Molecular Imaging

分子成像

• 批准号: 8993317
• 负责人: MICHAEL Douglas BOSKA
• 金额: $ 41.64万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8993317
• 关键词: AIDS/HIV problem; Adherence; Affect; Aftercare; Animals; Anti-Retroviral Agents; Behavioral; Biochemical; Biochemical Pathway; Biochemistry; Biodistribution; Biological Markers; Blood; Brain; Brain region; CD34 gene; CD4 Positive T Lymphocytes; CD4/CD8 ratio procedure; Cell physiology; Cells; Cerebellum; Cerebrospinal Fluid; Chemicals; Chronic; Clinical; Collaborations; Data; Data Set; Diffusion; Disease; Disease Progression; Drug Formulations; Drug Kinetics; Drug Targeting; Evaluation; Excipients; Eye; Fluorescence; Generations; Goals; Grant; HIV; HIV-1; Hippocampus (Brain); Histologic; Histology; Histopathology; Homeostasis; Human; Image; Immune; Immunologic Deficiency Syndromes; Immunology procedure; Impaired cognition; Individual; Infection; Injury; Investigation; Lead; Ligands; Link; Long-Term Effects; Macaca mulatta; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Membrane; Metabolic; Metabolism; Midbrain structure; Mitochondria; Modeling; Monkeys; Morbidity - disease rate; Morphology; Mus; Myelin; Nervous system structure; Neuraxis; Neurons; Neurophysiology - biologic function; Neurotransmitters; Organ; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Protons; Research; Research Institute; Rodent; Rodent Model; Stem cells; Structure; Synapses; Test Result; Testing; Tissues; Toxic effect; Toxicity Tests; Toxicology; Tryptophan 2,3 Dioxygenase; Validation; Viral; Viral Load result; Virus; Virus Diseases; Work; abstracting; antiretroviral therapy; behavior test; bioimaging; cognitive testing; density; drug of abuse; improved; inhibitor/antagonist; magnetite ferrosoferric oxide; metabolomics; molecular imaging; mouse model; myelination; nano; nanoformulation; nanoparticle; nanotoxicology; nerve injury; neuroAIDS; neurochemistry; neuroimaging; neuropsychological; neurotoxicity; novel; particle; programs; quantitative imaging; reconstitution; relating to nervous system; research study; translational study

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).

项目3摘要： 长期抗逆转录病毒治疗（ART）导致持续低水平的人类免疫缺陷病毒感染 以及包括中枢神经系统在内的终末器官疾病。这通常被视为亚临床认知 仅通过神经心理学检查记录的损伤。我们认为长效纳米制剂 项目 1 和 2 中开发的 ART（nanoART）在记录时即使没有毒性，也将导致最小程度的毒性。 常规免疫、化学、血液学、生化和组织学终点（项目 2）。然而，什么 这些参数无法看出亚细胞功能（线粒体）、细胞功能的测量 （能量和膜代谢）以及组织结构和功能（髓鞘形成、神经递质和 代谢异常）。标准行为和行为也可能会错过这些参数的变化 认知测试。为此，我们希望将纳米毒理学提升到另一个水平。在这里我们试图破译 病毒和nanoART疗法的微妙作用是通过脑代谢组学实现的。为了实现这一目标，我们 复制了在人类中观察到的部分行为、组织学和神经影像异常 HIV-1 感染人源化小鼠模型中的神经艾滋病。该模型与其他可用模型不同 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 损失和代谢组学变化。我们将使用该模型作为平台来确定长期影响（测量 数月内）神经功能和区域特定脑生物化学的畸变 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。此类研究将 高度敏感。具体来说，我们将把这些数据集与质子磁共振波谱连接起来， 扩散张量磁共振成像和磁化转移磁共振成像。这些 联系将有助于指导着眼于临床实用性的转化研究。验证 实验结果将通过组织病理学测试得出（使用Core C）。磁性验证 将在小鼠和猴子实验中使用配体涂覆的磁铁矿颗粒进行共振成像 通过完整的药代动力学分析（与项目 2 和核心 B 结合进行），以及 通过产生的小磁铁矿抗逆转录病毒颗粒以及病毒学和免疫学测定（用 项目 1 和核心 C)。