Brain metabolic imaging biomarkers of HIV-1 Infection During ART

ART 期间 HIV-1 感染的脑代谢成像生物标志物

• 批准号: 10761339
• 负责人: Yutong Liu
• 金额: $ 42.21万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-08-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761339
• 关键词: 3-Dimensional; Affect; Animals; Anti-Retroviral Agents; Biodistribution; Biological Availability; Biological Markers; Brain; CD4 Positive T Lymphocytes; Central Nervous System; Chemicals; Chronic Disease; Clinical Research; Cognition; Coin; Data; Detection; Development; Dimensions; Disease; Event; Future; Glutamates; Goals; Growth; HIV; HIV Infections; HIV-associated neurocognitive disorder; Human; Image; Imaging Techniques; Immune; Immune System Diseases; In Vitro; Infection; Inflammation; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetism; Measures; Medicine; Microglia; Mus; Neurocognitive; Neurologic; Neurotransmitters; Organ; Outcome; Pathology; Patients; Pharmaceutical Preparations; Prevention; Prevention strategy; Protons; Reporting; Resolution; Signal Transduction; Substance Use Disorder; Techniques; Testing; Translating; Viral; Virus; Water; antiretroviral therapy; comorbidity; drug testing; glial activation; humanized mouse; imaging biomarker; in vivo evaluation; metabolic imaging; myoinositol; neuroAIDS; neuropathology; neuroprotection; neurotoxicity; non-invasive imaging; novel; preclinical study; tool; treatment strategy

Project Summary/Abstract Our goal is to deploy novel magnetic resonance imaging (MRI) techniques to noninvasively track antiretroviral drugs (ARVs) in the CNS and measure virus-associated metabolites linked to neuropathological and neuroprotective outcomes resulting from ARVs. The MRI techniques employ a novel contrast coined as “chemical exchange saturation transfer (CEST)”. CEST is seen when an exchangeable proton of a biomolecule is magnetically saturated and transferred to water by chemical exchange causing signal reduction. Continuous exchange with bulk water protons leading to amplified signal reduction enables the detection of the signature biomolecule. CEST-based MRI provides specific detection of metabolites and greater sensitivity and spatial resolution compared to magnetic resonance spectroscopy (MRS). Indeed, our preliminary data demonstrate CEST MRI of myo-inositol and glutamate in mouse brains, which are a marker of glial activation, and a primary excitatory neurotransmitter, respectively. Employing the CEST contrasts of ARVs, we have successfully detected the drugs in the CNS using MRI. Based on these results, we posit neuropathological markers of altered myo- inositol and glutamate can be measured and linked to ART CNS biodistribution using noninvasive imaging techniques. The imaging techniques will be deployed in HIV-infected humanized mice including those animals enriched for human microglia. These animals are critical for preclinical studies to determine HIV-associated neuropathology and ART-linked neuroprotective activities. The imaging techniques can be translated to clinical research after optimization. Aim 1. Glutamate and myo-inositol will be measured using MRI employing their CEST contrasts in HIV-infected humanized microglial mice treated with combination ART (cART). We hypothesize that imaging results of glutamate and myo-inositol alterations reflect virus induced neuropathology as biomarkers of disease. The CEST contrasts of glutamate and myo-inositol will be first characterized in vitro followed by in vivo testing. There-dimensional (3D) CEST MRI sequences will be developed based on the in vitro results and used to measure the glutamate and myo-inositol simultaneously in the whole brain of HIV-infected humanized microglial mice treated with cART. Aim 2. ARV levels in the CNS will be measured using CEST MRI in infected mice. The results will be tested for association with metabolic imaging markers uncovered in aim 1 to study the effects of ART on neuropathological/neuroprotective outcomes. Viral, immune (CD4+ T cell) data will be acquired and compared with imaging results of metabolites and ART. The hypothesis is that the bioavailability/biodistribution of ARVs are associated with the mitigation of neuropathology. The overarching goal is to develop CEST as a reliable biomarker for measures of neuroHIV-1 pathology and ART neuroprotection. The project provides essential tools for preclinical studies of neuroHIV that can be translated for future human clinical research.

项目摘要/摘要 我们的目标是将新颖的磁共振成像（MRI）技术部署到非侵入性跟踪抗逆转录病毒 中枢神经系统中的药物（ARV），并测量与神经病理学相关的病毒相关的代谢产物 由ARV产生的神经保护效果。 MRI技术员工的新颖对比形成为 “化学交换饱和转移（CEST）。当生物分子的可交换质子可交换 磁性饱和，并通过化学交换转移到水中，从而导致信号降低。连续的 与散装水质子交换导致放大信号减少的质量可以检测到签名 生物分子。基于CEST的MRI提供了代谢物的特定检测以及更高的灵敏度和空间 与磁共振光谱（MRS）相比，分辨率。确实，我们的初步数据证明了 小鼠大脑中肌醇和谷氨酸的CEST MRI，它们是神经胶质激活的标志 兴奋性神经递质。使用ARV的CEST对比，我们已经成功检测到 中枢神经系统中的药物使用MRI。基于这些结果，我们对肌酸的阳性神经病理学标志物呈阳性 可以测量肌醇和谷氨酸，并使用非侵入性成像与ART CNS生物分布联系 技术。成像技术将部署在感染的HIV感染的人源化小鼠中，包括那些动物 富含人类小胶质细胞。这些动物对于确定与HIV相关的临床前研究至关重要 神经病理学和与艺术相关的神经保护活动。成像技术可以翻译成临床 优化后的研究。 AIM1。谷氨酸和肌醇，将使用MRI进行测量 CEST与联合艺术（CART）处理的HIV感染的人型小鼠小鼠对比。我们 假设谷氨酸和肌醇改变的成像结果反映了病毒诱导的神经病理学 作为疾病的生物标志物。首先在体外表征谷氨酸和肌醇的CEST对比 其次是体内测试。基于体外，将开发其维（3D）CEST MRI序列 结果，用于在HIV感染的整个大脑中测量谷氨酸和肌醇 用购物车处理的人源化小胶质细胞。 AIM 2。将使用CEST MRI测量中枢神经系统中的ARV水平 在被感染的小鼠中。结果将经过测试，以与AIM 1中发现的代谢成像标记相关 研究艺术对神经病理学/神经保护效果的影响。病毒，免疫（CD4+ T细胞）数据将 被获取并与代谢产物和艺术的成像结果进行比较。假设是 ARV的生物利用度/生物分布与神经病理学的缓解有关。 总体目标是将CEST作为一种可靠的生物标志物，用于测量神经hiv-1病理和 艺术神经保护。该项目为神经凝血的临床前研究提供了重要的工具 翻译成未来的人类临床研究。