REST-mediated epigenomic and transcriptomic signatures in neuropathic pain
REST 介导的神经病理性疼痛的表观基因组和转录组特征
基本信息
- 批准号:10256781
- 负责人:
- 金额:$ 39.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-15 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAcuteAffectAfferent NeuronsAmericanAnimal ModelAttenuatedBehavioral AssayBiochemicalBiological MarkersBiologyCellsChIP-seqChronic PhaseClinicalClinical ResearchCollaborationsDNADNA-Directed RNA PolymeraseDataDevelopmentDiseaseDown-RegulationDrug TargetingEpigenetic ProcessExhibitsG9a histone methyltransferaseGenesGeneticGenetic TranscriptionGoalsGrantHistonesHumanHypersensitivityImmunofluorescence ImmunologicKnockout MiceKnowledgeLengthMalignant neoplasm of brainMediatingMessenger RNAMethodsMicroRNAsMolecular ProbesMusNervous system structureNeuronsPainPatientsPeripheral nerve injuryPotassium ChannelPredispositionPreventionQuality of lifeRepressionResearchResistanceRestReverse Transcriptase Polymerase Chain ReactionRoleSpinal GangliaSystemTestingTranscription RepressorTraumatic Nerve InjuryUnited States National Institutes of HealthVP 16Workbasechemotherapychronic neuropathic painchronic painconditional knockoutepigenetic regulationepigenetic silencingepigenomicsexperiencegender differencegenetic corepressorgenetic signaturegenome-widegenome-wide analysisin vivoinhibitor/antagonistinnovationmouse modelmu opioid receptorsnerve injurynoveloverexpressionpain chronificationpainful neuropathypreclinical studypromotersomatosensorytherapeutic targettranscription factortranscriptometranscriptome sequencingtranscriptomics
项目摘要
PROJECT SUMMARY
Chronic neuropathic pain is difficult to treat and remains a major clinical problem despite numerous clinical and
preclinical studies. Our long-term goal is to identify new targets for treatment/prevention of chronic neuropathic
pain. Mounting evidence suggests that epigenetic mechanisms and regulation via microRNAs (miRs) are
associated with the transition from acute to chronic pain. The goal of this project is to identify REST- and G9a-
related transcriptomic and epigenomic regulatory networks in the dorsal root ganglion (DRG) and their roles in
the development of neuropathic pain. The transcriptional repressor REST is a major epigenomic regulator. In
nerve injury-induced neuropathic pain, epigenetic silencing by REST overexpression in DRG neurons has
been implicated in the repression of targets such as Oprm1, Kcnd3, Kcnq2, and scn10a genes. Histone
methyl-transferase G9a is also an epigenomic corepressor of many transcription factors including REST. We
recently found that G9a is critical in the epigenetic silencing of almost all K+ channel genes in DRG neurons via
increased histone H3K9me2 on the genes' promoters during acute-to-chronic pain transition. Accordingly, mice
with G9a ablated from DRG neurons do not develop chronic pain after nerve injury. Thus, both REST and G9a
present suitable molecular probes to decipher the genetic and epigenetic bases of chronic pain. However,
knowledge is limited about the transcriptomic and epigenomic networks associated with REST and G9a in
neuropathic pain development. This multiple-PI grant is a collaboration between two labs with complementary
expertise. In addition to the G9a mouse model described above, the two labs have developed an innovative
experimental system consisting of complementary Rest conditional knock-out (cKO) and new conditional
human REST overexpression (cOE) mouse models. Preliminary results indicate that whereas DRG-specific
Rest cKO mice show attenuated pain hypersensitivity after nerve injury, DRG-specific REST cOE mice exhibit
pain hypersensitivity. Thus, the two contrasting mouse models recapitulate the chronic pain transition, as
anticipated based on work in the field, and provide an in vivo system to study transcriptional mechanisms of
chronic pain. Here we propose to the test the central hypothesis that REST and G9a are involved in the
development of chronic pain after DRG nerve injury via unique transcriptomic and epigenomic signatures. If
successful, our proposed research will identify all REST and G9a targets in DRG neurons including mRNAs
and miRs, as well as REST- and G9a-mediated epigenomic changes in the development of chronic pain after
nerve injury. We will also functionally identify those REST- and G9a-regulated miRs that could be utilized to
block REST- and G9a-mediated chronic pain. We will compare our results to those obtained in chemotherapy-
induced chronic pain. In summary, the results from this work are likely to generate new signatures and
biomarkers that could potentially be utilized to predict patient susceptibility or resistance to chronic pain
development. The results could also be used to identify new actionable drug targets in chronic pain.
项目摘要
慢性神经性疼痛难以治疗,并且尽管存在许多临床和病理学问题,
临床前研究。我们的长期目标是确定治疗/预防慢性神经病变的新靶点。
痛苦越来越多的证据表明,表观遗传机制和通过microRNA(miRs)的调控是
与急性疼痛向慢性疼痛的转变有关。本项目的目标是识别REST和G9 a,
背根神经节(DRG)相关转录组和表观基因组调控网络及其在
神经性疼痛的发展。转录抑制因子REST是一种主要的表观基因组调节因子。在
神经损伤诱导的神经病理性疼痛,通过DRG神经元中REST过表达的表观遗传沉默,
与Oprm 1、Kcnd 3、Kcnq 2和scn 10a基因等靶基因的抑制有关。组蛋白
甲基转移酶G9 a也是包括REST在内的许多转录因子的表观基因组辅阻遏物。我们
最近发现,G9 a在DRG神经元中几乎所有K+通道基因的表观遗传沉默中至关重要,
在急性疼痛向慢性疼痛转变期间,基因启动子上的组蛋白H3 K9 me 2增加。因此,小鼠
从DRG神经元切除的G9 a在神经损伤后不产生慢性疼痛。因此,REST和G9 a
提出了合适的分子探针来破译慢性疼痛的遗传和表观遗传基础。然而,在这方面,
关于与REST和G9 a相关的转录组和表观基因组网络的知识有限,
神经性疼痛的发展。这个多PI补助金是两个实验室之间的合作,
专业知识除了上述G9 a小鼠模型外,这两个实验室还开发了一种创新的
由互补Rest条件性敲除(cKO)和新的条件性敲除组成的实验系统
人REST过表达(cOE)小鼠模型。初步结果表明,尽管DRG特异性
静息cKO小鼠在神经损伤后表现出减弱的疼痛超敏反应,DRG特异性REST cOE小鼠表现出
疼痛过敏因此,两种对比的小鼠模型概括了慢性疼痛转变,
基于本领域的工作预期,并提供了一个体内系统来研究转录机制,
慢性疼痛在这里,我们提出了一个中心假设,即REST和G9 a参与了测试。
通过独特的转录组学和表观基因组学标记,研究DRG神经损伤后慢性疼痛的发展。如果
成功,我们提出的研究将确定DRG神经元中的所有REST和G9 a靶点,包括mRNA
和miRs,以及REST和G9 a介导的表观基因组变化在慢性疼痛的发展,
神经损伤我们还将从功能上识别那些受REST和G9 a监管的miR,可用于
阻断REST和G9 a介导的慢性疼痛。我们将把我们的结果与化疗的结果进行比较-
引起慢性疼痛。总之,这项工作的结果可能会产生新的签名,
可能用于预测患者对慢性疼痛的易感性或抵抗力的生物标志物
发展研究结果也可用于确定慢性疼痛中新的可操作药物靶点。
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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SADHAN MAJUMDER其他文献
SADHAN MAJUMDER的其他文献
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{{ truncateString('SADHAN MAJUMDER', 18)}}的其他基金
2023 Basic Mechanisms to Clinical Trials in Brain Tumors Gordon Research Conference
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- 批准号:
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10532153 - 财政年份:2021
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10318992 - 财政年份:2021
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9977491 - 财政年份:2020
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$ 39.74万 - 项目类别:
REST-mediated regulation of opioid receptors in chronic pain mouse models
慢性疼痛小鼠模型中阿片受体的 REST 介导调节
- 批准号:
10205014 - 财政年份:2020
- 资助金额:
$ 39.74万 - 项目类别:
REST-mediated epigenomic and transcriptomic signatures in neuropathic pain
REST 介导的神经病理性疼痛的表观基因组和转录组特征
- 批准号:
10472694 - 财政年份:2019
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$ 39.74万 - 项目类别:
REST-mediated epigenomic and transcriptomic signatures in neuropathic pain
REST 介导的神经病理性疼痛的表观基因组和转录组特征
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9901187 - 财政年份:2019
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REST-mediated epigenomic and transcriptomic signatures in neuropathic pain
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