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:10118621
- 负责人:
- 金额:$ 24.86万
- 依托单位:
- 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 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS dementiaAffectAgingAstrocytesAutopsyAutoradiographyBindingBloodBrainBrain InjuriesBrain imagingCellsCerebrospinal FluidClinicalClinical ResearchClinical TrialsCognitionCognitiveDataData CollectionDiseaseDrug KineticsEarly DiagnosisHIVHeterogeneityHigh PrevalenceHippocampus (Brain)HumanImageImmuneImmune signalingImmunotherapyImpaired cognitionImpairmentIndividualInfectionInterventionInterviewLearningLinkLipopolysaccharidesMacacaMacaca mulattaMacaca nemestrinaMacrophage Colony-Stimulating Factor ReceptorMeasuresMedicalMemoryMethodsMicrogliaModelingMonitorMusMyeloid CellsNatureNerve DegenerationNeurodegenerative DisordersNeuroimmuneNeuropsychological TestsNeuropsychologyPathologicPatternPerformancePeripheralPhenotypePopulationPositron-Emission TomographyPropertyProteinsPublishingReceptor SignalingReportingRoleSIVSamplingShapesShort-Term MemorySignal TransductionSpecificityTechniquesTimeTissuesValidationVascular EndotheliumViralViral Load resultWorkantiretroviral therapybasecell typecognitive functioncognitive performancedensitydesignexecutive functionexperiencefrontal lobegray matterimaging agentimaging biomarkerin vivoinjury and repairinsightnerve injuryneural circuitneuroimagingneuroinflammationneuropsychiatric symptomneurotoxicnonhuman primateradiotracerreceptor bindingresponsetargeted imagingtargeted treatmenttooluptake
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.
项目总结
这个项目将在病毒中成像激活的小胶质细胞的增殖,这是大脑中的常驻免疫细胞。
抑制人类免疫缺陷病毒(VS+PWH)感染者。拟议的工作建立在我们先前工作的基础上
支持特定领域认知障碍和局部的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
靶向小胶质细胞表达的集落刺激因子1受体(CSF1R)。大脑中CSF1R的高水平
在包括VS+PWH在内的人类死后神经变性病例中已有报道。高CSF1R也是
在猴免疫缺陷病毒感染的猕猴模型的额叶皮质中发现艾滋病毒,包括病毒
抗逆转录病毒治疗后被抑制的病例。此外,其在促进神经毒物增殖方面的作用
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结合正电子发射断层扫描(PET)在人体中的应用效果良好
耐受性,并使我们能够在活体内定位和估计人脑中的小胶质细胞密度。基于已发布的
证据和我们的初步数据,我们假设较高的CSF1R,与激活的增殖一致
与匹配的未感染对照组(HIV-CON)相比,VS+PWH患者大脑中的小胶质细胞。在VS+PWH内,我们
假设较高的地区性CSF1R将与较低的认知表现相关,受影响的
高CSF1R区域模式塑造的认知域。因此,我们建议使用[11C]CPPC
在VS+PWH和HIV-CON中横断面评估两组在CSF1R中的差异
小胶质细胞活化和增殖。我们还将评估区域CSF1R和认知之间的关系
性能。综上所述,早期发现病理性小胶质细胞活动与神经心理学有关
损害仍然是一个未得到满足的医疗需求,CSF1R是一个引人注目的小胶质细胞靶点,无论是成像还是
心理治疗。我们的研究将为设计更大规模的方案提供初步数据,以进一步研究
CSF1R信号在VS+PWH认知损害中的作用此外,它还可以将CPPC PET确立为
一种有希望的研究工具,旨在监测VS+PWH随年龄和年龄增加而出现的局部小胶质细胞反应
对神经免疫治疗的反应。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jennifer Marie Coughlin其他文献
Poster #S49 AN INITIAL REPORT ON METABOLIC DEFECTS IN RECENT ONSET SCHIZOPHRENIA WITH A 7 TESLA MRI SCANNER: LINK TO CHANGES IN BRAIN TEMPERATURE AND COGNITION
- DOI:
10.1016/s0920-9964(14)70328-7 - 发表时间:
2014-04-01 - 期刊:
- 影响因子:
- 作者:
Sotirios Posporelis;Mark Varvaris;Anouk Marsman;Jennifer Marie Coughlin;Susanne Bonekamp;Pearl Kim;Richard Edden;David J. Schretlen;Nicola Cascella;Peter B. Barker;Akira Sawa - 通讯作者:
Akira Sawa
Jennifer Marie Coughlin的其他文献
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{{ truncateString('Jennifer Marie Coughlin', 18)}}的其他基金
Immune dynamics shaping blood brain barrier integrity in virally suppressed people with HIV
免疫动力学塑造病毒抑制的艾滋病毒感染者血脑屏障的完整性
- 批准号:
10264153 - 财政年份:2020
- 资助金额:
$ 24.86万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 24.86万 - 项目类别:
Immune dynamics shaping blood brain barrier integrity in virally suppressed people with HIV
免疫动力学塑造病毒抑制的艾滋病毒感染者血脑屏障的完整性
- 批准号:
10118741 - 财政年份:2020
- 资助金额:
$ 24.86万 - 项目类别:
Immune dynamics shaping blood brain barrier integrity in virally suppressed people with HIV
免疫动力学塑造病毒抑制的艾滋病毒感染者血脑屏障的完整性
- 批准号:
10651815 - 财政年份:2020
- 资助金额:
$ 24.86万 - 项目类别:
Immune dynamics shaping blood brain barrier integrity in virally suppressed people with HIV
免疫动力学塑造病毒抑制的艾滋病毒感染者血脑屏障的完整性
- 批准号:
10425438 - 财政年份:2020
- 资助金额:
$ 24.86万 - 项目类别:
Molecular imaging of brain injury and repair in NFL players
NFL 球员脑损伤和修复的分子成像
- 批准号:
10062525 - 财政年份:2018
- 资助金额:
$ 24.86万 - 项目类别:
Molecular imaging of brain injury and repair in NFL players
NFL 球员脑损伤和修复的分子成像
- 批准号:
10307103 - 财政年份:2018
- 资助金额:
$ 24.86万 - 项目类别:
JHU Center for the Advancement of HIV Neurotherapeutics (JHU CAHN)- Clinical Core
JHU 艾滋病毒神经治疗促进中心 (JHU CAHN) - 临床核心
- 批准号:
10584559 - 财政年份:2006
- 资助金额:
$ 24.86万 - 项目类别:
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