Imaging immune signaling in virally-suppressed HIV

病毒抑制的艾滋病毒中的免疫信号成像

• 批准号: 10260649
• 负责人: Jennifer Marie Coughlin
• 金额: $ 20.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260649
• 关键词: AIDS dementia; Affect; Aging; Astrocytes; Autopsy; Autoradiography; Binding; Blood; Brain; Brain Injuries; Brain imaging; Cells; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Data; Data Collection; Disease; Drug Kinetics; Early Diagnosis; HIV; Heterogeneity; High Prevalence; Hippocampus (Brain); Human; Image; Immune; Immune signaling; Immunotherapy; Impaired cognition; Impairment; Individual; Infection; Intervention; Interview; Learning; Link; Lipopolysaccharides; Macaca; Macaca mulatta; Macaca nemestrina; Macrophage Colony-Stimulating Factor Receptor; Measures; Medical; Memory; Methods; Microglia; Modeling; Monitor; Mus; Myeloid Cells; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Neuropsychological Tests; Neuropsychology; Pathologic; Pattern; Performance; Peripheral; Phenotype; Population; Positron-Emission Tomography; Property; Proteins; Publishing; Receptor Signaling; Reporting; Role; SIV; Sampling; Shapes; Short-Term Memory; Signal Transduction; Specificity; Techniques; Time; Tissues; Validation; Vascular Endothelium; Viral; Viral Load result; Work; antiretroviral therapy; base; cell type; cognitive function; cognitive performance; density; design; executive function; experience; frontal lobe; gray matter; imaging agent; imaging biomarker; in vivo; injury and repair; insight; nerve injury; neural circuit; neuroimaging; neuroinflammation; neuropsychiatric symptom; neurotoxic; nonhuman primate; radiotracer; receptor binding; response; targeted imaging; targeted treatment; tool; uptake

PROJECT SUMMARY This project will image the proliferation of activated microglia, resident immune cells in the brain, in virally suppressed people with human immunodeficiency virus (VS+PWH). The proposed work builds on our prior data that support a link between domain-specific cognitive impairment and localized, microglial activation in VS+PWH. In order to specifically image microglia in the living brain, we developed a radiotracer, [11C]CPPC that targets the colony stimulating factor 1 receptor (CSF1R) expressed by microglia. High CSF1R in brain has been reported in human postmortem cases of neurodegeneration including VS+PWH. High CSF1R was also found in frontal cortex of a simian immunodeficiency virus-infected macaque model of HIV, including virally suppressed cases after antiretroviral therapy. Furthermore, its role in potentiating proliferation of neurotoxic microglial response makes CSF1R an attractive target for therapeutic depletion of microglia in neurodegenerative disease. Use of [11C]CPPC with positron emission tomography (PET) in humans is well tolerated and allows us to localize and estimate microglial density in human brain in vivo. Based on published evidence and our preliminary data, we hypothesize higher CSF1R, consistent with proliferation of activated microglia, in the brains of VS+PWH compared to matched, uninfected controls (HIV-CON). Within VS+PWH, we hypothesize that higher regional CSF1R will be associated with lower cognitive performance, with the affected cognitive domains shaped by the regional pattern of high CSF1R. We therefore propose to use [11C]CPPC PET cross-sectionally in VS+PWH and HIV-CON to assess group differences in the CSF1R that marks microglial activation and proliferation. We will also assess relationships between regional CSF1R and cognitive performance. In summary, early detection of pathological microglial activity that is linked to neuropsychological impairment remains an unmet medical need, and CSF1R is a compelling microglial target for both imaging and therapy. Our study will provide preliminary data toward design of a larger scale proposal to study further the role of CSF1R signaling in cognitive impairment within VS+PWH. Furthermore, it may establish CPPC PET as a promising tool for studies aimed at monitoring localized microglial response in VS+PWH over aging and in response to neuroimmune therapy.

项目摘要 该项目将在病毒中成像活化的小胶质细胞，驻留的免疫细胞的增殖 抑制人类免疫缺陷病毒（VS+PWH）的人。拟议的工作是基于我们先前的 支持域特异性认知障碍与局部小胶质激活之间的联系的数据 VS+PWH。为了专门为活大脑中的小胶质细胞图像，我们开发了一个放射性示踪剂[11C] CPPC 该靶向小胶质细胞表达的刺激因子1受体（CSF1R）。大脑中的CSF1R高 在人类后神经变性病例中报道了包括VS+PWH。高CSF1R也是 发现在邻近免疫缺陷病毒感染的HIV的猕猴模型的额叶皮质中，包括病毒 抗逆转录病毒治疗后抑制病例。此外，它在增强神经毒性增殖中的作用 小胶质细胞反应使CSF1R成为小胶质细胞治疗耗竭的有吸引力的靶标 神经退行性疾病。在人类中使用[11C] CPPC与正电子发射断层扫描（PET）很好 耐受性，使我们能够在体内定位和估计人脑中的小胶质细胞密度。根据已出版 证据和我们的初步数据，我们假设CSF1R较高，与激活的增殖一致 与匹配的未感染对照（HIV-CON）相比，小胶质细胞在VS+PWH的大脑中。在VS+PWH中，我们 假设较高的区域CSF1R将与较低的认知表现有关 高CSF1R的区域模式形成的认知领域。因此，我们建议使用[11C] CPPC VS+PWH和HIV-CON中的PET横截面评估标记的CSF1R的组差异 小胶质激活和增殖。我们还将评估区域CSF1R与认知之间的关系 表现。总之，与神经心理学有关的病理小胶质细胞活性的早期检测 损伤仍然是未满足的医疗需求，CSF1R是成像和成像和 治疗。我们的研究将提供初步数据，以设计大规模建议，以进一步研究 CSF1R信号在VS+PWH内的认知障碍中的作用。此外，它可能会将CPPC宠物建立为 一种有前途的研究工具，旨在监测衰老和衰老中VS+PWH中的局部小胶质细胞反应 对神经免疫治疗的反应。