Origins of Brain Somatic Mosaicism in Developmental Brain Disease
发育性脑疾病中脑体细胞嵌合的起源
基本信息
- 批准号:10466904
- 负责人:
- 金额:$ 31.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-10 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAlgorithmsAllelesAnatomyAnimal ModelAstrocytesAutopsyBar CodesBehaviorBloodBrainBrain DiseasesCadaverCandidate Disease GeneCell LineageCell SizeCell divisionCellsChemicalsChildhoodClinicalComplexCortical DysplasiaDNADNA MethylationDNA RepairDNA Sequence AlterationDataDatabasesDetectionDevelopmentDevelopmental ProcessDiseaseDysplasiaElectroencephalographyElectroporationEmbryoEmbryonic DevelopmentEvaluationExcisionExposure toFRAP1 geneFreezingFrequenciesFunctional disorderFundingGeneticGenetic VariationGenomicsGenotypeGoalsGrowthHumanIndividualIntractable EpilepsyInvestmentsKnowledgeLifeMapsMetabolic stressMethodsMicrogliaMinorityModelingMosaicismMusMutationNeuronsNuclearOligodendrogliaOperative Surgical ProceduresOrganismOutcomePathogenicityPathway interactionsPatientsPatternPharmacologyPhenotypePlayPredispositionRecording of previous eventsResectedRoleSamplingShapesSignal TransductionSomatic CellSomatic MutationSorting - Cell MovementSynapsesTestingTissuesVariantWorkbrain cellbrain circuitrycell typeclinically significantcohortdaughter celldeep sequencingdemethylationdisabilitygene functiongenome sequencinggenomic variationhuman modelin uterointerestloss of functionmTOR Inhibitormigrationmouse modelmutantneocorticalneurogenesisneuron developmentneuronal circuitryneuropsychiatric disorderneuropsychiatrynovelrecruitrelating to nervous systemresilienceresponsesuccesssynaptic function
项目摘要
Abstract
Brain somatic mosaicism (BSM) refers to the accumulation of mutations within any of the billions of cells in
the human brain, which can occur from embryogenesis through adulthood. The extent, impact and
mechanisms of BSM on brain disease remain poorly understood. Prior work from the Brain Somatic
Mosaicism Network (BSMN), on which the PI served, made critical breakthroughs in reliability of mosaicism
detection, but also raised new questions, including the degree to which BSM exists in the healthy brain, and
the mechanisms by which BSM mutations explain disease.
Focal cortical dysplasia (FCD) is associated with substantial neuropsychiatric disability, and is the
most common cause of intractable epilepsy in childhood. Neuropsychiatric features are seen in 15-59% of
patients 5-7, and neuropathologically shows disrupted neurogenesis, migration, differentiation, and altered
neural excitability. We and others previously identified mosaic mutations in the mTOR pathway in a minority
of FCD cases, but most cases remain unsolved, and fundamental mechanisms are lacking.
We hypothesize that: 1] FCD mutations are similar to neutral somatic mutations in their patterns and
distributions, dictated by developmental processes, but differ in their functional effect. 2] BSM patterns, allelic
fractions (AFs) and allele sharing between cells can reconstruct cellular lineages and migratory histories. 3]
Study of FCD resected tissue can uncover novel causes of disease that would not be tolerated if present in
every cell. 4] BSM modeling in mouse can unravel disrupted signaling networks of complex mosaic mutations.
Our preliminary data shows: 1] From a post-mortem control cadaver, we validated 259 somatic
variants using 300X genome sequencing, and started to use these variants as ‘barcodes’ to reconstruct
lineage histories. 2] Deep sequencing from 314 FCD patient brain resections identified 12 new candidate
genes, highlighting signaling and synaptic dysfunction, and a novel ‘two-hit’ disease mechanisms. 3] We
established in utero mouse electroporation models to assess putative FCD variants as gain or loss of function,
and to assess effects of ‘single-hit’ and ‘two-hit’ mutations.
We propose three aims: 1] From control cadavers, we will reconstruct cell lineage across anatomical
domains using BSM as barcodes. 2] With this lineage information, we will study the origins of BSM
mutations in FCD, by recruiting new patients, performing both targeted and unbiased sequencing, and
identifying novel causes. 3] We will functionally validate putative deleterious alleles in animal models for
both ‘single-hit’ and ‘two-hit’ causes. The goal is to achieve a mechanistic understanding of the
extent of BSM in control individuals, to reconstruct neural lineages and to identify novel mechanisms in
developmental brain disease.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOSEPH G GLEESON其他文献
JOSEPH G GLEESON的其他文献
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{{ truncateString('JOSEPH G GLEESON', 18)}}的其他基金
University of California San Diego Neuroscience Microscopy Imaging Core
加州大学圣地亚哥分校神经科学显微成像核心
- 批准号:
10524688 - 财政年份:2021
- 资助金额:
$ 31.25万 - 项目类别:
Origins of Brain Somatic Mosaicism in Developmental Brain Disease
发育性脑疾病中脑体细胞嵌合的起源
- 批准号:
10299502 - 财政年份:2021
- 资助金额:
$ 31.25万 - 项目类别:
Origins of Brain Somatic Mosaicism in Developmental Brain Disease
发育性脑疾病中脑体细胞嵌合的起源
- 批准号:
10669715 - 财政年份:2021
- 资助金额:
$ 31.25万 - 项目类别:
Project I - Human genetics of meningomyelocele and risk mitigation by folic acid
项目 I - 脑膜脊髓膨出的人类遗传学和叶酸降低风险
- 批准号:
10300070 - 财政年份:2020
- 资助金额:
$ 31.25万 - 项目类别:
Developmental Mechanisms of Human Meningomyelocele
人类脑膜脊髓膨出的发生机制
- 批准号:
10533735 - 财政年份:2020
- 资助金额:
$ 31.25万 - 项目类别:
Developmental Mechanisms of Human Meningomyelocele
人类脑膜脊髓膨出的发生机制
- 批准号:
10300066 - 财政年份:2020
- 资助金额:
$ 31.25万 - 项目类别:
Developmental Mechanisms of Human Meningomyelocele
人类脑膜脊髓膨出的发生机制
- 批准号:
10154461 - 财政年份:2020
- 资助金额:
$ 31.25万 - 项目类别:
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