Stress and Visceral Hyperalgesia: Epigenetic Mechanisms
压力和内脏痛觉过敏:表观遗传机制
基本信息
- 批准号:8541353
- 负责人:
- 金额:$ 33.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-20 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:Abdominal PainAcetylationAdrenal Cortex HormonesAffectAgonistAnimalsAreaBehaviorBindingBiological AssayBiomedical ResearchBloodCNR1 geneCOS CellsCellsChronicChronic stressClinicalColonComplexCorticosteroneDNA MethylationDNA-Protein InteractionDataEndocannabinoidsEpigenetic ProcessEsthesiaExperimental DesignsFeedbackFluorescence Resonance Energy TransferFutureGastrointestinal tract structureGene ExpressionGene SilencingGenesGenetic TranscriptionGlucocorticoid ReceptorGlucocorticoidsGoalsHarvestHistone AcetylationHormonesHumanHydrocortisoneHyperalgesiaIn SituIn VitroInterventionLabelLasersLinkMediatingMedicineMethodsMethylationMicroscopyMineralocorticoidsMonitorMotorMutateNeuronsNociceptionPainPain DisorderPathway interactionsPatternPerceptionPeripheralPharmaceutical PreparationsPlayPromoter RegionsProteinsPsychological StressRNARattusReagentReceptor GeneRegulationRegulatory PathwayRodentRoleSensorySignal Transduction PathwaySiteSpinal GangliaStressTRPV1 geneTestingTherapeutic InterventionTotal Internal Reflection FluorescentVisceralVisceral painWateracute stressbiological adaptation to stresscolorectal distensionexperiencehistone acetyltransferasehistone modificationhypothalamic-pituitary-adrenal axisinhibitor/antagonistnovelpromoterreceptorreceptor expressionresponsetargeted deliverytransmission process
项目摘要
DESCRIPTION (provided by applicant): Chronic stress is a well-known trigger for abdominal pain, a common yet poorly understood presentation in the clinical setting. We will examine the novel hypothesis that chronic stress activates epigenetic regulatory pathways resulting in enhanced abdominal pain (visceral hyperalgesia). Epigenetic pathways regulate gene expression by modifying the level of methylation of upstream promoter regions of genes (increased methylation decreases gene expression) and histone acetylation (increased histone acetylation enhances gene expression). Stress activates the hypothalamic- pituitary-adrenal axis resulting in increased blood levels of the hormone cortisol in humans and corticosterone (CORT) in rodents which regulate gene expression via the intracellular corticoid receptors GR and MR. Acute stress activates the anti-nociceptive endocannabinoid CB1 receptor gene expression which, in turn, inhibits the function of pro-nociceptive endovanilloid TRPV1 receptors. Chronic stress down-regulates CB1 expression and up-regulates TRPV1 expression. We propose that chronic stress will increase methylation of GR promoter sites resulting in decreased CB1 expression, and augment histone acetylation resulting in increased TRPV1 expression, culminating in visceral hyperalgesia. DNA methylation sites will be characterized using methylation-specific PCR analysis and pyrosequencing, and histone acetylation sites dissected using ChIP. We propose that chronic stress will modulate these pathways selectively in primary sensory dorsal root ganglion (DRG) neurons innervating the colon that transmit pain. Studies will be performed in DRGs obtained from chronic water-avoidance stressed rats, control rats treated with CORT in situ and control DRG explants treated with CORT in vitro. We will examine whether the formation of GR-MR and CB1-TRPV1 receptor complexes plays a role in stress-related visceral hyperalgesia in DRG neurons transfected with either dual labeled GR and MR, or CB1 and TRPV1 using FRET/TIRF microscopy. We hypothesize that visceral hyperalgesia will be linked to epigenetic mechanisms that selectively affect promoter sites for the GR, CB1 and TRPV1 receptors in nociceptive DRG neurons innervating the colon. This subpopulation will be identified using immunohistochemical markers and laser capture microscopy to harvest different subpopulations of DRG neurons in conjunction with quantitative PCR of relevant targets. Confirmation of the role of specific receptors (GR/MR) and signal transduction pathways (methylation/acetylation) to the changes observed in CB and TRP pathways will be confirmed using targeted delivery of specific agonist/antagonist drugs and gene silencing (si-RNA) reagents in situ, and correlation of these interventions with behavior, e.g. visceral motor response to colorectal distension. We believe that the proposed studies will have high impact regarding our understanding of how stress affects pain perception. Therapeutic interventions that target epigenetic mechanisms are touted as a pathway to personalized medicine in the future.
描述(由申请人提供):慢性应激是腹痛的众所周知的触发因素,这是临床环境中常见但知之甚少的表现。我们将研究新的假设,即慢性应激会激活表观遗传调节途径,从而导致腹痛增强(内脏痛觉过敏)。表观遗传途径通过修饰基因上游启动子区域的甲基化水平(甲基化增加可降低基因表达)和组蛋白乙酰化(增加组蛋白乙酰化会增强基因表达)。应力激活下丘脑 - 垂体 - 肾上腺轴,导致人类和皮质酮(Cort)在啮齿动物中的血液水平增加,这些啮齿动物通过细胞内皮质激素受体GR和MR调节基因表达。急性应激激活抗伤心性内源性内源性内透明素CB1受体基因表达,这反过来抑制了促伤害感受性内伏型TRPV1受体的功能。慢性应激下调CB1表达并上调TRPV1表达。我们建议,慢性应激将增加GR启动子位点的甲基化,从而导致CB1表达降低,并增加组蛋白乙酰化,从而导致TRPV1表达增加,最终导致内脏女内度高温过敏。 DNA甲基化位点将使用甲基化特异性PCR分析和焦磷酸测序以及使用CHIP解剖的组蛋白乙酰化位点来表征。我们建议,慢性应激将在主要的背侧根神经节(DRG)神经元中选择性调节这些途径,从而支配了传递疼痛的结肠。研究将在从慢性水的胁迫大鼠中获得的DRG进行,该大鼠,用cort原位治疗的对照大鼠和用CORT在体外处理的对照DRG外植体。我们将检查GR-MR和CB1-TRPV1受体复合物的形成是否在使用FRET/TIRF显微镜使用双重标记的GR和MR,CB1和TRPV1转染的DRG神经元中与应力相关的内脏性痛觉过敏起作用。我们假设内脏痛觉过敏将与表观遗传机制相关,这些机制有选择地影响伤害性DRG神经元中GR,CB1和TRPV1受体的启动子位点,从而支配了结肠。将使用免疫组织化学标记和激光捕获显微镜确定该亚群,以收集DRG神经元的不同亚群以及相关靶标的定量PCR。通过针对特定的激动剂/拮抗剂/拮抗剂和基因沉默(SI-RNA)试剂的靶向递送,确认对CB和TRP途径中观察到的变化的特定受体(GR/MR)和信号转导途径的作用(甲基化/乙酰化)的证实将得到证实。对结直肠延伸的内脏运动响应。我们认为,拟议的研究将对我们对压力如何影响疼痛感的理解产生很大的影响。靶向表观遗传机制的治疗干预措施将来被吹捧为个性化医学的途径。
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)
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JOHN W WILEY其他文献
JOHN W WILEY的其他文献
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{{ truncateString('JOHN W WILEY', 18)}}的其他基金
Actions of Resolvins on Intestinal Inflammation and Pain
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- 批准号:
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- 资助金额:
$ 33.43万 - 项目类别:
Actions of Resolvins on Intestinal Inflammation and Pain
Resolvins 对肠道炎症和疼痛的作用
- 批准号:
10597042 - 财政年份:2020
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$ 33.43万 - 项目类别:
Chronic Stress and Abdominal Pain: Novel Mechanisms
慢性压力和腹痛:新机制
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8478935 - 财政年份:2013
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Chronic Stress and Abdominal Pain: Novel Mechanisms
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- 批准号:
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$ 33.43万 - 项目类别:
Chronic Stress and Abdominal Pain: Novel Mechanisms
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$ 33.43万 - 项目类别:
Chronic Stress and Abdominal Pain: Novel Mechanisms
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