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):亨廷顿舞蹈病(HD)是一种致命的常染色体显性神经退行性疾病,由亨廷顿舞蹈病基因CAG束扩大引起,导致记忆、认知技能和正常运动逐渐丧失。多项研究表明,转录失调是HD病理的一个普遍特征,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,到目前为止,还没有对人类HD大脑的组蛋白修饰进行全基因组分析。本文提出的研究应用新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的发病机制。我们的提案利用了两个独特的资源:(1)一种新的FACS-ChIP-seq方法,我们将应用于建立和比较来自HD和对照大脑的神经元甲基化组;(2)一组独特的HD大脑样本,包括一组与CAG重复扩增(42-44个重复)相匹配的样本,但发病年龄相差30岁或更久。大脑的纹状体和皮层受累程度已被广泛的神经病理学表征。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,我们也将HD大脑中观察到的改变的表观遗传特征与疾病不同阶段(症状前、早期和晚期HD)血液样本中的表观遗传特征进行了比较,因为这可能在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被破坏的基因表达具有翻译意义。我们使用FACS-ChIP-Seq方法在6个HD前额叶皮层样本和11个正常对照中获得了初步数据,这为提出的研究的重要性提供了诱人的证据,并证明了我们应用该技术并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最全面的分析,解决了组蛋白甲基化在HD发病机制中的作用。无论结果如何,这些研究将为HD发病机制的分子途径提供重要的新见解,也可能揭示HD治疗的新分子靶点。我们提出在HD血细胞中鉴定和表征一种独特的组蛋白甲基化生物标志物,从而增加了该建议的高翻译影响。如果成功,这种生物标志物的鉴定将极大地促进新型HD治疗的临床试验,并提供一种新的方法来评估新药治疗是否能纠正基因表达紊乱。
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
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
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
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
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
RICHARD H MYERS其他文献
RICHARD H MYERS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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
- 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:
7176190 - 财政年份:2001
- 资助金额:
$ 2.31万 - 项目类别:
相似海外基金
Determining the mechanism of action of cis-acting modifiers on the age of onset of Huntington Disease
确定顺式作用修饰剂对亨廷顿病发病年龄的作用机制
- 批准号:
417256 - 财政年份:2019
- 资助金额:
$ 2.31万 - 项目类别:
Studentship Programs
Effect of age of onset of contraception use on brain functioning.
避孕开始年龄对大脑功能的影响。
- 批准号:
511267-2017 - 财政年份:2017
- 资助金额:
$ 2.31万 - 项目类别:
University Undergraduate Student Research Awards
Non-random occurrence and early age of onset of diverse lymphoid cancers in families supports the existence of genetic risk factors for multiple lymphoid cancers.
家族中多种淋巴癌的非随机发生和发病年龄较早,支持多种淋巴癌存在遗传危险因素。
- 批准号:
347105 - 财政年份:2016
- 资助金额:
$ 2.31万 - 项目类别:
Polish-German Child Bilingualism: The Role of Age of Onset for Long-Term Achievement
波兰-德国儿童双语:发病年龄对长期成就的作用
- 批准号:
277135691 - 财政年份:2015
- 资助金额:
$ 2.31万 - 项目类别:
Research Grants
Bioinformatics strategies to relate age of onset with gene-gene interaction
将发病年龄与基因间相互作用联系起来的生物信息学策略
- 批准号:
9097781 - 财政年份:2015
- 资助金额:
$ 2.31万 - 项目类别:
Early Age-of-Onset AD: Clinical Heterogeneity and Network Degeneration
早期 AD 发病年龄:临床异质性和网络退化
- 批准号:
9212684 - 财政年份:2014
- 资助金额:
$ 2.31万 - 项目类别:
Early Age-of-Onset AD: Clinical Heterogeneity and Network Degeneration
早期 AD 发病年龄:临床异质性和网络退化
- 批准号:
8696557 - 财政年份:2014
- 资助金额:
$ 2.31万 - 项目类别:
Effects of delaying age of onset of binge drinking on adolescent brain development: A proposal to add neuroimaing measures to the CO-Venture Trial.
延迟酗酒的发病年龄对青少年大脑发育的影响:在 CO-Venture 试验中添加神经影像测量的建议。
- 批准号:
267251 - 财政年份:2012
- 资助金额:
$ 2.31万 - 项目类别:
Operating Grants
Stress Effects on Alcohol Consumption: Age of onset and genes in heavy drinkers
压力对饮酒的影响:酗酒者的发病年龄和基因
- 批准号:
8606722 - 财政年份:2012
- 资助金额:
$ 2.31万 - 项目类别:
Marijuana: Neurobiologic Correlates of Age of Onset
大麻:发病年龄的神经生物学相关性
- 批准号:
8644793 - 财政年份:2012
- 资助金额:
$ 2.31万 - 项目类别: