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:10172822
- 负责人:
- 金额:$ 98.42万
- 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 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:APP-PS1ActinsAdultAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmyloid beta-ProteinAmyloid beta-Protein PrecursorAmyloidosisAntidepressive AgentsBayesian AnalysisBehaviorBioinformaticsBiological MarkersBiological ModelsBrainBrain 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)和重度抑郁症(MDD)的合并症是常见的,但无法解释
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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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:
$ 98.42万 - 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:
10404989 - 财政年份:2018
- 资助金额:
$ 98.42万 - 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:
$ 98.42万 - 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:
$ 98.42万 - 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:
$ 98.42万 - 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:
$ 98.42万 - 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:
$ 98.42万 - 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:
$ 98.42万 - 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:
$ 98.42万 - 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:
$ 98.42万 - 项目类别:
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