PREVENTING ALZHEIMER’S DISEASE-LIKE BRAIN PATHOLOGY IN HIV INFECTION BY TARGETING CCR5
通过靶向 CCR5 预防 HIV 感染中的阿尔茨海默病样脑部病变
基本信息
- 批准号:10700624
- 负责人:
- 金额:$ 69.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-15 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:Abeta synthesisAddressAlzheimer like pathologyAlzheimer&aposs DiseaseAmyloid beta-ProteinAmyloid beta-Protein PrecursorAnimal ModelAnti-Retroviral AgentsAreaAutopsyBlood - brain barrier anatomyBlood VesselsBrainBrain PathologyCCL4 geneCCR5 geneCatabolismCellsCentral Nervous SystemCerebrovascular TraumaCerebrovascular systemDevelopmentDown-RegulationEndocytosisEndotheliumEnzymesFunctional disorderGenesGenetic TranscriptionHIVHIV InfectionsHIV-1HIV-associated neurocognitive disorderHIV/AIDSHumanImpaired cognitionImpairmentIn VitroIndividualInfectionInjuryInterleukin-6LDL-Receptor Related Protein 1LipoproteinsMacrophageMediatingMetabolismMolecular ProfilingNeprilysinNerve DegenerationNeurocognitive DeficitNeurofibrillary TanglesNeuronsPathologyPathway interactionsPeptide HydrolasesPersonsPharmaceutical PreparationsPhosphotransferasesPlayProductionRANTESRegimenResearch PriorityRoleSenile PlaquesStructureSystemTenofovirTestingTherapeuticUnited States National Institutes of HealthUp-RegulationVascular EndotheliumViral Load resultZidovudineamyloid formationamyloid precursor protein processingamyloidogenesisantagonistantiretroviral therapybeta-site APP cleaving enzyme 1brain tissuecentral nervous system injurycerebral microvasculaturedesignepigenomeepigenomicshumanized mousehyperphosphorylated tauin vivoneurofibrillary tangle formationneuroinflammationneuron lossneurotoxicnovelnovel therapeutic interventionpreventprotective effectreceptorreceptor expressionreceptor for advanced glycation endproductstau Proteinstau-1transcriptometranscriptomicsuptake
项目摘要
PROJECT ABSTRACT
Brain tissues from people living with HIV (PLWH) showed evidence of Alzheimer’s Disease (AD)-like pathologies,
including increased neurotoxic amyloid-b (Ab40/42), amyloid plaques and Tau hyperphosphorylation (pTau)
associated with neurodegeneration and HIV-associated neurocognitive disorders (HAND). The mechanisms
through which HIV increase Ab, pTau, and induce AD-like central nervous system (CNS) impairment are not
known. Although most PLWH with CNS Ab plaques and pTau had been on long-term antiretroviral therapy (ART),
the role of ART in pTau and Ab production, and AD-like pathologies has not been investigated. Findings from
our R21 studies, using in vitro, in vivo and ex vivo approaches, demonstrated that HIV-1 significantly increased
CNS Ab42 and pTau in humanized mice, and this was associated with significantly 1) increased expression and
activation/activity of b-secretase-1 (BACE1), soluble (s)APPb (amyloidogenic pathway effectors), and GSK3b
(kinase that phosphorylates Tau); 2) reduced expression/activity of neprilysin (NEP, Ab-degrading enzyme); 3)
increased blood-brain barrier (BBB) expression of the receptor for advanced glycation end products (RAGE,
mediates Ab CNS influx), and reduced BBB expression of low-density lipoprotein receptor–related protein-1
(LRP1, mediates CNS Ab efflux); and 4) increased neuroinflammation, neuronal damage and BBB injury. We
demonstrated that LRP1 and CCR5 mediated Ab transport through the BBB, that AZT potentiated HIV-induced
upregulation/activation of BACE1, sAPPb and GSK3b, and that AZT blocked NEP expression/activity.
Significantly, the CCR5 antagonist maraviroc (MVC) abrogated these HIV- and AZT- induced effects.
Thus, we hypothesize that CCR5, via LRP1, plays a major role in Ab formation, transport, and catabolism,
amyloidogenesis and pTau in PLWH, and that targeting CCR5 prevents HIV-induced Ab and pTau,
increases Ab CNS efflux, and abrogates CNS injury and HAND. Using a validated HIV/AIDS animal model,
primary human cells and human brain tissues, we will test this hypothesis and further investigate the effects of
commonly prescribed antiretroviral (ARV) drugs (AZT, TDF) on HIV-induced activation of BACE1 and APP
amyloidogenic pathway, Tau metabolism, and CNS injury (Aim-1); Ab transport, degradation, clearance, and
neuroinflammation (Aim-2); and associated BBB transcriptomic and epigenomic signatures (Aim-3). These
mechanistic studies will help determine whether HIV induces amyloidogenesis by i) activating BACE1 pathways
to increase Ab production or ii) by interfering with LRP1-mediated Ab transport, degradation, clearance; iii) the
role of ARVs; iv) whether CCR5 modulates these effects; and v) characterize the brain vascular transcriptome
and epigenome associated with HIV/ARVs-induced dysregulation and MVC protective effects. Our proposed
studies are of high-impact, translational significance, and address the NIH high priority research areas that focus
on “Examining the pathophysiologic mechanisms of HIV-induced CNS dysfunction in the setting of ART…and
development of novel therapeutic approaches to mitigate CNS complications of HIV infection.”
项目摘要
来自艾滋病毒感染者(PLWH)的脑组织显示出阿尔茨海默病(AD)样病理的证据,
包括增加的神经毒性淀粉样蛋白-b(Ab 40/42)、淀粉样蛋白斑块和Tau过度磷酸化(pTau)
与神经变性和HIV相关的神经认知障碍(HAND)相关。的机制
HIV增加Ab、pTau和诱导AD样中枢神经系统(CNS)损害的途径,
知道的尽管大多数患有CNS Ab斑块和pTau的PLWH一直在接受长期抗逆转录病毒治疗(ART),
ART在pTau和Ab产生以及AD样病理中的作用尚未研究。的结果
我们使用体外、体内和离体方法进行的R21研究表明,
人源化小鼠中的CNS Ab 42和pTau,这与1)表达显着增加和
b-分泌酶-1(BACE 1)、可溶性APPb(淀粉样蛋白生成途径效应物)和GSK 3b的活化/活性
(磷酸化Tau的激酶); 2)降低脑啡肽酶(NEP,Ab降解酶)的表达/活性; 3)
晚期糖基化终末产物受体的血脑屏障(BBB)表达增加(ESTA,
介导Ab CNS流入),并降低BBB低密度脂蛋白受体相关蛋白-1的表达
(LRP1介导CNS Ab流出);和4)增加的神经炎症、神经元损伤和BBB损伤。我们
表明LRP 1和CCR 5介导抗体转运通过血脑屏障,AZT增强HIV诱导的
AZT能抑制NEP的表达/活性,而BACE 1、sAPPb和GSK 3b的表达/活性则被AZT阻断。
值得注意的是,CCR 5拮抗剂马拉韦罗(MVC)消除了这些HIV和AZT诱导的作用。
因此,我们假设CCR 5通过LRP 1在抗体形成、转运和催化中起主要作用,
PLWH中的淀粉样蛋白生成和pTau,并且靶向CCR 5可以防止HIV诱导的Ab和pTau,
增加Ab CNS流出,消除CNS损伤和HAND。使用经验证的HIV/AIDS动物模型,
原代人类细胞和人脑组织,我们将测试这一假设,并进一步研究的影响,
常用抗逆转录病毒(ARV)药物(AZT、TDF)对HIV诱导的BACE 1和APP激活的影响
淀粉样蛋白生成途径、Tau代谢和CNS损伤(Aim-1); Ab转运、降解、清除和
神经炎症(Aim-2);以及相关的BBB转录组和表观基因组标记(Aim-3)。这些
机制研究将有助于确定HIV是否通过i)激活BACE 1通路诱导淀粉样蛋白生成
增加Ab产生或ii)通过干扰LRP 1介导的Ab转运、降解、清除; iii)
ARV的作用; iv)CCR 5是否调节这些作用;以及v)表征脑血管转录组
表观基因组与HIV/ARV诱导的失调和MVC保护作用有关。我们提出的
这些研究具有高影响力和转化意义,并涉及NIH高度优先的研究领域,
关于“在ART背景下检查HIV诱导的CNS功能障碍的病理生理机制.
开发新的治疗方法,以减轻HIV感染的CNS并发症。
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)
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GEORGETTE D. KANMOGNE其他文献
GEORGETTE D. KANMOGNE的其他文献
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{{ truncateString('GEORGETTE D. KANMOGNE', 18)}}的其他基金
Preventing Alzheimer's Disease Like Brain Pathology in HIV Infection by Targeting CCR5
通过靶向 CCR5 预防阿尔茨海默氏病,例如 HIV 感染中的脑病理学
- 批准号:
10161318 - 财政年份:2020
- 资助金额:
$ 69.07万 - 项目类别:
Preventing Alzheimer's Disease Like Brain Pathology in HIV Infection by Targeting CCR5
通过靶向 CCR5 预防阿尔茨海默病,例如 HIV 感染中的脑病理学
- 批准号:
10301369 - 财政年份:2020
- 资助金额:
$ 69.07万 - 项目类别:
HIV Genetic Diversity and Viral Neuropathogenesis
HIV遗传多样性和病毒神经发病机制
- 批准号:
8599489 - 财政年份:2012
- 资助金额:
$ 69.07万 - 项目类别:
HIV Genetic Diversity and Viral Neuropathogenesis
HIV遗传多样性和病毒神经发病机制
- 批准号:
8426089 - 财政年份:2012
- 资助金额:
$ 69.07万 - 项目类别:
HIV Genetic Diversity and Viral Neuropathogenesis
HIV遗传多样性和病毒神经发病机制
- 批准号:
8779742 - 财政年份:2012
- 资助金额:
$ 69.07万 - 项目类别:
HIV Genetic Diversity and Viral Neuropathogenesis
HIV遗传多样性和病毒神经发病机制
- 批准号:
8257050 - 财政年份:2012
- 资助金额:
$ 69.07万 - 项目类别:
Blood brain barrier immune compromise in NeuroAIDS
NeuroAIDS 中的血脑屏障免疫受损
- 批准号:
8055998 - 财政年份:2008
- 资助金额:
$ 69.07万 - 项目类别:
Blood brain barrier immune compromise in NeuroAIDS
NeuroAIDS 中的血脑屏障免疫受损
- 批准号:
7619271 - 财政年份:2008
- 资助金额:
$ 69.07万 - 项目类别:
Blood brain barrier immune compromise in NeuroAIDS
NeuroAIDS 中的血脑屏障免疫受损
- 批准号:
7806523 - 财政年份:2008
- 资助金额:
$ 69.07万 - 项目类别:
Blood brain barrier immune compromise in NeuroAIDS
NeuroAIDS 中的血脑屏障免疫受损
- 批准号:
8247819 - 财政年份:2008
- 资助金额:
$ 69.07万 - 项目类别:
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