Developmental Mechanisms of Human Meningomyelocele
人类脑膜脊髓膨出的发生机制
基本信息
- 批准号:10300066
- 负责人:
- 金额:$ 139.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-12-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAllelesAmericanAnimal ModelAttentionBioinformaticsBrain StemCandidate Disease GeneChildChromatinClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsCommunicationCommunitiesCongenital AbnormalityCountryCustomDNADNA MethylationDNA Sequence AlterationDNA Sequencing FacilityDataDefectDevelopmentDiagnosisDietary SupplementationDiseaseEmbryoEnsureFamilyFolic AcidGenesGeneticGenetic EngineeringGenetic TranscriptionGenotypeGeographyGoalsHeritabilityHumanHydrocephalusIncidenceInheritedInternationalKnock-inKnock-outKnowledgeLearning DisabilitiesLifeLive BirthMeasuresMeningomyeloceleModelingMolecularMolecular GeneticsMonitorMorbidity - disease rateMusMutateMutationNetwork-basedNeural Tube ClosureNeural Tube DefectsNeuraxisOutcomePatientsPenetrancePhenotypePopulationProteinsProtocols documentationRanaRecurrenceResearchResearch PersonnelRiskRisk FactorsRoleRunningSecureSeizuresSourceSpinal DysraphismStructural Congenital AnomaliesTechnologyUnited States National Institutes of HealthVariantWorkXenopusXenopus laeviscohortcomputerized data processingcomputerized toolscost estimatedata harmonizationdata qualityde novo mutationdesigndietarydisabilitydisease mechanisms studydisorder preventiondisorder riskepigenomeepigenomicsexomefolic acid supplementationfortificationgene environment interactiongene interactiongenome sequencinghuman modelimprovedinclusion criteriainterestmortalitymutantneuromechanismnext generation sequencingprogramsrecruitrelating to nervous systemrisk variantsocial mediatooltranscriptomewhole genome
项目摘要
Project Summary – Overall: Developmental Mechanisms of Human Meningomyelocele
The central goal of this Program Project application is to understand mechanisms of Meningomyelocele (MM),
the most severe neural tube defect (NTD) compatible with survival, a condition in which folic acid (FA)
fortification has had a major impact on disease risk. This PPG is designed to advance biomedical knowledge
and make a high impact on our understanding of the molecular genetics of MM across the evolutionary scale,
with the purpose of advancing our ability to determine disease risk, and establish mechanisms by which FA
alters risk. MM is the most common birth defect of the central nervous system, affecting 3.7 per 10,000 live
births, and is one of the high impact conditions prioritized by the NIH for research. In our preliminary data we
have: 1] Constructed a cohort of over 1500 human trios with MM, stratified by whether the child was
conceived in a FA-supplemented geography. 2] Established Xenopus laevis as a high-throughput model
to assess human mutant alleles, gene-gene interactions, and FA exposure. 3] Established a number of
murine NTD models with measured effect of FA on penetrance and expressivity. 4] Demonstrated a proven
track record of applying these tools to study mechanisms of disease. As a result of the extensive preliminary
data presented below, we have formulated this PPG with a two-fold thrust: 1] By taking advantage of the
technical revolution in next generation sequencing and CRISPR genetic engineering, we will uncover and
functionally assess new MM risk factors. 2] By comparing phenotypes across the evolutionary timescale, we
will enhance our understanding of the basic mechanisms of NTDs and the impact of FA. The central theme
running throughout the application is Gene-Environment Interaction (GXE), because of the important role
FA has on MM risk in human, mouse and frog, and because the theme applies to all three Projects and Cores.
Three Cores will carry out essential functions and benefit each Project. 1] Administrative Core to facilitate
communication and provide opportunities for scientific collaboration. 2] Epigenomics Sequencing Core to
provide essential functions in assessing FA-dependent DNA methylation and other impacts on chromatin and
transcription. 3] Bioinformatics Core to provide essential functions in data processing and harmonization,
mutation identification, and custom computational solutions.
Specific Aims of the PPG are: 1] To uncover a host of new developmental causes of MM from this unique
human cohort, as well as from mouse and frog models. 2] To explore mechanisms by which FA reduces
disease incidence in human, mouse and frog. 3] To utilize mechanisms uncovered in mouse and frog NTD
models to inform gene prioritization in human MM. We believe that this PPG will have a major impact on our
understanding of the cellular and molecular mechanisms underlying NTDs, taking advantage of new
breakthrough technology, and will set the stage for improved diagnosis and ultimately prevention of disease.
项目总结--总体:人类脑膜脊膜膨出的发育机制
本计划项目申请的中心目标是了解脑膜脊髓膨出(MM)的发病机制,
与存活相容的最严重的神经管缺陷(NTD),叶酸(FA)
防御工事对疾病风险产生了重大影响。这个PPG旨在提高生物医学知识
并对我们从进化尺度上理解MM的分子遗传学产生了很大的影响,
目的是提高我们确定疾病风险的能力,并建立FA
改变风险。多发性骨髓瘤是最常见的中枢神经系统出生缺陷,每10,000人中有3.7人患有多发性骨髓瘤
出生,是NIH优先进行研究的高影响条件之一。在我们的初步数据中,我们
有:1]构建了一个由1500多名患有MM的人类三人组组成的队列,根据儿童是否患有MM进行分层
在FA补充的地理位置上构思。2]建立了非洲爪哇的高通量模型
评估人类突变等位基因、基因-基因相互作用和FA暴露。3]建立了多个
测量FA对外显率和表现力的影响的小鼠NTD模型。4]展示了经过验证的
应用这些工具研究疾病机制的记录。由于广泛的初步调查
下面提供的数据,我们已经制定了这一PPG的两个推力:1]通过利用
下一代测序和CRISPR基因工程的技术革命,我们将揭示和
从功能上评估新的多发性骨髓瘤风险因素。2]通过比较进化时间范围内的表型,我们发现
将增进我们对非关税壁垒的基本机制和FA的影响的了解。中心主题
贯穿整个应用程序的是基因-环境相互作用(GxE),因为它具有重要的作用
FA对人类、老鼠和青蛙的MM风险有影响,因为这一主题适用于所有三个项目和核心。
三个核心将履行基本职能并使每个项目受益。1]行政核心以促进
并为科学合作提供机会。2]表观基因组测序核心至
在评估依赖FA的DNA甲基化和其他对染色质和
抄写。3]生物信息学核心在数据处理和协调方面提供基本功能,
突变识别和定制计算解决方案。
PPG的具体目标是:1]从这一独特的疾病中揭示MM的一系列新的发展原因
人类队列,以及来自老鼠和青蛙模型的。2]探索FA减少的机制
人类、小鼠和青蛙的发病率。3]利用在小鼠和青蛙NTD中发现的机制
人类MM基因优先顺序的模型。我们相信这种PPG将对我们的
了解NTDS的细胞和分子机制,利用新的
这是一项突破性的技术,将为改进诊断和最终预防疾病奠定基础。
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
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:
10466904 - 财政年份:2021
- 资助金额:
$ 139.06万 - 项目类别:
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:
$ 139.06万 - 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:
$ 139.06万 - 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:
$ 139.06万 - 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:
$ 139.06万 - 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:
$ 139.06万 - 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:
$ 139.06万 - 项目类别:
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