Human Neural Organoid Modeling of Alzheimer's Disease Neuroinflammation for Drug Discovery
阿尔茨海默病神经炎症的人类神经类器官模型用于药物发现
基本信息
- 批准号:10758939
- 负责人:
- 金额:$ 49.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAbeta synthesisAdoptedAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmericanAmyloid beta-ProteinAnti-Inflammatory AgentsAntibodiesApoptoticAreaBiologicalBiological AssayBiological ModelsBiologyBrainCellsControl GroupsDataData SetDementiaDepositionDisease associated microgliaDoseEngineeringFunctional disorderGene ExpressionGene Expression ProfileGene TargetingGenerationsGenesGenetic TranscriptionGliosisHealthHealthcareHumanHydrogelsImmuneIn VitroInflammationInflammation ProcessInflammatoryLabelLate Onset Alzheimer DiseaseMacrophageMeasuresMicrogliaModelingMorphologyMutationNCAM1 geneNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeurofilament-LNeuronsOrganoidsOutcomePatientsPhagocytosisPharmaceutical PreparationsPhasePhysiologicalPlayPluripotent Stem CellsPopulationProcessReproducibilityRisk FactorsRodentRodent ModelRoleRosaniline DyesSPI1 geneSamplingSenile PlaquesStimulantStimulusSystemTREM2 geneTechnologyTestingTherapeuticTherapeutic InterventionTimeTissuesTransgenic OrganismsWorkabeta accumulationabeta oligomerapolipoprotein E-3biomarker identificationcell typeclinical predictorscomparison controlcostcytokinedifferential expressiondrug discoveryexperimental studyflexibilitygenetic signaturegenome wide association studyhuman modelhuman stem cellsimmune modulating agentsimmunoregulationin vivoinduced pluripotent stem cellmetermutantneuralneuroinflammationneuron lossneuropathologynew therapeutic targetnoveloverexpressionphase 2 studyresponserisk variantscreeningsingle-cell RNA sequencingstemtau Proteinstherapeutic evaluationtranscription factortreatment grouptwo-dimensional
项目摘要
Project Summary/Abstract
Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disease with more than 6.5
million Americans currently living with AD dementia. AD is defined by its neuropathological
hallmarks which include Aβ peptide plaque deposits, intraneuronal tau tangles and neuronal loss.
A major component of the AD process is neuroinflammation. Genome-wide association studies
(GWAS) have revealed several immune genes which are risk factors for developing late-onset
AD. Several of these AD risk genes such as SPI1 and TREM2 are highly expressed in microglia,
the brain’s resident macrophage-like population. Microglia phagocytose Aβ and play a central role
in the brain’s response to amyloid plaques and the neurodegenerative process. While pluripotent
stem cell-derived neural organoids do not typically contain immune cell populations, Stem
Pharm’s hydrogel-enabled neural organoids allow for incorporation of microglia in a reproducible,
96-well plate format amenable to screening applications. Using this technology, our preliminary
data demonstrate microglia incorporate into the neural organoids and respond appropriately to
inflammatory stimuli including Aβ oligomers and apoptotic neurons. Work in this proposal will lead
to the generation of a human AD-neuroinflammation organoid model by exposing cultures with
oligomeric Aβ and apoptotic neuronal cells to induce AD-like neuroinflammatory responses,
ultimately enabling a more biologically relevant human AD model for drug discovery applications
focused on immune modulation. Specific Aims will 1) optimize the model and establish the gene
expression signature of the microglia; 2) and incorporate microglia engineered with mutations in
the AD associated gene TREM2. Completion of these specific aims will establish a flexible
neuroinflammation model system capable of screening the effects of compounds or incorporating
microglia harboring mutant AD-associated genes. Phase II studies will seek to expand the
capabilities of the model by establishing and optimizing readouts to measure the effect of
inflammation on the neuronal cell populations and establish organoids from additional donors.
Ultimately, this work will develop commercially available, novel models of the AD inflammation
process which can serve to supplement the many rodent model systems currently available.
项目总结/文摘
项目成果
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Connie S Lebakken其他文献
Connie S Lebakken的其他文献
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{{ truncateString('Connie S Lebakken', 18)}}的其他基金
Neural organoid models of the immunological microenvironment of glioblastoma for drug discovery applications
用于药物发现应用的胶质母细胞瘤免疫微环境的神经类器官模型
- 批准号:
10761235 - 财政年份:2023
- 资助金额:
$ 49.99万 - 项目类别:
Hydrogel-enabled self-assembled human brain organoids for neurotoxicity applications
用于神经毒性应用的水凝胶自组装人脑类器官
- 批准号:
10374175 - 财政年份:2019
- 资助金额:
$ 49.99万 - 项目类别:
Hydrogel-enabled self-assembled human brain organoids for neurotoxicity applications
用于神经毒性应用的水凝胶自组装人脑类器官
- 批准号:
10259033 - 财政年份:2019
- 资助金额:
$ 49.99万 - 项目类别:
Synthetic hydrogels for biomanufacturing of iPSC-derived neural cells for precision medicine
用于精准医学 iPSC 衍生神经细胞生物制造的合成水凝胶
- 批准号:
10237392 - 财政年份:2018
- 资助金额:
$ 49.99万 - 项目类别:
Synthetic hydrogels for biomanufacturing of iPSC-derived neural cells for precision medicine
用于精准医学 iPSC 衍生神经细胞生物制造的合成水凝胶
- 批准号:
10081193 - 财政年份:2018
- 资助金额:
$ 49.99万 - 项目类别: