Routes to enhanced HIV neuropathogenesis through expression of subclinical levels of endogenous amyloid-beta
通过表达亚临床水平的内源性β淀粉样蛋白增强HIV神经发病机制的途径
基本信息
- 批准号:10415699
- 负责人:
- 金额:$ 247.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmyloid beta-ProteinAmyloid beta-Protein PrecursorApolipoprotein EApoptosisApplications GrantsBehavioralBiochemicalBioinformaticsBiologicalBiological AssayBiological ProcessBrainBrain DiseasesBrain regionCREB1 geneCa(2+)-Calmodulin Dependent Protein KinaseCell Culture TechniquesCognition DisordersCorpus striatum structureDefectDevelopmentDiseaseDisease ProgressionDoseElementsFunctional disorderGene ExpressionGenesGoalsGrantHIVHIV InfectionsHippocampus (Brain)HumanImmunohistochemistryImpaired cognitionInfectionInjuryInterdisciplinary StudyJointsKnock-in MouseKnowledgeLaboratoriesLate Onset Alzheimer DiseaseLearningLearning DisabilitiesLibrariesLong-Term PotentiationMemoryMemory LossMemory impairmentModelingMolecularMouse StrainsMusMutationMyeloid CellsNeurocognitive DeficitNeuronal PlasticityNeuronsNeuropathogenesisNuclear RNAOnset of illnessOverlapping GenesPathogenesisPathogenicityPathologyPathway interactionsPatientsPersonsPrefrontal CortexProcessProteinsProteolysisReportingResearchResearch Project GrantsRoleRouteSenile PlaquesSeveritiesSiblingsSideSiteSliceSymptomsSynapsesSynaptic plasticitySystemSystems BiologyTestingTranscriptTransgenic OrganismsVirusVirus ReplicationWNT Signaling PathwayWestern BlottingWorkabeta accumulationage relatedage related neurodegenerationamyloid pathologyamyloid precursor protein processingantiretroviral therapybrain cellcalmodulin-dependent protein kinase IIcell typefamilial Alzheimer diseasemouse modelneuropathologynext generationnoveloAβpre-clinicalpreferencesynergismtau Proteinstherapy developmenttranscriptometranscriptome sequencing
项目摘要
This is a resubmission of a collaborative project between HIV and Alzheimer’s Disease (AD) laboratories to
investigate potential synergy between HIV infection and amyloid β (Aβ), a hallmark of AD, in promoting memory
impairment. Half of HIV patients on antiretroviral therapy develop neurocognitive impairments (NCI) despite low
HIV brain burdens. Age is the most consistent factor affecting NCI progression. We reproduced HIV-NCI
pathogenesis in conventional mice infected with EcoHIV, a mouse-tropic HIV. The Project MPI, Dr. Arancio,
reported that non-synaptotoxic doses of exogenous oligomeric Aβ (oAβ) and Tau, another AD hallmark,
cooperate in synaptic dysfunction and memory impairment in mice, suggesting that AD proteins have pathogenic
potential at their subclinical concentrations. Our revised preliminary results show such cooperation between
EcoHIV and oAβ in multiple formats including after EcoHIV infection of AD mouse models prior to their cognitive
decline. The models included transgenic APP/PS1 mouse model of familial AD (FAD) and two late onset AD
(LOAD) mouse models expressing humanized AD proteins. We propose that HIV and subclinical oAβ processes
cooperate in disrupting synaptic plasticity to exacerbate HIV-NCI beyond each agent alone. The Specific Aims
are to: 1) Characterize enhanced HIV-NCI pathogenesis in FAD and LOAD mouse models prior to onset of their
AD symptoms. (A) optimize the onset of memory deficits with EcoHIV infection in preclinical APP/PS1 mice; (B)
determine HIV-NCI severity at disease onset by infected APP/PS1 mice by hippocampal LTP, synaptodendritic
injury, apoptosis, APP processing, and amyloid pathology (C) Conduct similar studies by EcoHIV infection of
LOAD model mice expressing various humanized AD genes and select one LOAD model for further studies 2)
Using APP/PS1 mice and one LOAD strain, conduct next generation RNA sequencing (RNA-seq) in EcoHIV
infected mice upon reaching HIV disease state (A) generate transcriptome from hippocampus (HPC), prefrontal
cortex (PFC), and striatum (STR), and define biological processes specifically associated with memory defects
caused jointly by HIV and oAβ; B) confirm some gene modulation by RT-QPCR in HPC and STR extracts or by
immunostaining in brain section; and C) conduct limited nuclear-RNA-seq analysis in HPC to assign altered HIV-
oAβ processes/transcripts to specific cell types. 3) Study molecular mechanisms responsible for promoting HIV-
NCI pathogenesis in the setting of naturally produced subclinical levels of human oAβ in mice. (A) since both
HIV and Aβ disturb wnt signaling and cause dendritic pruning, examine how HIV infection of myeloid cells works
with Aβ in dysregulating Wnt function in dendritic integrity. B) since EcoHIV downmodulates CaMKII and CREB
in mice study potential Aβ-HIV convergence in oAβ dysregulation of the CREB role in synaptic strengthening.
Studies will include EcoHIV infection of moderate and late onset AD mice, tests of learning and memory, HPC
long-term potentiation, HPC synaptodendritic integrity, apoptosis, APP processing, and amyloid pathology
system and brain HIV burdens, bioinformatics of mouse brain and select cell types.
这是艾滋病毒和阿尔茨海默氏病(AD)实验室之间的合作项目的重新提交
研究HIV感染和淀粉样β(Aβ)的潜在协同作用,AD的标志是促进记忆
损害。抗逆转录病毒疗法的HIV患者中有一半发展神经认知障碍(NCI)dospite低
HIV脑燃烧。年龄是影响NCI进展的最一致因素。我们复制了HIV-NCI
感染EcoHIV的传统小鼠的发病机理,一种小鼠 - 热带HIV。 MPI项目Arancio博士,
报道了非鼻毒性剂量的外源性寡聚Aβ(OAβ)和Tau,另一个AD标志,
在小鼠的突触功能障碍和记忆力障碍方面合作,表明AD蛋白具有致病性
潜在的亚临床浓度。我们修订的初步结果表明
Ecohiv和OAβ的多种格式,包括AD小鼠模型的Ecohiv感染之后
衰退。这些模型包括转基因应用/ps1鼠标family AD(FAD)和两个晚期发作广告
(负载)表达人源化AD蛋白的小鼠模型。我们提出HIV和亚临床OAβ过程
合作,破坏突触可塑性,使HIV-NCI仅超过每个药物。具体目标
为:1)在FAD和负载小鼠模型中表征增强的HIV-NCI发病机理
广告符号。 (a)优化临床前应用/PS1小鼠中生态感染的内存开始; (b)
通过海马LTP,突触drimention,SynaptoDondritics确定受感染的APP/PS1小鼠的疾病发作时的HIV-NCI严重程度
损伤,凋亡,应用程序加工和淀粉样病理学(C)通过生态感染进行类似的研究
表达各种人性化AD基因并为进一步研究选择一个负载模型的负载模型2)
使用APP/PS1小鼠和一只负载应变,在EcoHIV中进行下一代RNA测序(RNA-SEQ)
感染小鼠到达HIV疾病状态后(a)从海马(HPC),前额叶产生转录组
皮层(PFC)和纹状体(Str),并定义与记忆缺陷有关的生物学过程
由HIV和OAβ共同引起; b)在HPC和Str提取物中通过RT-QPCR确认一些基因调制或通过
在大脑部分中进行免疫染色; c)在HPC中进行有限的核-RNA-seq分析以分配改变的HIV-
OAβ的过程/转录本针对特定细胞类型。 3)研究负责促进HIV-的分子机制
NCI发病机理在小鼠中自然产生的人OAβ的亚临床水平。 (a)两者既是
HIV和Aβ干扰Wnt信号传导并引起树突修剪,研究髓样细胞的HIV感染如何作用
在树突完整性中aβ的Wnt功能失调。 b)由于Ecohiv下调Camkii和Creb
在研究中,在CREB在突触增强中的CREB作用的OAβ失调中,潜在的Aβ-HIV收敛。
研究将包括中度和晚期AD小鼠的生态感染,学习和记忆测试,HPC
长期增强,HPC突触跨性完整性,凋亡,应用程序加工和淀粉样蛋白病理学
系统和脑HIV伯伦斯,小鼠脑的生物信息学和选择细胞类型。
项目成果
期刊论文数量(0)
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{{ truncateString('OTTAVIO ARANCIO', 18)}}的其他基金
Understanding the role of ECSIT in neurodegeneration and Alzheimer's Disease
了解 ECSIT 在神经退行性疾病和阿尔茨海默病中的作用
- 批准号:
10629415 - 财政年份:2021
- 资助金额:
$ 247.5万 - 项目类别:
Understanding the role of ECSIT in neurodegeneration and Alzheimer's Disease
了解 ECSIT 在神经退行性疾病和阿尔茨海默病中的作用
- 批准号:
10216433 - 财政年份:2021
- 资助金额:
$ 247.5万 - 项目类别:
Preclinical development of a novel small molecule inhibitor of Alzheimer's disease-related cognitive impairment
阿尔茨海默病相关认知障碍的新型小分子抑制剂的临床前开发
- 批准号:
10396647 - 财政年份:2020
- 资助金额:
$ 247.5万 - 项目类别:
Routes to enhanced HIV neuropathogenesis through expression of subclinical levels of endogenous amyloid-beta
通过表达亚临床水平的内源性β淀粉样蛋白增强HIV神经发病机制的途径
- 批准号:
10206405 - 财政年份:2020
- 资助金额:
$ 247.5万 - 项目类别:
Preclinical development of a novel small molecule inhibitor of Alzheimer's disease-related cognitive impairment
阿尔茨海默病相关认知障碍的新型小分子抑制剂的临床前开发
- 批准号:
10159812 - 财政年份:2020
- 资助金额:
$ 247.5万 - 项目类别:
Preclinical development of a novel small molecule inhibitor of Alzheimer's disease-related cognitive impairment
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- 批准号:
10765513 - 财政年份:2020
- 资助金额:
$ 247.5万 - 项目类别:
Preclinical development of a novel small molecule inhibitor of Alzheimer's disease-related cognitive impairment
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- 批准号:
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$ 247.5万 - 项目类别:
The role of SUMOylation in Tau-mediated pathology
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10083243 - 财政年份:2019
- 资助金额:
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