Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease
对共病重度抑郁症和阿尔茨海默病潜在的共享和不同分子机制进行系统建模
基本信息
- 批准号:10404989
- 负责人:
- 金额:$ 84.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:APP-PS1ActinsAdultAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmyloid beta-ProteinAmyloid beta-Protein PrecursorAmyloidosisAntidepressive AgentsBayesian AnalysisBehaviorBioinformaticsBiological MarkersBiological ModelsBlack raceBrainBrain regionBrain-Derived Neurotrophic FactorCognitive deficitsDNADUSP1 geneDUSP3 geneDUSP6 proteinDataData SetDementiaDevelopmentDiseaseFamilyFemaleGene ExpressionGene Expression RegulationGene ProteinsGenesGeneticGenomicsHippocampus (Brain)HyperactivityImmuneImmunologic ReceptorsImpaired cognitionInterventionKnockout MiceLate Onset Alzheimer DiseaseMAPK phosphataseMacrophage Colony-Stimulating Factor ReceptorMajor Depressive DisorderManicMediatingMedicineMental DepressionMitogen-Activated Protein KinasesModelingMolecularMusNamesNaturePathogenesisPathway AnalysisPathway interactionsPatientsPeptidesPhosphoric Monoester HydrolasesPlayPrefrontal CortexProteinsProteomicsPublic HealthPublishingRNARefractoryRoleSpecificitySystems BiologyTYROBP geneTestingTissue SampleTransgenic OrganismsValidationVariantabeta oligomeraquaporin 4astrogliosisbehavioral phenotypingcohortcomorbid depressioncomorbiditydepression modeldifferential expressiondisorder controlexhaustionfrontal lobegenetic variantmembermild cognitive impairmentmolecular modelingmouse modelmultiple omicsnetwork modelsneuroinflammationneuropathologyneuropsychiatric disordernoveloverexpressionprogramsprospectiveprotein expressionsexual dimorphismtau Proteinstranscriptomicsvalidation studieswater channel
项目摘要
Comorbidity of Alzheimer's disease (AD) and Major Depressive Disorder (MDD) is frequent but unexplained by
common genetic variants. Members of the Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD)
program have exhaustively profiled gene expression in multiple brain regions from AD and control subjects
through multiple cohorts and then performed systems biology analyses to identify molecular networks and
drivers implicated in late onset AD. VGF (non-acronymic) is one of the top ranked AD drivers conserved in
multiple cohorts. We show that VGF overexpression in hippocampus reduces neuropathology and cognitive
impairment in the 5xFAD mouse model of amyloidosis (Beckmann et al., under review), and VGF is already
known to have a role in depression. Its AD network includes the dual-specificity phosphatases DUSP4 and
DUSP6 (MAP Kinase Phosphatases 2 and 3, respectively), all reduced in level in AD, connected via their
network to Amyloid Precursor Protein/Abeta and Tau, and also previously identified by our group to be part of a
network that contributes to MDD in females only. Our published and preliminary studies further demonstrate
that VGF levels are reduced in MDD, in hippocampus and PFC, and that VGF overexpression in these regions
has antidepressant efficacy in mice. Preliminary network analysis further identifies (1) an immune module with
colony stimulating factor 1 receptor (CSF1R), a protein required for adult microglial survival, as a driver down-
regulated in AD plus MDD, but up-regulated in AD alone, and (2) aquaporin-4 (AQP4), a brain water channel,
which is down-regulated in AD plus MDD vs AD, is expressed in astroglial endfeet, and is implicated in AD.
We hypothesize that members of our identified VGF, CSF1R, and AQP4 causal networks contribute to
cognitive decline, depression-like behavior, and neuropathology in mouse models and patients with AD and
MDD. In Aim 1, high throughput transcriptomics, proteomics, and multiscale network molecular modeling will
be carried out on dorsolateral prefrontal cortex (DLPFC) from a new cohort of AD patients with and without
comorbid MDD, MDD patients without AD, and control subjects, to identify additional shared and distinct
molecular mechanisms that regulate these two diseases. In Aim 2, we propose to determine the role(s) that
the VGF/DUSP shared network plays in comorbid MDD plus AD, by determining the underlying pathways by
which VGF, DUSP4, and DUSP6 block or delay cognitive dysfunction, depression-like behavior, and the
development of neuropathology, including microglial changes, utilizing AAV-mediated overexpression
strategies in APP/PS1 mice. In Aim 3, we will validate the novel subnetworks and key drivers identified in Aim
1 that differentiate AD plus MDD from AD alone. Initially, we will investigate CSF1R/immune/microglial and
AQP4/astroglial network function in depression-like behavior, neuropathology, and the regulation of gene
expression (transcriptomics), in APP/PS1 mice overexpressing either CSF1R or AQP4, and also for CSF1R, in
APP/PS1 mice that lack TYROBP, resulting in a normalized immune module and rescued cognitive impairment.
阿尔茨海默病(AD)和严重抑郁障碍(MDD)的共病是常见的,但无法解释
常见的遗传变异。加速药物伙伴关系-阿尔茨海默病(AMP-AD)成员
程序在AD和对照受试者的多个大脑区域中详尽地描述了基因的表达
通过多个队列,然后执行系统生物学分析以识别分子网络和
司机与迟发性阿尔茨海默病有关。VGF(非首字母缩写)是排名靠前的AD司机之一,在
多个队列。我们发现VGF在海马区的过度表达降低了神经病理和认知能力
淀粉样变性5xFAD小鼠模型中的损伤(Beckmann等人,正在审查中),VGF已经
已知在抑郁症中起作用。它的AD网络包括双特异性磷酸酶DUSP4和
DUSP6(分别是MAP激酶磷酸酶2和3),在AD中水平都降低,通过它们的
到淀粉样前体蛋白/Abeta和Tau的网络,也被我们的小组先前鉴定为
仅在女性中促成MDD的网络。我们已发表的和初步的研究进一步证明
在MDD、海马区和PFC,VGF水平降低,而VGF在这些区域过度表达
对小鼠有抗抑郁作用。初步网络分析进一步识别(1)具有
集落刺激因子1受体(CSF1R)是一种成年小胶质细胞生存所需的蛋白质,作为向下的驱动因素-
在AD+MDD中上调,但在单独AD中上调,以及(2)脑水通道水通道蛋白-4(AQP4),
该基因在AD+MDD组较AD组下调,在星形胶质细胞末端表达,并与AD有关。
我们假设我们识别的VGF、CSF1R和AQP4因果网络的成员对
小鼠模型和阿尔茨海默病患者的认知功能下降、抑郁样行为和神经病理学
MDD。在目标1中,高通量转录组学、蛋白质组学和多尺度网络分子建模将
对患有和不患有AD的新队列患者的前额叶背外侧皮质(DLPFC)进行检查
共患MDD、无AD的MDD患者和对照受试者,以确定其他共享和不同的
调节这两种疾病的分子机制。在目标2中,我们建议确定以下角色(S)
VGF/DUSP共享网络通过以下方式确定底层路径,从而在MDD和AD并存的情况下发挥作用
VGF、DUSP4和DUSP6阻断或延迟认知功能障碍、抑郁样行为和
利用AAV介导的过表达,包括小胶质细胞改变在内的神经病理学的发展
APP/PS1小鼠的策略。在AIM 3中,我们将验证AIM中确定的新子网络和关键驱动程序
1区分AD加MDD与单纯AD。首先,我们将研究CSF1R/免疫/小胶质细胞和
AQP4/星形胶质细胞网络在抑郁样行为、神经病理和基因调控中的作用
在APP/PS1小鼠中过度表达CSF1R或AQP4,以及CSF1R,在
缺乏TYROBP的APP/PS1小鼠,导致免疫模块正常化,并挽救了认知障碍。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development.
- DOI:10.3390/cells11223629
- 发表时间:2022-11-16
- 期刊:
- 影响因子:6
- 作者:Bose, Meenakshi;Quipildor, Gabriela Farias;Ehrlich, Michelle E.;Salton, Stephen R.
- 通讯作者:Salton, Stephen R.
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MICHELLE E EHRLICH其他文献
MICHELLE E EHRLICH的其他文献
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{{ truncateString('MICHELLE E EHRLICH', 18)}}的其他基金
Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease
对共病重度抑郁症和阿尔茨海默病潜在的共享和不同分子机制进行系统建模
- 批准号:
10214197 - 财政年份:2018
- 资助金额:
$ 84.3万 - 项目类别:
Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease
对共病重度抑郁症和阿尔茨海默病潜在的共享和不同分子机制进行系统建模
- 批准号:
10172822 - 财政年份:2018
- 资助金额:
$ 84.3万 - 项目类别:
Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease
对共病重度抑郁症和阿尔茨海默病潜在的共享和不同分子机制进行系统建模
- 批准号:
9788267 - 财政年份:2018
- 资助金额:
$ 84.3万 - 项目类别:
Integrative Network Modeling of Cognitive Resilience to Alzheimer's Disease
阿尔茨海默病认知复原力的综合网络建模
- 批准号:
9439453 - 财政年份:2017
- 资助金额:
$ 84.3万 - 项目类别:
Integrative Network Modeling of Cognitive Resilience to Alzheimer's Disease
阿尔茨海默病认知弹性的综合网络建模
- 批准号:
10170187 - 财政年份:2017
- 资助金额:
$ 84.3万 - 项目类别:
Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease
识别、表征和验证阿尔茨海默病分子亚型的综合网络生物学方法
- 批准号:
10251248 - 财政年份:2014
- 资助金额:
$ 84.3万 - 项目类别:
Identification and characterization of receptors targeting VGF-derived peptides.
针对 VGF 衍生肽的受体的鉴定和表征。
- 批准号:
10312413 - 财政年份:2014
- 资助金额:
$ 84.3万 - 项目类别:
Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease
识别、表征和验证阿尔茨海默病分子亚型的综合网络生物学方法
- 批准号:
10005927 - 财政年份:2014
- 资助金额:
$ 84.3万 - 项目类别:
Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease
识别、表征和验证阿尔茨海默病分子亚型的综合网络生物学方法
- 批准号:
10475089 - 财政年份:2014
- 资助金额:
$ 84.3万 - 项目类别:
Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease
识别、表征和验证阿尔茨海默病分子亚型的综合网络生物学方法
- 批准号:
9922436 - 财政年份:2014
- 资助金额:
$ 84.3万 - 项目类别:
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