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

• 批准号: 10331250
• 负责人: JAMES T. BECKER
• 金额: $ 52.6万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331250
• 关键词: SIGNATURES; CANNABIS; ABUSE; NEUROHIV; SCAN

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.

项目总结/摘要 在西方世界，感染艾滋病毒的成年人的预期寿命接近一般人口， 认知缺陷的风险显著增加。这种损伤是最常见的神经系统疾病 艾滋病毒疾病并发症，患病率估计占所有艾滋病毒感染者的35-70%， 针对这些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）。物质使用障碍（SUD）在艾滋病毒感染人群中也更为普遍，但 他们对这一群体中认知障碍率增加的相对贡献仍然知之甚少。 在这一领域取得进展的一个关键障碍是历史上缺乏诊断测试和生物标志物， 精确评估艾滋病毒感染的神经系统并发症，这几乎排除了量化艾滋病毒感染的可能性。 SUD共患病的累加影响。该屏障是RFA-DA-18-023的核心，要求申请 “促进生物标志物和签名识别，可以促进对疾病程度的临床评估。 功能储备和宿主防御机制的恢复力，对艾滋病毒的恶化或损害， HIV感染和SUD合并症。”特别是，RFA要求提出识别生物标志物的建议， 来源于血液、血浆、非侵入性神经成像模式和/或其他来源，重点是 可以定量的生物标志物，其水平评估其预测疾病进展的能力。 目前的项目直接针对RFA中确定的科学差距，确定艾滋病毒的生物标志物 发病机制和药物滥用并发症，使用多管齐下的方法，包括最先进的 神经生理学、结构和光谱非侵入性成像、认知评估以及细胞和 大麻使用障碍（CUD）背景下的血液/血浆分子分析。具体来说，签名 神经艾滋病毒中的大麻滥用（SCAN）联盟将利用先进的脑磁图（MEG） 成像以量化用于认知处理的神经动力学，3-Tesla MRI和多模式分割 绘制大脑结构的方法，用于血流动力学和内在网络的功能性MRI（fMRI），以及7特斯拉 光谱成像来量化整个大脑的局部GABA水平。这些数据将与一个 全面的分子筛选，包括35个血浆生物标志物，涵盖免疫，炎症， 凝血、内皮和神经系统，描绘CD 4和CD 8的10色流式细胞术面板 T细胞、B细胞、NK细胞、单核细胞亚群和活化标志物、已知的临床标志物和线粒体标志物。 使用海马分析仪方法检测免疫细胞的功能。为了提高严谨性，人口统计学上匹配 将招募未感染的对照组（有和无CUD），这将使HIV和 CUD将被量化。总之，为了真正实现RFA的目标，我们将使用广泛的神经成像， 分子和细胞功能测定，以发现HIV和CUD的生物标志物特征，这将使 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。