High-resolution 3D in situ Spatial Gene Expression Profiling Technology for Human Brain Specimens
人脑标本高分辨率3D原位空间基因表达谱分析技术
基本信息
- 批准号:10385072
- 负责人:
- 金额:$ 50万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcademiaAffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAmericanAmyloidAnimal ExperimentsAnimal ModelAnimalsAreaAstrocytesBasic ScienceBiologicalBiological SciencesBrainBrain DiseasesCatalogingCause of DeathCellsChemistryChromosome MappingCollagenCytoplasmic GranulesDataData AnalyticsDatabasesDetectionDevelopmentDiagnosisDigestionDiseaseDrug TargetingEnsureErythrocytesExcisionFluorescenceFluorescence MicroscopyFormaldehydeFoundationsGene ExpressionGene Expression ProfilingGenesHomologous GeneHumanImageIn SituIndividualIndustryInvestigational DrugsKnowledgeLaboratoriesLateralLegal patentLibrariesLipofuscinMarketingMetastatic breast cancerMethodsMicrogliaMicroscopeMicroscopyMissionModelingMolecularMusNamesNatureNeurodegenerative DisordersNeuronsNoiseOpticsPF4 GenePathologicPathologyPatientsPhasePopulationPreparationProcessProtocols documentationPublic HealthPublicationsPublishingRNAReaction TimeReagentReproducibilityResearchResearch PersonnelResolutionSamplingScienceScientistSenile PlaquesSensitivity and SpecificitySignal TransductionSpecimenSpeedStandardizationSynapsesSystemTechnologyTemperatureTestingTherapeuticTherapeutic Human ExperimentationThickThinnessTissuesTranscriptUpdateVisualization softwareagedanalytical toolanimal tissuebasebehavior influencebiomarker discoverybrain researchbrain tissuecell typeclinical biomarkerscostdata analysis pipelinedata pipelinedesignfluorescence imaginggene panelgenome-wideglobal healthhigh resolution imaginghuman diseasehuman tissueimage processingimage registrationimaging systemimprovedinventionmicroscopic imagingnew technologyprotein aggregationresearch and developmentsample fixationtherapeutic developmenttooltranscriptomicsusabilityvalidation studies
项目摘要
Project Title: High-resolution 3D in situ Spatial Gene Expression Profiling Technology for
Human Brain Specimens
Project Description
The overall aim of this Phase I project is to apply Expansion Sequencing, a
genome-wide in situ transcriptomics profiling technology with unprecedented spatial resolution
in 3D, to human brain tissues to empower brain disease research and therapeutic development.
Neurodegenerative diseases, such as Alzheimer’s disease affects over 11% of the population
aged above 65, causing ⅓ of death in seniors, and costs hundreds of billions of dollars a year.
Yet, no disease modifying therapeutics have been approved for marketing. The ability to obtain
data and validate discoveries directly in human samples is paramount to our ability to
characterize and understand brain disorders. Spatially resolved transcriptomics, helps
scientists understand how the different cells are organized, using fluorescence microscopy
imaging has shown unmatched promise in characterizing different cell types in native tissue,
change during development and aging, and how they influence behavior and disease.
However, many of existing spatial technologies are limited to thin animal brain sections.
They are bound by optical diffraction-limited resolution, restraining the ability to precisely define
a large variety of cell types organized in 3D. Tissues from humans and those with
neurodegenerative disease have high degree of autofluorescence caused by protein aggregates
(such as Amyloid plaques), lipofuscin granules and dense vessels. Recently published in
Science, Expansion Sequencing (ExSeq) is the first in situ genome-wide 3D spatial gene
expression profiling technology. It provides unprecedented imaging resolution in 3D using thick
mouse brain sections. This allows for clear definition of synapse junctions and mapping gene
transcripts with single- and sub-cellular precision, which had not been possible with
conventional fluorescence confocal microscopes used by most researchers. In order to make
ExSeq suitable for human studies and commercially available, we identified and tested a new
set of methods that will allow us to optimise ExSeq for human specimens, and improve
sensitivity and specificity. We are building a set of analytical tools to help visualize, debug and
improve the robustness of the analytics pipeline. We have also obtained access to a wide
variety of precious human brain tissues, to help us test different sample preparation conditions
and validate our methods.
For this Phase I project, we will develop ExSeq protocol for human brain tissue
characterisation with a proof-of-concept gene panel, and create a robust image processing and
analytical pipeline that can accommodate images generated from different experimental and
laboratory settings. Finally, we will process and analyse a set of human normal and
Alzheimer’s diseased brain tissues, and validate results against published data and prior
research. Building upon a strong scientific foundation supported with publications, we are
bringing together extensive expertise in protocol optimization and sequencing technology for
ExSeq and deep knowledge of Alzheimer’s and neurodegenerative disease pathology to make
it an impactful tool for both basic science and therapeutic research and development.
项目名称:高分辨率3D原位空间基因表达谱技术
项目成果
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