标志物的鉴定》中确定的科学差距发病机制和药物滥用合并症，采用多管齐下的方法，包括最先进的方法神经生理学、结构和光谱无创成像、认知评估以及细胞和大麻使用障碍 (CUD) 背景下的血液/血浆的分子分析，特别是特征。 NeuroHIV (SCAN) 联盟中的大麻滥用研究将利用先进的脑磁图 (MEG) 成像以量化服务于认知处理、3-特斯拉 MRI 和多模态分割的神经动力学绘制大脑结构图的方法、用于血流动力学和内在网络的功能性 MRI (fMRI) 以及 7-Tesla 光谱成像来量化整个大脑的局部 GABA 水平，这些数据将与全面的分子筛查，包括 35 种血浆生物标志物，涵盖免疫、炎症、凝血、内皮和神经系统，10 色流式细胞仪面板描绘 CD4 和 CD8 T 细胞、B 细胞、NK 细胞、单核细胞亚群和激活标记物、已知临床标记物和线粒体使用 Seahorse 分析仪方法检测免疫细胞的功能，以增强严格性、人口统计匹配性。将招募有和没有 CUD 的未感染对照组，这将使 HIV 和 HIV 之间的相互作用成为可能。总之，为了真正实现本次 RFA 的目标，我们将使用广泛的神经影像学、分子和细胞功能测定，以揭示 HIV 和 CUD 的生物标志物特征，从而使识别早期功能障碍、进展和预后，使未来的预防和治疗试验成为可能。