Construction of an Integrated Immune - Vascular Brain - Chip as a Platform for the Study, Drug Screening, and Treatments of Alzheimer's Disease
构建集成免疫血管脑芯片作为阿尔茨海默病研究、药物筛选和治疗的平台
基本信息
- 批准号:10622543
- 负责人:
- 金额:$ 115.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-20 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAccelerationAffectAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease therapeuticAmyloidAmyloid depositionAnatomyAstrocytesAutopsyBiochemicalBiopolymersBlood - brain barrier anatomyBlood VesselsBrainBrain DiseasesCalciumCell LineCellsCerebral Amyloid AngiopathyCerebrovascular DisordersClinicClinicalClinical ResearchCommunitiesComplexComputer ModelsCoupledDataDepositionDepressed moodDevelopmentDiseaseDissectionDrug ScreeningDrug toxicityDrug usageElderlyEngineeringExhibitsFemaleFinancial costFunctional disorderFundingGene Expression ProfileGeneticGenetic ModelsGenetic PolymorphismGenetic Predisposition to DiseaseGenetic RiskGenetic TranscriptionGenetic VariationGenetic studyGenomicsGrantHeterogeneityHistologicHistologyHumanImageImmuneIn VitroIndividualLeadLibrariesMapsMediatingMicrogliaModelingMolecularMonitorNeurodegenerative DisordersNeuronsOligodendrogliaOrganPathogenesisPathologicPathologyPatientsPericytesPharmaceutical PreparationsPhasePhysiologicalPhysiologyPluripotent Stem CellsPredispositionPropertyRNARapid screeningRecording of previous eventsReporterResourcesRiskSamplingSeveritiesSignal PathwayTauopathiesTechnologyTherapeuticTissue EngineeringTissuesToxic effectTranslationsVariantapolipoprotein E-3apolipoprotein E-4brain dysfunctionbrain endothelial cellbrain tissuecell typecerebrovascularcerebrovascular pathologyclinical biomarkerscohortconstrictiondrug developmentdrug discoveryefficacy evaluationgenetic risk factorhuman diseasehuman tissuein vitro Modelin vivoinsightmalemultimodalitynon-invasive imagingnovelnovel strategiesnovel therapeuticsoligodendrocyte precursoroptogeneticsorgan on a chippharmacologicpre-clinicalprecursor cellresearch and developmentresponsescaffoldscreeningsingle-cell RNA sequencingstem cell biologystem cell technologysuccesstau Proteinstherapeutically effectivetimelinetooltranscriptomicstreatment responsetwo-photonvoltage
项目摘要
Abstract
Alzheimer's disease (AD) is a debilitating brain disorder, with staggering human and financial cost. While
genetic studies are increasingly identifying polymorphisms that correlate with AD, there still is no clear picture
of the molecular and cellular players and the extent to which each contributes to AD. The genetic and
molecular complexity of AD and the lack of technology for experimentally unraveling it in human tissues create
a bottleneck constricting the discovery of therapeutics and their successful translation into the clinic. Using
human iPSCs we recently developed an in vitro blood-brain barrier (iBBB) and deployed it to discover
mechanisms causing genetic predisposition to cerebral amyloid angiopathy (CAA). Identical to clinical studies,
we found that APOE4, the strongest genetic risk factor for CAA and AD significantly increased amyloid
deposition in our iBBB. The tractability of our engineered tissues then enabled dissection of the cellular causes
of the disease. We found expression of APOE4 in pericytes alone was sufficient to increase cerebral vascular
amyloid accumulation. Pinpointing the causal cells mediating CAA risk then enabled molecular and
biochemical studies that established the underlying mechanism and revealed new therapeutic opportunities for
mitigating genetic risk of CAA and potentially AD. Here, we will build upon our success, using the iBBB as a
scaffold; we will incorporate neurons, oligodendrocytes, and microglia to generate a micro-integrated brain on
a chip (miBrain-chip). In UG3 Aim1.1 we will establish miBrain-chips that represent healthy and diseased
states of the human brain through iterative rounds of optimization that incorporate state-of-the-art biopolymers
and engineering expertise from Robert Langer's lab at MIT. UG3 Aim1.2 will integrate and validate genetically
encoded modulators and reporters of neuronal activity enabling the miBrain-chip to investigate how neuronal
activity is influenced, and in turn, influences AD pathogenesis. UG3 Aim2 will model the pathological
progression of AD in miBrain-chips across cohort of male and female sAD iPSC lines for which we have
matched brains samples, clinical history, and genomic sequences. We will build computational models
describing the transcriptional, cellular-dynamics and histological transformations that lead up to the end-states
of post-mortem AD brains. These longitudinal pathological maps from genetically diverse healthy and sAD
individuals will yield mechanistic insight into AD development and create a platform for discovery and efficacy
screening of therapeutics. We hypothesize that the mechanisms underlying AD are significantly influenced by
genetic variability. In UH3 we will establish the mechanisms underlying APOE4 pathogenesis (UH3 Aim1) and
then ascertain the efficacy, toxicity, and therapeutic window of a panel of preclinical and clinical AD drugs
using isogenic APOE3 and APOE4 miBrain-chips (UH3 Aim2). Our multimodal strategy will shed light on how
genetic variation influences AD pathogenesis and therapeutic response, opening up new avenues for
expeditious drug discovery and translation of effective therapeutics to the clinic.
摘要
项目成果
期刊论文数量(0)
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Joel William Blanchard其他文献
Joel William Blanchard的其他文献
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{{ truncateString('Joel William Blanchard', 18)}}的其他基金
Understanding cell-type vulnerability and oxidative stress pathology in Parkinson's Disease using isogenic human dopaminergic neurons
使用同基因人类多巴胺能神经元了解帕金森病的细胞类型脆弱性和氧化应激病理学
- 批准号:
10247522 - 财政年份:2020
- 资助金额:
$ 115.85万 - 项目类别:
Understanding cell-type vulnerability and oxidative stress pathology in Parkinson's Disease using isogenic human dopaminergic neurons
使用同基因人类多巴胺能神经元了解帕金森病的细胞类型脆弱性和氧化应激病理学
- 批准号:
10458745 - 财政年份:2020
- 资助金额:
$ 115.85万 - 项目类别:
Understanding Cell-type Vulnerability and Oxidative Stress Pathology in Parkinson's Disease Using Isogenic Human Dopaminergic Neurons
使用同基因人类多巴胺能神经元了解帕金森病的细胞类型脆弱性和氧化应激病理学
- 批准号:
10841881 - 财政年份:2020
- 资助金额:
$ 115.85万 - 项目类别:
Understanding Cell-type Vulnerability and Oxidative Stress Pathology in Parkinson's Disease Using Isogenic Human Dopaminergic Neurons
使用同基因人类多巴胺能神经元了解帕金森病的细胞类型脆弱性和氧化应激病理学
- 批准号:
10682394 - 财政年份:2020
- 资助金额:
$ 115.85万 - 项目类别:
Construction of an integrated immune - vascular brain - chip as a platform for the study, drug screening, and treatments of Alzheimer's disease
构建集成免疫血管脑芯片作为阿尔茨海默病研究、药物筛选和治疗的平台
- 批准号:
9894186 - 财政年份:2019
- 资助金额:
$ 115.85万 - 项目类别:
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