Probing Heterogeneity of Alzheimer's disease using iPSCs
Probing Heterogeneity of Alzheimer's disease using iPSCs
批准号:
10400951
负责人:
Tracy L YOUNG-PEARSE
金额:
$48.93万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-15 至 2023-05-31
关键词:
AddressAdultAge of OnsetAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAmyloidAmyloid beta-ProteinAstrocytesAutopsyBrainBrain PathologyCategoriesCell LineCell modelCellsCellular AssayCerebral cortexClinicalClinical DataClinical TrialsCoculture TechniquesCognitionCognitiveCoupledDataData SetDegenerative DisorderDementiaDeteriorationDiseaseEarly InterventionEarly Onset Alzheimer DiseaseEarly intervention trialsEnzyme-Linked Immunosorbent AssayEnzymesEtiologyFunctional disorderFunding AgencyGenerationsGenesGeneticGoalsHeterogeneityHumanINPPL1 geneImpaired cognitionIn VitroIndividualInduced pluripotent stem cell derived neuronsInheritedInositolInterventionLate Onset Alzheimer DiseaseLocationMapsMeasurementMeasuresMemoryMemory LossMethodsMicrogliaMissense MutationModelingMolecularMolecular ProfilingMutationNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeurogliaNeuronsOutcomePathogenesisPathologicPathologistPathologyPathway AnalysisPathway interactionsPeptide HydrolasesPhenotypePhosphoric Monoester HydrolasesPlayPredispositionProsencephalonProtein PrecursorsProteomeProteomicsRiskRisk FactorsRoleSenile PlaquesSeriesSignal PathwayStatistical ModelsStudy SubjectSubgroupSusceptibility GeneSystemSystems BiologyTauopathiesTestingTherapeutic InterventionWestern Blottingagedbrain cellbrain tissuechemokinecohortcomorbiditycytokinediagnostic toolearly detection biomarkersearly onsetextracellularfamilial Alzheimer diseasegenome wide association studyglial activationhuman subjecthyperphosphorylated tauimprovedinduced pluripotent stem cellinduced pluripotent stem cell technologyinositol-1,4,5-trisphosphate 5-phosphataseneuropathologyneurotoxicnovelpatient populationpatient subsetsphosphoinositide-3,4,5-triphosphatephosphoinositide-3,4-bisphosphatepredictive markerpresenilinprognostic toolreligious order studystem cellssymptom managementtargeted treatmenttau Proteinstau-1therapeutic developmenttherapeutically effectivetranscriptometranscriptome sequencingtranscriptomics
中文摘要
阿尔茨海默氏病(AD)是一种神经退行性疾病,其特征在于神经系统的功能障碍和退化。
导致记忆丧失和进行性认知衰退的神经元。 目前的治疗方法只针对
症状管理有效治疗开发的三个障碍包括:1)缺乏对药物的定义,
AD发病机制的异质性,2)缺乏高度预测性的生物标志物以促进早期干预,以及
3)需要确定参与认知下降和AD的途径,这些途径可以作为治疗的靶点。
干预我们正在使用诱导多能干细胞(iPSC)技术,并结合全面的研究,
患者群体询问AD的细胞和分子机制,
这些障碍。我们认为存在多种形式的AD,它们具有不同的根本原因,
可能需要多种治疗干预来解决不同的病因。 通过其他资金
来源,我们已经从两个队列中产生了50个iPSC系,即宗教秩序研究(ROS)和记忆研究(MLS)。
老龄化项目(MAP) 在这里,我们建议研究这些线,我们集中在三类,
处于病理谱极端的受试者:1)没有大脑病理,没有认知
受损的,2)未认知受损的高病理学,和3)高病理学,晚发性阿尔茨海默病。在
此外,我们已经从家族性AD受试者中产生和/或收集了iPSC系,将在
并联 使用来自60名人类受试者的iPSC衍生的神经元、星形胶质细胞和小胶质细胞,我们将测量AD
Aim 1中的相关结果(Aβ,p-tau,细胞因子/趋化因子),并获得无偏倚的转录组学和
蛋白质组学数据在Aim 2中。这些数据将与临床数据、神经病理学数据和遗传学数据进行整合
从使用多种计算方法获得细胞的相同受试者获得。
我们假设:1)死后脑组织的某些病理学发现可以通过体外细胞学方法预测。
对iPSC衍生的神经元和神经胶质细胞的测定(目的1),和2)在一些实验中,
人类受试者可以通过iPSC衍生的转录组学和蛋白质组学水平的网络分析来预测,
神经元和神经胶质。来自12个细胞系的初步数据支持这样的前提,即iPSC-10衍生的细胞将捕获某些细胞因子。
这些细胞和分子特征定义了老年人的亚群。来自所有50个ROS/MAP系和EOAD的数据
目标1和目标2中产生的模型将提供一个定义明确的框架来解决机械问题。
关于AD 在目标3中,我们将利用一组具有深刻特征的iPSC-β衍生培养物来解决
假设INPP 5D(SHIP 1)和/或INPPL 1(SHIP 2)的肌醇5-磷酸酶活性失调导致
在受试者的一个子集中,LOAD的风险升高。通过这些研究,我们的目标是评估iPSC是否能够
衍生的细胞可以作为认知衰退和AD的诊断或预后工具,并且开始解决
LOAD异质性的细胞和分子机制。
英文摘要
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by dysfunction and deterioration of
neurons resulting in loss of memory and progressive cognitive decline. Current treatments are aimed only at
symptom management. Three barriers to effective therapeutic development include: 1) a lack of definition of the
heterogeneity of AD pathogenesis, 2) a lack of highly predictive biomarkers to facilitate early intervention, and
3) a need to identify pathways involved in cognitive decline and AD that can be targeted for therapeutic
intervention. We are using induced pluripotent stem cell (iPSC) technology coupled to comprehensive studies of
patient populations to interrogate the cellular and molecular mechanisms underlying AD in an effort to break
down these barriers. We propose that there exist multiple forms of AD that have different underlying causes, and
that multiple therapeutic interventions may be needed to address disparate etiologies. Through other funding
sources, we have generated 50 iPSC lines from two cohorts, the Religious Order Study (ROS) and the Memory
and Aging Project (MAP). Here, we propose to study these lines, where we focus upon three categories of
subjects that lie on the extreme ends of the pathological spectrum: 1) no brain pathology, not cognitively
impaired, 2) high pathology not cognitively impaired, and 3) high pathology, late onset Alzheimer’s disease. In
addition, we have generated and/or collected iPSC lines from familial AD subjects, which will be analyzed in
parallel. Using iPSC derived neurons, astrocytes, and microglia from 60 human subjects, we will measure AD
relevant outcomes (Aβ, p-tau, cytokines/chemokines) in Aim 1 and acquire unbiased transcriptomic and
proteomic data in Aim 2. These data will be integrated with clinical data, neuropathology data, and genetic data
acquired from the same subjects from whom the cells were derived using multiple computational approaches.
We hypothesize that: 1) Some pathological findings in the postmortem brain can be predicted by in vitro cellular
assays on iPSC derived neurons and glia (Aim 1), and 2) Both neuropathology and cognitive decline in some
human subjects can be predicted by transcriptomic and proteomic level network analyses of iPSC derived
neurons and glia. Preliminary data from 12 lines supports the premise that iPSC-derived cells will capture certain
cell and molecular signatures that define subgroups of aged adults. Data from all 50 ROS/MAP lines and EOAD
models generated in aims 1 and 2 will provide a well-defined framework to address mechanistic questions
regarding AD. In Aim 3 we will leverage the deeply characterized set of iPSC-derived cultures to address the
hypothesis that dysregulated inositol 5-phosphatase activity of INPP5D (SHIP1) and/or INPPL1 (SHIP2) leads
to an elevated risk for LOAD in a subset of subjects. Through these studies, we aim to evaluate whether iPSC-
derived cells can act as a diagnostic or prognostic tool for cognitive decline and AD, and begin to address the
cell and molecular mechanisms underlying heterogeneity in LOAD.
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