Single cell transcriptome profiling of aqueous humor outflow development for discovery of novel childhood glaucoma genes
房水流出发育的单细胞转录组分析以发现新的儿童青光眼基因
基本信息
- 批准号:10510279
- 负责人:
- 金额:$ 23.33万
- 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:ANGPT1 geneAddressAffectAgeAmericanAnimalsAqueous HumorArchitectureAtlasesBiological AssayBiologyBlindnessCYP1B1 geneCandidate Disease GeneCellsCharacteristicsChildChildhoodClinical ManagementComplexCorneaDataData SetDevelopmentDevelopmental BiologyDiagnostic testsDiseaseDrainage procedureExpression ProfilingEyeEye DevelopmentEye EnucleationEye diseasesFailureFamilyFemaleGenderGene ExpressionGene set enrichment analysisGenesGeneticGenetic CounselingGenomeGlaucomaGoalsHumanIn Situ HybridizationInbreedingIndividualInfantKnowledgeLinkLiquid substanceMelaninsModelingMoldsMolecularMolecular DiseaseMorphologyMusMutationOcular HypertensionOperative Surgical ProceduresOptic NerveOutcomePainPathogenesisPathogenicityPathway interactionsPharmacologic SubstancePhysiologic Intraocular PressurePopulationPopulation HeterogeneityPositioning AttributePreparationProteinsRNARattusRegulationResearchResource SharingResourcesST13 geneSamplingSex BiasStretchingStructureStructure of sinus venosus of scleraTechnologyTestingTextTissue DifferentiationTissue-Specific Gene ExpressionTissuesTrabecular meshwork structureTranscriptVariantVisualalbino ratanterior chamberbasecell typecohortconvictdesigndifferential expressiondisabilityeffective therapyexomeexome sequencingexperimental groupgene functiongenetic variantimprovedin silicomalemolecular markernerve damagenoveloverexpressionpopulation basedprimary congenital glaucomapublic health relevanceselective expressionsexsingle-cell RNA sequencingtherapy developmenttranscriptome
项目摘要
Project Summary / Abstract
Primary congenital glaucoma (PCG) is a devastating eye disorder that affects infants and demonstrates an
overall gender bias towards males (1.5:1). It is triggered by elevated intraocular pressure (IOP) which leads to
painful enlargement of the eye and severe tissue damage, often resulting in blindness and eye enucleation in a
significant proportion of children. All known causes are due to failure to correctly develop the aqueous humor
outflow (AHO) structures important for regulation of fluid drainage - primarily the trabecular meshwork (TM)
and Schlemm’s canal (SC). Mutations in 4 genes, CYP1B1, LTBP2, TEK, and ANGPT1, are currently known to
cause 25% of PCG in diverse populations. CYP1B1 mutations alone account for 20% of cases and effect more
females (1:2). These known genes are all important for development of the TM and/or SC. Despite global
exome sequencing efforts to date, the mechanisms underlying the remaining 75% cases remain undiscovered
and male sex-linked genes have yet to be identified. We hypothesize that the elusive genes underlying
PCG are critical for and therefore expressed during the development of the AHO pathway, but we
currently lack a comprehensive knowledge of gene expression during the formation of these important
ocular structures. We propose that the identification of these vital pathways will enable discovery of
the elusive molecular mechanisms of PCG, which in-turn will permit the development of treatments
aimed at the underlying disease biology. Until recently, the feasibility of expression profiling the AHO
pathway was limited due to its complex architecture and variety of cell types. Now, single-cell RNA sequencing
(scRNAseq) technology has enabled such studies by molecular separation of different cell populations based
on expression profiles at the single-cell level. To address our central hypothesis, we will profile transcriptomes
from all cell types within the AHO pathway throughout of its development utilizing scRNAseq. Rat tissues will
be utilized because they share with humans all major stages and morphological characteristics of AHO
pathway development, can be bred to defined developmental ages, and will supply significantly larger tissues
versus mice for scRNAseq profiling. We will generate separate datasets from male and female tissues at 6
different ages (P4, P8, P16, P48, P80, and P180), enabling identification of differentially expressed genes and
pathways specific to each cell type, developmental stage, and gender. We will then use this resource to reveal
likely disease-causing gene variants within existing exome sequencing data from molecularly unsolved PCG
cases. Candidate disease gene expression within the developing AHO structures will be confirmed by in situ
hybridization (RNAscope) studies. Finally, wild-type and variant mini-genes will be created to test the effect of
each candidate disease-causing variant on the gene’s function using a variety of cell-based assays.
项目摘要/摘要
项目成果
期刊论文数量(0)
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Stuart William James Tompson其他文献
Stuart William James Tompson的其他文献
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{{ truncateString('Stuart William James Tompson', 18)}}的其他基金
Single cell transcriptome profiling of aqueous humor outflow development for discovery of novel childhood glaucoma genes
房水流出发育的单细胞转录组分析以发现新的儿童青光眼基因
- 批准号:
10682543 - 财政年份:2022
- 资助金额:
$ 23.33万 - 项目类别:
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