Molecular Imaging

项目3摘要： 长期抗逆转录病毒疗法(ART)导致持续低水平的人类免疫缺陷病毒感染 并结束包括中枢神经系统在内的器官疾病。这通常被视为亚临床认知。 仅通过神经心理检查记录的损害。我们假设长效纳米配方 在项目1和2中开发的ART(纳米艺术)将导致最小的毒性，如果没有毒性的话 常规免疫、化学、血液学、生化和组织学终点(项目2)。然而，什么？ 无法通过这些参数看到的是亚细胞功能(线粒体)、细胞功能 (能量和膜代谢)和组织结构和功能(髓鞘形成、神经递质和 代谢异常)。这些参数的更改也可能被标准行为和 认知测试。为此，我们希望将纳米毒理学提高到另一个水平。在这里，我们试图破译 病毒和纳米艺术疗法的微妙效果是通过大脑代谢组学实现的。为了实现这一目标，我们 已经复制了在人类身上观察到的部分行为、组织和神经成像异常 神经艾滋病人源化小鼠HIV-1感染模型。该模型不同于 它支持持续的病毒复制，导致与CD4+T细胞相关的自发性神经疾病 损失和新陈代谢组学改变。我们将使用此模型作为确定长期影响(测量的)的平台 以月计)神经功能和区域特定的脑生化异常 代谢组学。已确定的生化途径将通过有针对性的措施进行验证。这样的研究将是 高度敏感。具体地说，我们将用质子磁共振波谱来连接这些数据集， 扩散张量磁共振成像和磁化传递磁共振成像。这些 Links将用于指导着眼于临床实用的转化性研究。验证 实验结果将通过组织病理学测试(核心C)得出。磁性材料的验证 将在小鼠和猴子的实验中使用配基包裹的磁铁矿粒子进行共振成像 通过完整的药代动力学分析(结合项目2和核心B进行)，以及 经生产的小磁铁抗逆转录病毒颗粒以及病毒学和免疫学分析确认(与 项目1和核心C)。

Project 3 Abstract: Long-term antiretroviral therapy (ART) leads to continuous low-level human immunodeficiency viral infection and end organ disease that includes the central nervous system. This is often seen as subclinical cognitive impairments recorded only by neuropsychological examination. We posit that the long-acting nanoformulated ART (nanoART) developed in Projects 1 and 2 would lead to minimal if no toxicities when recorded by conventional immune, chemical, hematologic, biochemical and histologic endpoints (Project 2). However, what cannot be seen by such parameters are measures of subcellular function (mitochondria), cellular function (energy and membrane metabolism) and tissue structure and function (myelination, neurotransmitter and metabolic aberrations). Changes in these parameters may also be missed by standard behavioral and cognitive tests. To these ends, we wish to take nanotoxicology to yet another level. Here we seek to decipher subtle effects of the virus and nanoART therapy is through brain metabolomics. To accomplish this goal, we have replicated a portion of the behavioral, histological, and neuroimaging abnormalities observed in human neuroAIDS in a humanized mouse model of HIV-1 infection. The model is divergent from others available in that it supports sustained viral replication, results in spontaneous neural disease associated with CD4+ T cell loss and metabolomics change. We will use this model as a platform to determine long-term effects (measured in months) of aberrations in neural function and region specific brain biochemistry with untargeted metabolomics. Identified biochemical pathways will be validated by targeted measures. Such studies will be highly sensitive. Specifically, we will bridge these data sets with proton magnetic resonance spectroscopy, diffusion tensor magnetic resonance imaging and magnetization transfer magnetic resonance imaging. These linkages will serve to guide translational studies with an eye towards clinical utility. Validation of the experimental results will be made through histopathological tests (with Core C). Validation of magnetic resonance imaging using ligand coated magnetite particles in mouse and monkey experiments will be done through complete pharmacokinetic analyses (performed in conjunction with Project 2 and Core B), and confirmed by produced small magnetite antiretroviral particles and virologic and immunologic assays (with Project 1 and Core C).