Imaging immune signaling in virally-suppressed HIV

病毒抑制的艾滋病毒中的免疫信号成像

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该项目将成像激活的小胶质细胞（大脑中的常驻免疫细胞）在病毒中的增殖情况。抑制人类免疫缺陷病毒（VS+PWH）患者。拟议的工作建立在我们之前的基础上支持特定领域认知障碍与局部小胶质细胞激活之间联系的数据 VS+PWH。为了对活体大脑中的小胶质细胞进行特异性成像，我们开发了一种放射性示踪剂，[11C]CPPC 其目标是小胶质细胞表达的集落刺激因子 1 受体 (CSF1R)。大脑中的高 CSF1R 在人类死后神经变性病例（包括 VS+PWH）中已有报道。 CSF1R 也较高在感染猿猴免疫缺陷病毒的艾滋病毒猕猴模型的额叶皮层中发现，包括病毒性抗逆转录病毒治疗后病例受到抑制。此外，它在增强神经毒性物质增殖方面的作用小胶质细胞反应使 CSF1R 成为治疗耗竭小胶质细胞的有吸引力的靶点神经退行性疾病。 [11C]CPPC 与正电子发射断层扫描 (PET) 在人类中的应用效果良好耐受性并允许我们在体内定位和估计人脑中的小胶质细胞密度。根据已发表的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，VS+PWH 大脑中的小胶质细胞。在 VS+PWH 内，我们假设较高的区域 CSF1R 与较低的认知表现相关，受影响的由高 CSF1R 的区域模式塑造的认知域。因此我们建议使用[11C]CPPC VS+PWH 和 HIV-CON 中的 PET 横断面评估 CSF1R 的组间差异小胶质细胞的激活和增殖。我们还将评估区域 CSF1R 和认知之间的关系表现。总之，早期检测与神经心理学相关的病理性小胶质细胞活动损伤仍然是一个未满足的医疗需求，CSF1R 是成像和成像方面引人注目的小胶质细胞靶标。治疗。我们的研究将为设计更大规模的提案提供初步数据，以进一步研究 CSF1R 信号传导在 VS+PWH 认知障碍中的作用。此外，它可以将 CPPC PET 建立为一种很有前景的研究工具，旨在监测 VS+PWH 随衰老和衰老过程中的局部小胶质细胞反应对神经免疫治疗的反应。