Functional characterization of an enhancer RNA in cerebral ischemia
增强子 RNA 在脑缺血中的功能表征
基本信息
- 批准号:10472073
- 负责人:
- 金额:$ 37.38万
- 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:2021-09-25 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAcuteAdultAffectBindingBinding SitesBiologicalBiological AssayBrainBrain InjuriesBudgetsCell AdhesionCell CycleCell DeathCerebral IschemiaCerebral cortexChIP-seqChromatinCyclic AMPDNADNA Polymerase IIDataDevelopmentDiseaseDown-RegulationEnhancersEstrogensExtracellular MatrixFemaleFluorescent in Situ HybridizationFunctional disorderFutureGene ExpressionGene Expression RegulationGene ProteinsGenesGenetic Enhancer ElementGenetic TranscriptionGenomicsHistonesImmunoprecipitationInfarctionInvestigationIschemiaIschemic StrokeLysineMapsMediatingMethodsMiddle Cerebral Artery OcclusionMolecularMolecular TargetMusNeurologicNeuronsOutcomePathologicPathway interactionsPhasePhenotypePhysiologicalPlayProteinsRNARegulator GenesReperfusion TherapyReporterReportingRoleRunningSensorimotor functionsSignal TransductionStimulusStrokeStructureTP53 geneTestingTherapeuticTimeTranscriptTranslationsUbiquitinationUntranslated RNAWestern BlottingWorkbaseblood-brain barrier disruptioncdc Genescell typecrosslinkendoplasmic reticulum stressexperimental studygenome-widegenomic locusimprovedin vivoknock-downloss of functionmacrophagemalenew therapeutic targetnovelpost strokeprogramsresponsesexstroke outcometranscription factortranscriptome sequencingvirtual
项目摘要
Recent studies have reported widespread transcription of mammalian enhancers into noncoding RNA
transcripts in a stimulus-dependent manner. Growing evidence shows that these enhancer RNAs (eRNAs)
have essential roles in orchestrating higher-order chromatin interactions to facilitate gene expression and
phenotypic outcomes during development and disease. As a result, eRNAs are emerging as an important
component of the gene regulatory machinery. Due to their very recent discovery, the expression and roles of
eRNAs in stroke is virtually unknown. Recently, we applied a combination of genome-wide RNA-seq and
genome-wide enhancer mapping using ChIP-seq to identify a number of stroke-induced eRNAs at multiple
time-points of reperfusion in the mouse cerebral cortex. Our preliminary data confirmed enhancer activity of the
genomic loci encoding the eRNAs, showed that the eRNAs are localized to the chromatin, and revealed an
important role for one such eRNA in modulating post-stroke brain damage and gene expression. The
molecular interactions, functional mechanisms and sex-dependent effects of eRNAs on the post-stroke
pathophysiology are unexplored. In the current project, we build upon our preliminary data to evaluate eRNA
functionality in-depth during stroke in the adult mouse cortex. Specific Aim 1 will use a combination of
crosslinking-immunoprecipitation, fluorescence in situ hybridization and transcriptional-state analysis to
determine the molecular targets of the eRNAs as a function of post-stroke reperfusion time in the mouse
cortex. Specific Aim 2 will employ eRNA loss-of-function in vivo followed by cellular, physiological, pathological
and neurological analyses to evaluate the role of the eRNA in propagating the post-stroke pathophysiology.
Specific Aim 3 will evaluate the molecular targets and pathophysiological effects of the eRNA in the female
mouse cortex. Together, this work will illuminate the significance of eRNAs in the cerebral cortex and may
reveal novel gene regulatory relationships in stroke. This work will pave the way for future studies exploring the
therapeutic manipulation of eRNAs to improve post-stroke outcomes.
最近的研究报告哺乳动物增强子广泛转录为非编码RNA
以刺激依赖性方式转录。越来越多的证据表明这些增强子 RNA (eRNA)
在协调高阶染色质相互作用以促进基因表达和
发育和疾病期间的表型结果。因此,eRNA 正在成为一种重要的
基因调控机制的组成部分。由于他们最近的发现,表达和角色
中风中的 eRNA 几乎是未知的。最近,我们结合了全基因组RNA-seq和
使用 ChIP-seq 进行全基因组增强子作图,以识别多个中风诱发的 eRNA
小鼠大脑皮层再灌注的时间点。我们的初步数据证实了增强剂活性
编码 eRNA 的基因组位点,表明 eRNA 定位于染色质,并揭示了
其中一种 eRNA 在调节中风后脑损伤和基因表达中发挥着重要作用。这
eRNA 对中风后的分子相互作用、功能机制和性别依赖性影响
病理生理学尚未探索。在当前项目中,我们根据初步数据来评估 eRNA
成年小鼠皮层中风期间的深入功能。具体目标 1 将结合使用
交联免疫沉淀、荧光原位杂交和转录状态分析
确定 eRNA 的分子靶标作为小鼠中风后再灌注时间的函数
皮质。具体目标 2 将采用体内 eRNA 功能丧失,然后进行细胞、生理、病理学分析
和神经学分析,以评估 eRNA 在传播中风后病理生理学中的作用。
具体目标 3 将评估女性 eRNA 的分子靶点和病理生理学效应
小鼠皮质。总之,这项工作将阐明 eRNA 在大脑皮层中的重要性,并可能
揭示中风中新的基因调控关系。这项工作将为未来的研究铺平道路
eRNA 的治疗操作可改善中风后的结果。
项目成果
期刊论文数量(0)
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Ashutosh Dharap其他文献
Ashutosh Dharap的其他文献
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{{ truncateString('Ashutosh Dharap', 18)}}的其他基金
Functional characterization of an enhancer RNA in cerebral ischemia
增强子 RNA 在脑缺血中的功能表征
- 批准号:
10679009 - 财政年份:2021
- 资助金额:
$ 37.38万 - 项目类别:
Functional characterization of an enhancer RNA in cerebral ischemia
增强子 RNA 在脑缺血中的功能表征
- 批准号:
10453890 - 财政年份:2021
- 资助金额:
$ 37.38万 - 项目类别:
Functional characterization of an enhancer RNA in cerebral ischemia
增强子 RNA 在脑缺血中的功能表征
- 批准号:
10118570 - 财政年份:2020
- 资助金额:
$ 37.38万 - 项目类别:
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