MR Spectroscopy of SIV Brain Injury

SIV 脑损伤的磁共振波谱分析

• 批准号: 7210689
• 负责人: RAMON GILBERTO GONZALEZ
• 金额: $ 67.47万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210689
• 关键词: AIDS neuropathy; Animals; Area; Blood; Bone Marrow; Brain; Brain Injuries; Brain region; Cell Count; Cells; Complement; Contrast Media; DNA; Data; Encephalitis; Event; Experimental Designs; Highly Active Antiretroviral Therapy; Histology; Human body; Image; Immune system; Immunohistochemistry; Immunologics; Laboratories; Light; Localized; Macaca; Magnetic Resonance Spectroscopy; Microglia; Modeling; Neuronal Injury; Neurons; Pathogenesis; Phagocytes; Plasma; RNA; Rate; Recovery; Role; SIV; Series; Severities; Testing; Time; Variant; Viral Load result; Virus; Virus Diseases; Week; astrogliosis; central nervous system injury; cytokine; in vivo; macrophage; monocyte; nanoparticle; novel; research study; theories; trafficking; viral DNA

DESCRIPTION (PROVIDED BY APPLICANT): A leading theory for the pathogenesis of neuroAIDS is that a specific bone marrow derived blood monocyte is virally infected and activated, then traffics into the CNS where it becomes a perivascular macrophage and sets off a cascade of events that result in neuronal injury. In light of experiments performed in our laboratory, we extend this theory and propose that accumulation of neuronal injury in neuroAIDS requires continuous trafficking of infected/activated CD 14/16 monocytic phagocytes (MPs) into the CNS to surmount turnover of these cells and endogenous neuronal recovery mechanisms. We seek to understand the dynamics of MP trafficking, MP turnover in the CNS and neuronal recovery through an experimental design that tests a series of specific hypotheses derived from the central theory. We will use 1H magnetic resonance spectroscopy (MRS) at high field (7T) in an accelerated simian immunodeficiency virus (SIV) macaque model of neuroAIDS that reliably produces SIV encephalitis and neuronal injury within weeks. Moreover, we will use HAART to experimentally manipulate CNS trafficking of activated blood monocytes, and modulate neuronal injury. Simultaneously with imaging, we will quantify levels of activated (CD14+/CD16+) monocytes, their SPV DNA and RNA levels, and virus in blood. We will complete this study with detailed immunological, virological, neuropathologic and MRS studies of the brains of the same animals. Our specific aims are: Specific Aim 1. Determine the amount of virally infected/activated CD14/16 MPs in blood, and at the same time determine regional neuronal injury in SIV infected/CD8 depleted macaques and similar animals undergoing HAART. Specific Aim 2. Determine the severity of CNS injury by in vivo & ex vivo MRS and immunohistochemistry in different brain regions, and determine the levels of perivascular MPs in those regions.

描述（申请人提供）：神经艾滋病发病机制的主要理论是，特定骨髓来源的血液单核细胞被病毒感染并激活，然后进入CNS，在CNS中成为血管周围巨噬细胞，并引发导致神经元损伤的级联反应。根据我们实验室进行的实验，我们扩展了这一理论，并提出neuroAIDS中神经元损伤的积累需要感染/活化的CD 14/16单核吞噬细胞（MP）持续运输到CNS中，以克服这些细胞的周转和内源性神经元恢复机制。 我们试图了解MP贩运的动态，MP营业额在中枢神经系统和神经元的恢复，通过实验设计，测试一系列特定的假设来自中央理论。我们将使用1H磁共振波谱（MRS）在高场（7 T）在加速猴免疫缺陷病毒（SIV）猕猴模型的neuroAIDS，可靠地产生SIV脑炎和神经元损伤在几周内。此外，我们将使用HAART来实验性地操纵活化的血液单核细胞的CNS运输，并调节神经元损伤。在成像的同时，我们将定量活化（CD 14 +/CD 16+）单核细胞的水平，其SPV DNA和RNA水平，以及血液中的病毒。我们将通过对相同动物的大脑进行详细的免疫学、病毒学、神经病理学和MRS研究来完成本研究。我们的具体目标是： 具体目标1.测定血液中病毒感染/活化的CD 14/16 MP的量，同时测定SIV感染/CD 8耗尽的猕猴和经历HAART的类似动物中的局部神经元损伤。 具体目标2。通过在体和离体MRS和免疫组化方法检测不同脑区CNS损伤的严重程度，并检测这些脑区血管周围MP的水平。