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
基本信息
- 批准号:10264153
- 负责人:
- 金额:$ 71.17万
- 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:2020-09-15 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:ALCAM geneAddressAdherens JunctionAffectAgeAlbuminsAlzheimer&aposs DiseaseAreaBaltimoreBiological MarkersBloodBlood - brain barrier anatomyBlood PlateletsBlood specimenBrainBrain scanCCL19 geneCCL2 geneCCL23 geneCD14 geneCX3CL1 geneCXCL12 geneCXCL9 geneCaliberCaringCell Surface ProteinsCell physiologyCellsCerebrospinal FluidChronicClinicCognitionCognitiveCommunitiesDevelopmentFCGR3B geneFractalkineFrequenciesFunctional disorderFundingHIVHIV InfectionsHealthHospitalsImageImaging DeviceImaging TechniquesImmuneImpaired cognitionIndividualInfectionInfrastructureInterleukin-6InvestigationLinkLymphocyteMagnetic Resonance ImagingMajor Depressive DisorderMeasuresMembrane ProteinsMemory impairmentMental HealthMethodsModelingMolecularMolecular WeightNIH Office of AIDS ResearchNeuraxisNeuronsNeurotoxinsOutcomePeripheral Blood Mononuclear CellPhasePhenotypePlayProteinsPublic HealthResearchRoleSamplingSerum AlbuminShapesSpinal PunctureStrategic PlanningSupporting CellSurfaceTNF geneTechniquesTestingTherapeuticTight JunctionsTimeUp-RegulationVascular Endothelial Growth FactorsVascular EndotheliumViralWaterantiretroviral therapyblood-brain barrier disruptionblood-brain barrier permeabilizationcell motilitychemokinecognitive testingcytokinedaltonexperiencein vivoinflammatory markerinnovationmigrationmild cognitive impairmentmonocyteneuroinflammationneuropsychiatrynew therapeutic targetnovelrecruitsmall moleculetherapeutic developmenttrafficking
项目摘要
PROJECT SUMMARY/ABSTRACT
Neuropsychiatric complications persist in people with HIV (PWH) despite suppressive antiretroviral therapy. Two
common, often disabling conditions in PWH are cognitive impairment (CI) and major depressive disorder (MDD).
However, the pathophysiology of central nervous system (CNS) dysfunction in PWH that results in these
conditions remain elusive and thus a HIV high priority topic. The trafficking of activated peripheral blood
mononuclear cells (PBMCs), specifically CD14+CD16+ monocytes, into brains of virally suppressed (VS)-PWH
has emerged a putative contributor to neuroinflammation. We propose to test our hypothesis that VS-PWH will
have blood brain barrier (BBB) disruption mechanistically linked to targeted, circulating soluble
cytokines/chemokines and upregulation of PBMC surface proteins. The latter interact with tight junction and
adherens junction proteins to weaken the BBB, promoting PBMC diapedesis into brain. BBB disruption may
promote persistent neuroinflammation and altered neuronal activity contributing to neuropsychiatric sequela. To
this end, we propose cross-sectional imaging and lumbar puncture to assess BBB integrity, with baseline and
longitudinal neuropsychiatric assessments and blood sampling. 350 VS-PWH and 100 HIV-uninfected (HIV-)
individuals will be recruited from the Johns G. Bartlett Clinic within the Johns Hopkins Hospital and in the
surrounding Baltimore community. First, we aim to assess the effects of well-controlled HIV on the BBB and its
contribution to neuropsychiatric conditions (Aim 1). We will assess BBB integrity using a novel, non-contrast
magnetic resonance imaging technique that uses water-extraction-with-phase-contrast-arterial-spin-tagging
(WEPCAST), to determine BBB permeability to water, and thereby to small molecules. We have shown this to
be sensitive to BBB change in mild cognitive impairment, a precursor to Alzheimer’s disease. Moreover, we have
found WEPCAST to be well-tolerated and estimate PS values well in VS-PWH. Second, we aim to assess the
relationship between circulating soluble markers, PBMC-associated markers, and BBB permeability to small
molecules, which collectively may promote diapedesis into brain (Aim 2). We target factors implicated in a
heightened transmigration of activated PBMCs across the BBB into brain, where they may contribute to neuronal
damage and neuropsychiatric burden in VS-PWH. Finally, we aim to examine the relationship of activated
PBMCs that transmigrate an intact BBB model to BBB permeability to small molecules (Aim 3). We innovate with
the real-time assessment of ex vivo cellular function (BBB model) and in vivo BBB measures (WEPCAST). After
5 years of funding, this R01 will advance our understanding of BBB integrity and related PBMC migration into
the brains of VS-PWH, which may contribute to neuroinflammation and related neuropsychiatric burden. These
findings will inform next steps in the development of therapeutic approaches to minimize PBMC contribution to
neuroinflammation in VS-PWH.
项目总结/摘要
尽管进行了抑制性抗逆转录病毒治疗,但HIV感染者(PWH)的神经精神并发症仍持续存在。两
PWH中常见的、常常致残的病症是认知障碍(CI)和重度抑郁症(MDD)。
然而,PWH中中枢神经系统(CNS)功能障碍的病理生理学导致这些
条件仍然难以捉摸,因此是艾滋病毒的高度优先主题。活化外周血的运输
单核细胞(PBMC),特别是CD 14 + CD 16+单核细胞,进入病毒抑制(VS)-PWH的脑中。
被认为是神经炎症的诱因我们建议测试我们的假设,即VS-PWH将
血脑屏障(BBB)破坏机制与靶向,循环可溶性
细胞因子/趋化因子和PBMC表面蛋白的上调。后者与紧密连接相互作用
粘附连接蛋白削弱BBB,促进PBMC渗出进入大脑。BBB破坏可能
促进持续的神经炎症和改变的神经元活动,从而导致神经精神后遗症。到
为此,我们建议采用横断面成像和腰椎穿刺来评估血脑屏障的完整性,
纵向神经精神评估和血液采样。350名VS-PWH患者和100名未感染艾滋病毒的患者(艾滋病毒-)
将从约翰·G。巴特利特诊所在约翰霍普金斯医院和
在巴尔的摩社区周围。首先,我们的目标是评估控制良好的艾滋病毒对血脑屏障及其
对神经精神疾病的贡献(目标1)。我们将使用一种新的非造影剂,
使用相位对比动脉自旋标记水提取的磁共振成像技术
(WEPCAST),以确定BBB对水的渗透性,从而对小分子的渗透性。我们已经向
对轻度认知障碍的BBB变化敏感,这是阿尔茨海默病的前兆。而且我们
发现WEPCAST耐受性良好,在VS-PWH中可很好地估计PS值。第二,我们的目标是评估
循环可溶性标志物、PBMC相关标志物和血脑屏障对小细胞的通透性之间的关系
分子,其共同地可促进渗出进入脑(Aim 2)。我们针对的是
活化的PBMC穿过BBB进入脑的迁移增加,在脑中它们可能有助于神经元的增殖。
VS-PWH的损害和神经精神负担。最后,我们的目标是检查激活的关系
将完整BBB模型的PBMC迁移至BBB对小分子的渗透性(目的3)。我们创新与
离体细胞功能的实时评估(BBB模型)和体内BBB测量(WEPCAST)。后
经过5年的资助,该R 01将促进我们对BBB完整性和相关PBMC迁移的理解,
VS-PWH的大脑,这可能有助于神经炎症和相关的神经精神负担。这些
研究结果将为下一步开发治疗方法提供信息,以最大限度地减少PBMC对肿瘤的贡献。
VS-PWH中的神经炎症。
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 }}
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
{{
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('Jennifer Marie Coughlin', 18)}}的其他基金
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:
$ 71.17万 - 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:
$ 71.17万 - 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:
$ 71.17万 - 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:
$ 71.17万 - 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:
10118621 - 财政年份:2020
- 资助金额:
$ 71.17万 - 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:
$ 71.17万 - 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:
$ 71.17万 - 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:
$ 71.17万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
Research Grant