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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要我们的目标是部署新型磁共振成像 (MRI) 技术来无创追踪抗逆转录病毒药物中枢神经系统药物（ARV），并测量与神经病理学和神经病理学相关的病毒相关代谢物抗逆转录病毒药物产生的神经保护效果 MRI 技术采用了一种新颖的对比技术，称为 “化学交换饱和转移（CEST）”是指生物分子的可交换质子。被磁饱和并通过化学交换转移到水中，导致信号连续减弱。与大量水质子交换导致放大信号减少，从而能够检测特征基于 CEST 的 MRI 提供代谢物的特异性检测以及更高的灵敏度和空间。与磁共振波谱 (MRS) 相比的分辨率确实，我们的初步数据表明。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物，也是主要的利用 ARV 的 CEST 对比，我们成功地检测到了兴奋性神经递质。基于这些结果，我们提出了改变肌细胞的神经病理学标志物。可以使用非侵入性成像测量肌醇和谷氨酸并将其与 ART CNS 生物分布联系起来成像技术将应用于感染艾滋病毒的人源化小鼠，包括这些动物。这些动物对于确定 HIV 相关的临床前研究至关重要。神经病理学和 ART 相关的神经保护活动可以转化为临床。目标 1. 谷氨酸和肌醇将利用 MRI 进行测量。 CEST 对比了接受联合 ART (cART) 治疗的 HIV 感染人源化小胶质细胞小鼠。追求谷氨酸和肌醇改变的成像结果反映病毒诱导的神经病理学作为疾病的生物标志物，谷氨酸和肌醇的 CEST 对比将首先在体外进行表征。随后将基于体外开发三维（3D）CEST MRI 序列。结果并用于同时测量 HIV 感染者全脑中的谷氨酸和肌醇使用 cART 治疗的人源化小胶质细胞目标 2. 将使用 CEST MRI 测量中枢神经系统中的 ARV 水平。将在受感染的小鼠中测试结果与目标 1 中发现的代谢成像标记物的关联。研究 ART 对神经病理/神经保护结果的影响。获得并与代谢物和 ART 的成像结果进行比较。抗逆转录病毒药物的生物利用度/生物分布与神经病理学的缓解有关。总体目标是开发 CEST 作为一种可靠的生物标志物，用于测量神经 HIV-1 病理学和该项目为神经艾滋病毒的临床前研究提供了重要的工具。翻译用于未来的人类临床研究。