Toward Understanding the Role of Adult Human Microglia in the Ongoing Persistence of HIV and its Associated Neuropsychiatric Comorbidities
了解成人小胶质细胞在艾滋病毒持续存在及其相关神经精神合并症中的作用
基本信息
- 批准号:10330823
- 负责人:
- 金额:$ 20.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAnatomyAnimal ModelAnxietyApoptosisAutopsyBiochemicalBloodBone MarrowBrainCell LineCellsComplementCytokine ActivationCytokine GeneDNADataDevelopmentEngraftmentExhibitsExperimental ModelsGene ExpressionGenesGeneticGoalsGoldHIVHIV InfectionsHomeostasisHumanImmuneImmunityIn VitroInflammationInflammatoryInjectionsInjuryInterruptionInvadedInvestigationKineticsLeadMaintenanceMental DepressionMental HealthMicrogliaModelingMolecularMusMyelogenousMyeloid CellsNeuronsPathologicPlayProcessProteinsProxyRegulationReportingRiskRoleSeedsSignal TransductionSiteStimulusSynapsesTNF geneTestingTransgenic MiceTreesUmbilical Cord BloodWomanWorkantiretroviral therapybiological systemsbrain healthbrain tissuecomorbiditycytokinegenetic signaturehuman tissuehumanized mouseimprovedin vivoin vivo Modelinduced pluripotent stem cellintrahepaticlatent infectionmacrophagemanmonocyteneonatal miceneural circuitneuroAIDSneuroimagingneuroinflammationneuropsychiatrynovel strategiesosteopontinpathogenpostnatalprogenitorresiliencesuccesstranscriptome
项目摘要
PROJECT SUMMARY
Despite effective suppression of HIV replication, current treatments do not provide sterilizing immunity or
eradicate anatomical reservoirs. Studies conducted in HIV animal models and infected humans demonstrate the
strong likelihood that the brain's long-lived microglia (MG) play an essential role in reservoir
formation/maintenance. Elevated inflammatory cytokines and infected immune cells with HIV DNA have been
found in the CSF of HIV-infected people on antiretroviral therapy (ART), revealing the increased risks to brain
health and homeostasis. However, a deep understanding of the molecular mechanisms at work in human MG-
HIV host-pathogen interaction that foments reservoir formation and maintenance has been very difficult and until
recently, near intractable to study. Three key limitations must be overcome to achieve progress. First, is the
limited ability to procure large quantities of adult human MG for experimentation. Second, cultured human MG
must be relatively long-lived in vitro in order to conduct antiretroviral treatment interruption and reactivation
studies. Third, to advance translational goals, an in vivo model to test the full complement of human adult MG
function is needed and to validate mechanistic findings obtained in vitro. Exciting progress by several groups
has been made on these fronts. Mathews et al., reported on the successful engraftment and HIV infection of
human MG derived from fetal cord blood progenitors into the brains of NOG-IL-34 transgenic mice. A recent
study by Rai et al., comparing transcriptomes found ~78% conservation in a previously validated MG conserved
gene signature between human blood monocyte-derived MG, iPSC-derived human MG and human tissue adult
MG that was not shared with two MG cell lines suggesting a possible path forward. Collectively, these data show
that a subset of blood myeloid progenitors found in both mouse and man, retain genetic plasticity and resiliency
built into a biological system that is overall crucial for proper brain functioning. The goals of this exploratory
proposal are to build upon advances in culturing adult human MG from blood myeloid progenitors to allow study
of somatic genetics and improve the translational potential of neuroHIV in vitro and in vivo experimental models.
The long-term goal is to decipher the contribution of microglia and inflammatory stimuli to the maintenance of
the HIV CNS reservoir. The Specific Aims are to: 1) characterize the extent, breadth and fidelity of human blood
myeloid progenitors from unrelated adult healthy donors to populate and serve as HIV reservoirs in the brain and
2) identify and study the hierarchy of proinflammatory gene network expression kinetics in HIV-infected adult
human microglia and impact on HIV persistence during ART. The findings from the proposed studies will lay the
groundwork for deeper investigation of MG function, proinflammatory signaling, and the potential development
of novel strategies for identifying and understanding the mechanisms and impact on mental health of HIV-
infected myeloid reservoirs in the brain.
项目摘要
尽管有效地抑制了HIV复制,但目前的治疗不能提供绝育免疫,
根除解剖学上的储库在HIV动物模型和感染者中进行的研究表明,
大脑中长寿命的小胶质细胞(MG)在储存中发挥重要作用的可能性很大。
形成/维持。升高的炎性细胞因子和感染HIV DNA的免疫细胞已经被证实是HIV感染的主要原因。
在接受抗逆转录病毒治疗(ART)的HIV感染者的CSF中发现,
健康和体内平衡。然而,深入了解在人类MG中起作用的分子机制-
HIV宿主-病原体相互作用促进储库的形成和维持是非常困难的,
最近,几乎难以研究。要取得进展,必须克服三个关键限制。首先,
获得大量成人MG用于实验的能力有限。第二,培养的人MG
必须在体外相对较长的寿命,以便进行抗逆转录病毒治疗中断和再激活
问题研究第三,为了推进翻译目标,测试人成人MG的完全补体的体内模型
功能,并验证在体外获得的机制研究结果。几个小组取得了令人振奋的进展
在这些方面取得了进展。马修斯等人,报告了成功植入和艾滋病毒感染的
将来自胎儿脐带血祖细胞的人MG植入NOG-IL-34转基因小鼠的脑中。最近的一
Rai等人研究,比较转录组发现,在先前验证的MG保守序列中,约78%的保守性
人血液单核细胞衍生的MG、iPSC衍生的人MG和成人人组织之间的基因特征
MG与两个MG细胞系不共享,表明可能的前进路径。总的来说,这些数据显示
在小鼠和人类中发现血液髓系祖细胞亚群保留了遗传可塑性和弹性
这是一个对大脑正常运作至关重要的生物系统。本次探索性的
建议是建立在从血液髓系祖细胞培养成人MG的进展上,以允许研究
的体细胞遗传学和提高体外和体内实验模型中的neuroHIV的翻译潜力。
长期的目标是破译小胶质细胞和炎症刺激对维持神经细胞增殖的贡献。
HIV中枢神经系统储存库具体目标是:1)表征人类血液的程度、广度和保真度
- 来自无关的成年健康供体的髓系祖细胞,以在脑中填充并充当HIV储库,
2)鉴定和研究HIV感染成人中促炎基因网络表达动力学的层次
人类小胶质细胞和对艾滋病毒的影响持久性在艺术。从拟议的研究结果将奠定
为深入研究MG功能、促炎信号传导和潜在的发展奠定了基础。
新的战略,以确定和理解机制和对心理健康的影响,艾滋病毒-
感染了大脑中的骨髓储库
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
AMANDA MARIA BROWN其他文献
AMANDA MARIA BROWN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('AMANDA MARIA BROWN', 18)}}的其他基金
The Johns Hopkins NeuroHIV Comorbidities Scholar Program
约翰·霍普金斯大学 NeuroHIV 合并症学者计划
- 批准号:
10586039 - 财政年份:2019
- 资助金额:
$ 20.47万 - 项目类别:
The Johns Hopkins NeuroHIV Comorbidities Scholar Program
约翰·霍普金斯大学 NeuroHIV 合并症学者计划
- 批准号:
10372044 - 财政年份:2019
- 资助金额:
$ 20.47万 - 项目类别:
The Johns Hopkins Neuroscience Scholars Program (JHNSP)
约翰·霍普金斯大学神经科学学者计划 (JHNSP)
- 批准号:
10448383 - 财政年份:2018
- 资助金额:
$ 20.47万 - 项目类别:
The Johns Hopkins Neuroscience Scholars Program (JHNSP)
约翰·霍普金斯大学神经科学学者计划 (JHNSP)
- 批准号:
9569960 - 财政年份:2018
- 资助金额:
$ 20.47万 - 项目类别:
The Johns Hopkins Neuroscience Scholars Program (JHNSP)
约翰·霍普金斯大学神经科学学者计划 (JHNSP)
- 批准号:
10200915 - 财政年份:2018
- 资助金额:
$ 20.47万 - 项目类别:
A New Model to Dissect the Molecular Mechanisms for ApoE-Associated Lipoprotein Complex Aggregation in the Brain
剖析大脑中 ApoE 相关脂蛋白复合物聚集分子机制的新模型
- 批准号:
10115987 - 财政年份:2016
- 资助金额:
$ 20.47万 - 项目类别:
HIV-OPN/SPP1Triad II: Molecular Pathways Regulating Neuronal-Glial Inflammation in the Brain
HIV-OPN/SPP1Triad II:调节大脑神经元胶质炎症的分子途径
- 批准号:
10707336 - 财政年份:2016
- 资助金额:
$ 20.47万 - 项目类别:
The HIV-Osteopontin-HAND Triad: Inflammation and Neuronal Injury in the Brain
HIV-骨桥蛋白-HAND 三联征:大脑炎症和神经元损伤
- 批准号:
9271454 - 财政年份:2016
- 资助金额:
$ 20.47万 - 项目类别:
HIV-OPN/SPP1Triad II: Molecular Pathways Regulating Neuronal-Glial Inflammation in the Brain
HIV-OPN/SPP1Triad II:调节大脑神经元胶质炎症的分子途径
- 批准号:
10560338 - 财政年份:2016
- 资助金额:
$ 20.47万 - 项目类别:
相似海外基金
Linking Epidermis and Mesophyll Signalling. Anatomy and Impact in Photosynthesis.
连接表皮和叶肉信号传导。
- 批准号:
EP/Z000882/1 - 财政年份:2024
- 资助金额:
$ 20.47万 - 项目类别:
Fellowship
Digging Deeper with AI: Canada-UK-US Partnership for Next-generation Plant Root Anatomy Segmentation
利用人工智能进行更深入的挖掘:加拿大、英国、美国合作开发下一代植物根部解剖分割
- 批准号:
BB/Y513908/1 - 财政年份:2024
- 资助金额:
$ 20.47万 - 项目类别:
Research Grant
Simultaneous development of direct-view and video laryngoscopes based on the anatomy and physiology of the newborn
根据新生儿解剖生理同步开发直视喉镜和视频喉镜
- 批准号:
23K11917 - 财政年份:2023
- 资助金额:
$ 20.47万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Genetics of Extreme Phenotypes of OSA and Associated Upper Airway Anatomy
OSA 极端表型的遗传学及相关上呼吸道解剖学
- 批准号:
10555809 - 财政年份:2023
- 资助金额:
$ 20.47万 - 项目类别:
computational models and analysis of the retinal anatomy and potentially physiology
视网膜解剖学和潜在生理学的计算模型和分析
- 批准号:
2825967 - 财政年份:2023
- 资助金额:
$ 20.47万 - 项目类别:
Studentship
Computational comparative anatomy: Translating between species in neuroscience
计算比较解剖学:神经科学中物种之间的翻译
- 批准号:
BB/X013227/1 - 财政年份:2023
- 资助金额:
$ 20.47万 - 项目类别:
Research Grant
Doctoral Dissertation Research: Social and ecological influences on brain anatomy
博士论文研究:社会和生态对大脑解剖学的影响
- 批准号:
2235348 - 财政年份:2023
- 资助金额:
$ 20.47万 - 项目类别:
Standard Grant
Development of a novel visualization, labeling, communication and tracking engine for human anatomy.
开发一种新颖的人体解剖学可视化、标签、通信和跟踪引擎。
- 批准号:
10761060 - 财政年份:2023
- 资助金额:
$ 20.47万 - 项目类别:
Understanding the functional anatomy of nociceptive spinal output neurons
了解伤害性脊髓输出神经元的功能解剖结构
- 批准号:
10751126 - 财政年份:2023
- 资助金额:
$ 20.47万 - 项目类别:
The Anatomy of Online Reviews: Evidence from the Steam Store
在线评论剖析:来自 Steam 商店的证据
- 批准号:
2872725 - 财政年份:2023
- 资助金额:
$ 20.47万 - 项目类别:
Studentship