Assay and Data Generation Center (ADGC) for the Model of iPSC-derived Neurons for NPD (MiNND)
Assay and Data Generation Center (ADGC) for the Model of iPSC-derived Neurons for NPD (MiNND)
批准号:
10653338
负责人:
Jubao Duan
金额:
$177.06万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-17 至 2028-04-30
关键词:
AccelerationAfrican AmericanAllelesAtlasesBar CodesBiologicalBiological AssayBiological ModelsBiologyBipolar DisorderCell LineCellsCoculture TechniquesCollaborationsCommunitiesComputer ModelsCytosineDataData AnalysesData SetDiseaseElectrophysiology (science)European ancestryFemaleFoundationsFunctional disorderFutureGenerationsGenesGeneticGenomicsGlutamatesHumanImageIndividualInduced pluripotent stem cell derived neuronsKnowledgeMajor Depressive DisorderMental disordersMessenger RNAMethodsModelingMolecularMorphologyNational Institute of Mental HealthNeurobiologyNeurodevelopmental DisorderNeuronsNeurosciencesNonsense CodonNonsense-Mediated DecayPathway AnalysisPatientsPenetrancePhenotypePopulationPropertyProtein TruncationReproducibilityResearchResourcesSchizophreniaSynapsesSynaptic TransmissionSystemTimeTranslatingValidationVariantWorkautism spectrum disorderbase editingbase editorcell typeclinically actionablecost effectivedata integrationdisease mechanisms studyeffective therapyexcitatory neuronexome sequencingfunctional genomicsgamma-Aminobutyric Acidgene functiongene networkgenome wide association studyhuman stem cellsimprovedinduced pluripotent stem cellinhibitory neuronknowledge baseknowledge integrationloss of functionmalemultimodalitymultiplexed imagingmutantneuralneural modelneurodevelopmental effectnext generationnoveloptical imagingoptical sensorpatch clamppatch sequencingrare variantresponserisk variantscale upsensorsingle-cell RNA sequencingstem cell biologystem cell modelsynaptic functiontranscriptomics
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
In the past decade, the scientific community has witnessed accelerated genetic discoveries for
neurodevelopmental and psychiatric disorders (NPD) such as schizophrenia (SZ), autism spectrum disorder
(ASD), bipolar disorder, and major depression. Genome-wide association studies (GWAS) and whole-exome
sequencing (WES) have identified a mounting number of NPD risk genes. However, translating these exciting
genetic discoveries into clinically actionable biology has been impeded by our limited knowledge of gene function
and related disease mechanisms. A bottleneck in the field is that most biological characterization has focused
on very few NPD genes, which have not necessarily been selected for study based on pathophysiological
importance. Furthermore, genes are often studied one at a time, hindering the pace of our understanding of
disease mechanisms. We propose an alternative strategy: large-scale, unbiased, parallel study of NPD genes
in disease-relevant model systems, in response to the RFA-MH-22-111 (Scalable and Systematic Neurobiology
of Psychiatric and Neurodevelopmental Disorder Risk Genes-SSPsyGene). We propose to establish the Assay
and Data Generation Center (ADGC) for the Model of induced pluripotent stem cell (iPSC)-derived Neurons for
NPD (MiNND), where we will implement and optimize novel scalable and systematic assays for interrogating the
molecular and neurobiological functions of up to 200 NPD risk genes. Teaming up with the SSPsyGene
Consortium and leveraging our team’s respective expertise in stem cell biology, functional genomics,
neuroscience, and functional analysis, our MiNND-ADGC will generate loss-of-function (LoF) iPSC human neural
models, and perform high-content morphometric and single-cell transcriptomic (scRNA-seq) analyses of NPD
LoF alleles. We will also assay synaptic functions using optical sensors in a high-throughput fashion and carry
out multimodal PatchSeq analyses and modeling to predict neuronal properties from scRNA-seq data. Finally,
working with the SSPsyGene Consortium, we will conduct data integration, curation, and dissemination to the
research community and public for further analysis. Our MiNND-ADGC will build a valuable resource and
integrated knowledge base that will provide a fertile foundation for future studies of disease mechanisms. The
data from studying the selected NPD risk genes on multiple genetic backgrounds, including the understudied
African American iPSC lines, will enable robust inferences of potential cross-disorder and cross-population
biological convergence and divergence relevant to NPD.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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海外基金