Epigenetic Markers in Huntington's disease Brain
亨廷顿病大脑中的表观遗传标记
基本信息
- 批准号:9119217
- 负责人:
- 金额:$ 2.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2017-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAge of OnsetAppearanceBiological MarkersBloodBlood CellsBlood specimenBrainCAG repeatCD4 Positive T LymphocytesCell NucleusCerebral cortexCerebrumCessation of lifeChIP-seqChoreaClinical TrialsComplementComputing MethodologiesCorpus striatum structureDataDiagnosisDiffuseDiseaseDisease ProgressionDrug EvaluationEpigenetic ProcessExonsGene ExpressionGene Expression ProfileGenesGeneticGenetic TranscriptionGenome MappingsGenomicsGlutamatesGoalsHereditary DiseaseHistone H3HistonesHumanHuntington DiseaseImpaired cognitionInvestigationLymphocyteLysineMapsMeasuresMemory LossMessenger RNAMethodsMethylationModelingMolecularMolecular TargetMovementMutationNeurodegenerative DisordersNeuronsNuclear InclusionOutcome StudyPathogenesisPathologyPathway interactionsPatientsPatternPharmaceutical PreparationsPrefrontal CortexProcessResearchResourcesRoleSNP genotypingSamplingSignal TransductionSiteSorting - Cell MovementStagingSynapsesSystemTechniquesTechnologyTissuesTranscription Initiation SiteTrinucleotide Repeat ExpansionUbiquitinbrain cellcognitive skillcomparativedensitydisorder controlepigenetic markerexcitotoxicitygain of functiongenome wide association studygenome-widegenome-wide analysishistone methylationhistone modificationhuman Huntingtin proteininsightmethylation biomarkermethylomemind controlmulticatalytic endopeptidase complexmutantneuron lossnovelpromotertransmission process
项目摘要
DESCRIPTION (provided by applicant): Huntington's disease (HD) is a fatal, autosomal dominant neurodegenerative disorder caused by an expanded CAG tract in the HD gene that results in gradual loss of memory, cognitive skills and normal movements. Multiple lines of research point to dysregulated transcription as a prevailing feature of HD pathology and suggest that altered histone modification by the mutant protein (Htt) may contribute to this process. However, thus far there has been no genome-wide analysis of histone modifications in human HD brain. The studies proposed here apply novel genomic technology to the search for epigenetic signatures in HD brains with the goal of gaining insight into HD pathogenesis. Our proposal capitalizes on two unique resources: (1) a novel FACS-ChIP-seq method which we will apply to establish and compare the methylomes of neurons from HD and control brains; and (2) a unique sample of HD brains, including a set matched for CAG repeat expansion (range 42-44 repeats) but onset ages differing by 30 years or more. The brains have been extensively neuropathologically characterized for degree of both striatal and cortical involvement. Since we found that histone H3 methylation markings in HD brains overlap highly with the signal in CD4+ cells, we are also comparing the altered epigenetic signature seen in HD brain to that in blood samples at varying stages of disease (presymptomatic, early and advanced HD) as this may offer a novel epigenetic biomarker in HD blood. Such biomarkers are of translational significance for the evaluation of drug treatments to realign the disrupted gene expression. We have preliminary data using the FACS-ChIP-Seq method in six HD prefrontal cortex samples and eleven normal controls, which provides tantalizing evidence for the significance of the proposed studies and demonstrates our capabilities to apply the techniques and to meaningfully interpret the findings. Our approach represents the most comprehensive analysis to date addressing the role of histone methylation in HD pathogenesis. Regardless of outcome, these studies will provide critical new insights into the molecular pathways of HD pathogenesis and may also uncover novel molecular targets for HD treatment. The high translational impact of this proposal is increased by our proposal to identify and characterize a unique histone methylation biomarker in HD blood cells. If successful, identification of such a biomarker will greatly facilitate clinical trials for novel HD therapies and offers a novel method to evaluate whether new drug treatments rectify disrupted gene expression.
描述(由申请人提供):亨廷顿病 (HD) 是一种致命的常染色体显性神经退行性疾病,由 HD 基因中的 CAG 束扩张引起,导致记忆力、认知能力和正常运动逐渐丧失。多项研究表明转录失调是 HD 病理学的一个普遍特征,并表明突变蛋白 (Htt) 改变的组蛋白修饰可能有助于这一过程。然而,迄今为止,还没有对人类 HD 大脑中组蛋白修饰进行全基因组分析。这里提出的研究应用新颖的基因组技术来寻找 HD 大脑的表观遗传特征,目的是深入了解 HD 发病机制。我们的提案利用了两个独特的资源:(1)一种新颖的 FACS-ChIP-seq 方法,我们将应用该方法来建立和比较来自 HD 和对照大脑的神经元的甲基化组; (2) HD 大脑的独特样本,包括一组与 CAG 重复扩展(范围 42-44 次重复)匹配的组,但发病年龄相差 30 年或更长时间。大脑的纹状体和皮质受累程度已得到广泛的神经病理学特征。由于我们发现 HD 大脑中的组蛋白 H3 甲基化标记与 CD4+ 细胞中的信号高度重叠,因此我们还将 HD 大脑中观察到的改变的表观遗传特征与不同疾病阶段(症状前、早期和晚期 HD)的血液样本中的表观遗传特征进行比较,因为这可能为 HD 血液中提供一种新的表观遗传生物标志物。这些生物标志物对于评估药物治疗以重新调整破坏的基因表达具有转化意义。我们在六个 HD 前额皮质样本和 11 个正常对照中使用 FACS-ChIP-Seq 方法获得了初步数据,这为拟议研究的重要性提供了诱人的证据,并证明了我们应用这些技术和有意义地解释研究结果的能力。 我们的方法代表了迄今为止针对组蛋白甲基化在 HD 发病机制中的作用的最全面的分析。无论结果如何,这些研究都将为 HD 发病机制的分子途径提供重要的新见解,并可能揭示 HD 治疗的新分子靶点。我们提出的鉴定和表征 HD 血细胞中独特的组蛋白甲基化生物标志物的建议增加了该建议的高转化影响。如果成功,这种生物标志物的鉴定将极大地促进新的 HD 疗法的临床试验,并提供一种新的方法来评估新的药物治疗是否可以纠正破坏的基因表达。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Novel microRNA discovery using small RNA sequencing in post-mortem human brain.
- DOI:10.1186/s12864-016-3114-3
- 发表时间:2016-10-04
- 期刊:
- 影响因子:4.4
- 作者:Wake C;Labadorf A;Dumitriu A;Hoss AG;Bregu J;Albrecht KH;DeStefano AL;Myers RH
- 通讯作者:Myers RH
microRNA Profiles in Parkinson's Disease Prefrontal Cortex.
- DOI:10.3389/fnagi.2016.00036
- 发表时间:2016
- 期刊:
- 影响因子:4.8
- 作者:Hoss AG;Labadorf A;Beach TG;Latourelle JC;Myers RH
- 通讯作者:Myers RH
Study of plasma-derived miRNAs mimic differences in Huntington's disease brain.
- DOI:10.1002/mds.26457
- 发表时间:2015-12
- 期刊:
- 影响因子:0
- 作者:Hoss AG;Lagomarsino VN;Frank S;Hadzi TC;Myers RH;Latourelle JC
- 通讯作者:Latourelle JC
Evidence of Extensive Alternative Splicing in Post Mortem Human Brain HTT Transcription by mRNA Sequencing.
- DOI:10.1371/journal.pone.0141298
- 发表时间:2015
- 期刊:
- 影响因子:3.7
- 作者:Labadorf AT;Myers RH
- 通讯作者:Myers RH
Feasibility of Huntington disease trials in the disease prodrome.
亨廷顿病试验在疾病前驱症状中的可行性。
- DOI:10.1212/wnl.0000000000000197
- 发表时间:2014
- 期刊:
- 影响因子:9.9
- 作者:McCusker,ElizabethA;Myers,RichardH
- 通讯作者:Myers,RichardH
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RICHARD H MYERS其他文献
RICHARD H MYERS的其他文献
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{{ truncateString('RICHARD H MYERS', 18)}}的其他基金
Characterization of the role of cyclin G-associated kinase in Parkinson disease
细胞周期蛋白 G 相关激酶在帕金森病中作用的表征
- 批准号:
8219844 - 财政年份:2011
- 资助金额:
$ 2.31万 - 项目类别:
Characterization of the role of cyclin G-associated kinase in Parkinson disease
细胞周期蛋白 G 相关激酶在帕金森病中作用的表征
- 批准号:
8462710 - 财政年份:2011
- 资助金额:
$ 2.31万 - 项目类别:
Epigenetic Markers in Huntington's disease Brain
亨廷顿病大脑中的表观遗传标记
- 批准号:
8842207 - 财政年份:2011
- 资助金额:
$ 2.31万 - 项目类别:
Epigenetic Markers in Huntington's disease Brain
亨廷顿病大脑中的表观遗传标记
- 批准号:
8085037 - 财政年份:2011
- 资助金额:
$ 2.31万 - 项目类别:
Epigenetic Markers in Huntington's disease Brain
亨廷顿病大脑中的表观遗传标记
- 批准号:
8291969 - 财政年份:2011
- 资助金额:
$ 2.31万 - 项目类别:
Characterization of the role of cyclin G-associated kinase in Parkinson disease
细胞周期蛋白 G 相关激酶在帕金森病中作用的表征
- 批准号:
8320241 - 财政年份:2011
- 资助金额:
$ 2.31万 - 项目类别:
Epigenetic Markers in Huntington's disease Brain
亨廷顿病大脑中的表观遗传标记
- 批准号:
8462706 - 财政年份:2011
- 资助金额:
$ 2.31万 - 项目类别:
Epidemiological and Genetic Studies of Body Mass Index
体重指数的流行病学和遗传学研究
- 批准号:
6421942 - 财政年份:2001
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$ 2.31万 - 项目类别:
Epidemiological and Genetic Studies of Body Mass Index
体重指数的流行病学和遗传学研究
- 批准号:
7176190 - 财政年份:2001
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$ 2.31万 - 项目类别:
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