Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease
解读阿尔茨海默病神经网络功能障碍的多因素病因
基本信息
- 批准号:10670331
- 负责人:
- 金额:$ 465.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-15 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAlgorithmsAlzheimer like pathologyAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAmino Acid SequenceAmino Acid SubstitutionAmyloid beta-ProteinApolipoprotein EApolipoproteinsAutopsyBehaviorBehavioralBiochemicalBioinformaticsBiological AssayBrainCell NucleusCellsCognitive deficitsCommunitiesComplexDataData Science CoreData SetDatabasesDevelopmentDiseaseDisease ProgressionElectrophysiology (science)EnsureEtiologyExperimental DesignsFunctional disorderGoalsHistopathologyHumanHyperactivityImpaired cognitionInfectionInterneuronsInterventionLeadLinkModelingMolecularMusNatureNeurogliaNeuronsNeurosciencesPathogenesisPathologicPathway interactionsPatientsPhenotypeProtein IsoformsPublic HealthResearchResearch ActivityRoleStatistical ModelsStressSystemSystems BiologyTherapeuticTherapeutic InterventionTransgenic OrganismsValidationVirulence Factorsapolipoprotein E-4behavior testbrain dysfunctionbrain tissuecell typecohortdata harmonizationdiverse datadrug developmentepigenomicsepileptiformexperimental studyfamilial Alzheimer diseasehuman datahuman tissueimprovedin vivoinnovationinsightknock-downmouse modelnetwork dysfunctionneural networkneuromechanismneuropathologyneurophysiologynovelnovel strategiesnovel therapeutic interventionoverexpressionpreventprogramsresearch and developmenttau Proteinstranscriptomicsworking group
项目摘要
OVERALL – SUMMARY
Alzheimer’s disease (AD) is a major unresolved public health problem. Efforts to prevent or stall this disease
have failed, in good part because of inadequate understanding of its complex pathogenesis. Mounting evidence
suggest that neural network dysfunction may underlie or promote AD-related cognitive deficits and contribute to
disease progression. Yet, the causes and consequences of this dysfunction and the therapeutic potential of
counteracting it remain sorely understudied. Therefore, the overarching goal of this program project is to decode
the multifactorial etiology of AD-related neural network dysfunction and to leverage the novel mechanistic
insights we will gain toward the development of better therapeutic strategies. Through collaborative interactions
among four projects and two cores, our program will use systems neuroscience (neurophysiology and behavior)
in combination with systems biology (single-cell transcriptomics and epigenomics), as well as neuropathology
and improved mouse models, to determine how copathogenic interactions among apolipoprotein (apo) E4,
amyloid-b (Ab), and tau cause neural network dysfunctions and cognitive decline in AD. An Administrative Core
will coordinate all activities. Projects 1–3 will use novel mouse models of sporadic and familial AD to study
interactions of different apoE isoforms with wildtype (WT) human tau (Project 1) or APP/Ab (Project 2), or among
apoE4, Ab, and tau that is WT or bears disease-associated amino acid substitutions (Project 3). Project 4 will
carry out single-nucleus transcriptomic and epigenomic analyses on postmortem brain tissues from deeply
phenotyped human AD cases to gain novel insights into the multifactorial etiology of the human condition,
validate leads from mouse studies, and encourage backtranslation into the models. An Integrative Data-Science
Core will help us integrate results from all projects through innovative statistical modeling. This approach will
reveal which aspects of human AD are most faithfully reproduced in the mouse models and help establish the
causal drivers of cell-specific alterations in the human tissues, increasing the mechanistic resolving power of the
latter studies. Therapeutic interventions in mouse models will determine whether reducing apoE4 expression in
specific cell types can block copathogenic effects of apoE4 and tau on brain functions (Project 1), modulating
the activity of specific interneurons can counteract copathogenic effects of apoE4 and APP/Ab (Projects 2 and
4), and knocking down tau can prevent and reverse brain dysfunction in models expressing all three pathogenic
factors (Project 3). Through these highly cohesive efforts, our program will dissect the multifactorial interactions
among AD-related pathogenic factors, define their relative contributions to the complex pathogenesis of brain
dysfunctions, and help distinguish among neuropathological alterations that cause, result from, or are
coincidental to neural network dysfunctions and cognitive decline. Sharing the diverse data sets we will generate
and disseminating the novel integrative approaches we plan to develop for their analysis could enhance the
progress of many other groups working in AD research and drug development or biomedicine in general.
Overall—概要
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)
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YADONG HUANG其他文献
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{{ truncateString('YADONG HUANG', 18)}}的其他基金
Develop AD Connectivity Maps with Human iPSC-Derived Brain Cells and their Use
使用人类 iPSC 衍生脑细胞开发 AD 连接图及其用途
- 批准号:
10504728 - 财政年份:2022
- 资助金额:
$ 465.72万 - 项目类别:
Develop AD Connectivity Maps with Human iPSC-Derived Brain Cells and their Use
使用人类 iPSC 衍生脑细胞开发 AD 连接图及其用途
- 批准号:
10686182 - 财政年份:2022
- 资助金额:
$ 465.72万 - 项目类别:
Study Susceptibility and Resistance to ApoE4 in Alzheimer's Disease
研究阿尔茨海默病中 ApoE4 的易感性和耐药性
- 批准号:
10418144 - 财政年份:2022
- 资助金额:
$ 465.72万 - 项目类别:
Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease
解读阿尔茨海默病神经网络功能障碍的多因素病因
- 批准号:
10525204 - 财政年份:2021
- 资助金额:
$ 465.72万 - 项目类别:
Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease
解读阿尔茨海默病神经网络功能障碍的多因素病因
- 批准号:
10691620 - 财政年份:2021
- 资助金额:
$ 465.72万 - 项目类别:
Project 1: Differential Roles of ApoE Isoforms in Neural Network Dysfunction of Alzheimer's Disease
项目 1:ApoE 同工型在阿尔茨海默病神经网络功能障碍中的不同作用
- 批准号:
10461842 - 财政年份:2021
- 资助金额:
$ 465.72万 - 项目类别:
Neuronal ApoE Drives Selective Neurodegeneration in Alzheimer's Disease
神经元 ApoE 驱动阿尔茨海默病的选择性神经变性
- 批准号:
10640879 - 财政年份:2021
- 资助金额:
$ 465.72万 - 项目类别:
Neuronal ApoE Drives Selective Neurodegeneration in Alzheimer's Disease
神经元 ApoE 驱动阿尔茨海默病的选择性神经变性
- 批准号:
10458692 - 财政年份:2021
- 资助金额:
$ 465.72万 - 项目类别:
Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease
解读阿尔茨海默病神经网络功能障碍的多因素病因
- 批准号:
10461839 - 财政年份:2021
- 资助金额:
$ 465.72万 - 项目类别:
Project 1: Differential Roles of ApoE Isoforms in Neural Network Dysfunction of Alzheimer's Disease
项目 1:ApoE 同工型在阿尔茨海默病神经网络功能障碍中的不同作用
- 批准号:
10670337 - 财政年份:2021
- 资助金额:
$ 465.72万 - 项目类别:
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