Epigenetic mechanisms of disrupted neurodevelopment in Menke-Hennekam syndrome
Menke-Hennekam 综合征神经发育障碍的表观遗传机制
基本信息
- 批准号:10816703
- 负责人:
- 金额:$ 16.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-15 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcetylationAddressAstrocytesAutomobile DrivingBehaviorBioinformaticsBiological AssayBrainBrain DiseasesCREBBP geneCalcium SignalingCell LineChIP-seqCharacteristicsChromatin Remodeling FactorCollaborationsDataDefectDendritesDevelopmentDiagnosisDiseaseDisease modelEP300 geneEctodermEnhancersEpigenetic ProcessExonsFDA approvedFaceFoundationsFrequenciesFutureGene ExpressionGenesGlutamatesHennekam syndromeHeterochromatinHeterozygoteHistone AcetylationHumanIndividualIntellectual functioning disabilityKnowledgeLeftLengthMeasuresMediatingMethodsMicrocephalyMicrogliaMissense MutationModelingMolecularMolecular TargetMutateMutationNeocortexNerve DegenerationNervous SystemNeurogliaNeurologicNeuronal DifferentiationNeuronsOrganPathway interactionsPatientsPharmaceutical PreparationsPhenotypePilot ProjectsPlayPopulationPrefrontal CortexProteinsRNARadialReportingResearchRoleSeizuresSignal TransductionSolidSpecificitySymptomsSynapsesTechnical ExpertiseTestingTimeTranscription CoactivatorVariantVertebral columnWorkautism spectrum disordercell typecomparison controlcraniofacialdirected differentiationdruggable targetepigenetic regulationepigenomicsexcitatory neurongene networkhistone acetyltransferasehuman pluripotent stem cellinduced pluripotent stem cellinterestmalformation in cortical developmentneocorticalnerve stem cellnervous system disorderneurodevelopmentneuroinflammationneuron lossparalogous genepostsynapticpresynapticpromoterpublic health relevancerepetitive behaviorstemstem cell differentiationsynaptogenesis
项目摘要
Project Summary
Heterozygous variants in EP300, a histone acetyltransferase, cause two rare multi-organ chromatinopathies:
Menke-Hennekam syndromes type 2 (MKHK2; MIM618333, specifically mutations in exon 30-31) and
Rubinstein-Taybi type 2 (RSTS2; MIM613684). Interestingly, based on “inverse” patient craniofacial
characteristics with RSTS and the alignment of MKHK2 facial features with another disorder with duplicated
regions of CREBBP (EP300's paralog), authors have proposed mutations causing MKHK and RSTS have
potentially different functions (i.e., gain [GOF] versus loss [LOF], respectively).1,2 In addition, individuals with
MKHK2 have overlapping manifestations with disorders with malformations in cortical development (MCD),
such as microencephaly, seizures, intellectual disability, repetitive behaviors, and increased rates of co-diagnoses
with autism spectrum disorder, demonstrating a potential role in cortical neuron function.3 While the specialized
exon 30-31 missense mutations found in MKHK2 have yet to be modeled, RSTS2 LOF models have yielded
phenotypic changes of shorter branches and hypo-excitability. However, the RSTS2 LOF bulk neuronal
bioinformatical analyses contained contaminating cell types with differential regional specificity, therefore,
EP300 specific gene network/pathways are uninterpretable. Together this demonstrates a critical need to
understand EP300's role in maturation and function of cortical excitatory neurons before treatment of MKHK2
neurological issues can be tackled. We hypothesize that MKHK2 EP300 mutation causes accelerated
maturation rate, decreased dendrite formation, and altered neuronal function.
This proposal is a collaboration between Drs. Potter and Barski who specialize in epigenomics and Dr. Tchieu, a
developmental biologist who developed methods for human induced pluripotent stem cell (hPSC) differentiation
into nervous system cell types. In this study, we will use this approach to differentiate MKHK2 mutated EP300
and corresponding isogenic control hPSCs into radial glia-like neural stem cells and PFC excitatory neurons in
order to: (1) identify MKHK2-related defects in neuronal maturation and signaling and (2) to identify epigenetic
and gene expression changes driving them.
This pilot project will provide a solid foundation for the study of the mechanism(s) behind neurocortical
developmental defects in MKHK2 and allow identification of molecular targets for potential therapies for
MKHK2 seizures and other related MCD-like symptoms. Further, we can apply knowledge and technical
expertise gained from this project to other epigenetic proteins to further expand our knowledge of epigenetic
regulation during corticogenesis, specifically neuronal maturation and signaling allowing for a broader impact
on the treatment of MCD, neurodegenerative, neurodevelopment, and neuroinflammatory disorders.
项目摘要
EP 300(一种组蛋白乙酰转移酶)的杂合变体会导致两种罕见的多器官染色质病:
Menke-Hennekam综合征2型(MKHK 2; MIM 618333,特别是外显子30-31突变)和
Rubinstein-Taybi 2型(RSTS 2; MIM 613684)。有趣的是,基于“反向”患者颅面
RSTS的特征以及MKHK 2面部特征与另一种具有重复的
CREBBP区域(EP 300的Parkinson),作者提出了导致MKHK和RSTS的突变,
可能不同的功能(即,分别获得[GOF]和损失[LOF])。1,2此外,
MKHK 2与具有皮质发育畸形(MCD)的病症具有重叠的表现,
例如,小脑畸形、癫痫发作、智力残疾、重复行为和合并诊断率增加
自闭症谱系障碍,表现出在皮层神经元功能的潜在作用。
在MKHK 2中发现的外显子30-31错义突变尚未建模,RSTS 2 LOF模型已经产生了
短枝和低兴奋性的表型变化。然而,RSTS 2 LOF大块神经元
生物信息学分析包含具有不同区域特异性的污染细胞类型,因此,
EP 300特异性基因网络/通路无法解释。这一切表明,迫切需要
在MKHK 2治疗前了解EP 300在皮层兴奋性神经元成熟和功能中的作用
神经系统的问题是可以解决的。我们假设MKHK 2 EP 300突变导致加速
成熟率降低、树突形成减少和神经元功能改变。
这项提议是波特博士和巴斯基博士与Tchieu博士的合作,他们专门研究表观基因组学,
开发人类诱导多能干细胞(hPSC)分化方法的发育生物学家
神经系统细胞类型。在本研究中,我们将使用这种方法来区分MKHK 2突变的EP 300,
和相应的同基因对照hPSC转化为放射状胶质样神经干细胞和PFC兴奋性神经元。
目的:(1)鉴定神经元成熟和信号传导中的MKHK 2相关缺陷,以及(2)鉴定表观遗传缺陷。
基因表达的变化来驱动它们。
本实验项目将为研究神经皮层的机制提供坚实的基础
MKHK 2的发育缺陷,并允许鉴定用于潜在治疗的分子靶点,
MKHK 2癫痫发作和其他相关的MCD样症状。此外,我们可以应用知识和技术
从该项目中获得的专业知识用于其他表观遗传蛋白质,以进一步扩展我们对表观遗传蛋白质的了解。
在皮质生成过程中的调节,特别是神经元成熟和信号传导,允许更广泛的影响
治疗MCD、神经退行性疾病、神经发育和神经炎性疾病。
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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Artem Barski其他文献
Artem Barski的其他文献
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{{ truncateString('Artem Barski', 18)}}的其他基金
An experimentally-refined, dynamic gene regulatory network model of T-cell memory
经过实验改进的 T 细胞记忆动态基因调控网络模型
- 批准号:
10576265 - 财政年份:2021
- 资助金额:
$ 16.05万 - 项目类别:
An experimentally-refined, dynamic gene regulatory network model of T-cell memory
经过实验改进的 T 细胞记忆动态基因调控网络模型
- 批准号:
10210685 - 财政年份:2021
- 资助金额:
$ 16.05万 - 项目类别:
Commercialization of SciDAP, a next generation universal platform for collaborative data analysis
SciDAP 的商业化,下一代协作数据分析通用平台
- 批准号:
10338010 - 财政年份:2021
- 资助金额:
$ 16.05万 - 项目类别:
An experimentally-refined, dynamic gene regulatory network model of T-cell memory
经过实验改进的 T 细胞记忆动态基因调控网络模型
- 批准号:
10368121 - 财政年份:2021
- 资助金额:
$ 16.05万 - 项目类别:
An experimentally-refined, dynamic gene regulatory network model of T-cell memory
经过实验改进的 T 细胞记忆动态基因调控网络模型
- 批准号:
10213550 - 财政年份:2020
- 资助金额:
$ 16.05万 - 项目类别:
Death-Seq, a Method for Genome-wide Identification of Functional Silencer Elements
Death-Seq,一种全基因组识别功能性沉默元件的方法
- 批准号:
9979291 - 财政年份:2020
- 资助金额:
$ 16.05万 - 项目类别:
SciDAP: a next generation universal platform for collaborative data analysis
SciDAP:下一代协作数据分析通用平台
- 批准号:
10081764 - 财政年份:2020
- 资助金额:
$ 16.05万 - 项目类别:
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