Defining the role of peripheral Adrb3 in chronic pain and inflammation
定义外周 Adrb3 在慢性疼痛和炎症中的作用
基本信息
- 批准号:10009478
- 负责人:
- 金额:$ 52.47万
- 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 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdipocytesAdipose tissueAffectAnimal ModelBehaviorBehavioralBiological AssayBiological MarkersBloodC57BL/6 MouseCatechol O-MethyltransferaseCatecholaminesCellsChronicClinicalCorticosteroneDataDevelopmentDown-RegulationEnzymesExhibitsFemaleFibromyalgiaFlow CytometryGenotypeGoalsHealthcareHindlimbImmuneImmune responseImmunohistochemistryIndividualInflammationInflammatoryInterleukin-6KnowledgeLeadMaintenanceMeasuresMediatingMetabolismMethodologyMethyltransferase GeneMicroRNAsMitogen-Activated Protein KinasesMolecularMusMuscleNerveNeurogliaNeuronal PlasticityNeuronsNociceptorsPainParentsPathway interactionsPatientsPatternPeripheralPeripheral NervesPersistent painPharmacologyPhosphorylationPhysiologyPlasmaPopulationQuality of lifeReceptors, Adrenergic, beta-3ReportingResolutionRodentRodent ModelRoleSignal TransductionSiteSkinSpecificitySpinalSpinal CordSpinal GangliaStressStressful EventSwimmingSyndromeTemporomandibular Joint DisordersTestingTimeTissuesTumor-infiltrating immune cellsUp-RegulationVariantVolitionWorkadipokinesbehavioral phenotypingbeta-adrenergic receptorcalcium indicatorcell typecentral sensitizationchronic painclinically relevantcytokineeffective therapygenetic variantimprovedin vivo calcium imaginginhibitor/antagonistinsightmalemolecular phenotypeneuroinflammationnew therapeutic targetnovelpain behaviorpreventrelating to nervous systemside effecttreatment strategy
项目摘要
ABSTRACT
Functional pain syndromes affect over 100 million people, yet remain ineffectively treated because the causes
are largely unknown. Accumulating evidence suggests that these syndromes are due, in large part, to low
activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. An estimated
66% of patients with functional pain syndromes, such as fibromyalgia, possess variants in the COMT gene that
lead to low activity of the COMT enzyme. Individuals with the ‘low COMT activity’ genotype report greater pain
at baseline and enhanced pain following stressful events that potentiate catecholamine release from
sympathetic nerves. Consistent with clinical syndromes, our lab has shown that pharmacologic inhibition of
COMT in rodents produces pain at multiple body sites and enhances pain following repeated stress. In
subsequent studies, we demonstrated that COMT-dependent pain is initiated by peripheral adrenergic receptor
beta-3 (Adrb3) through the release of pro-inflammatory cytokines in local tissues. The pain is maintained by
subsequent increases in pro-inflammatory cytokines in spinal tissues and activation of mitogen activated
protein kinases (MAPKs) in the cell bodies and central terminals of pain-sensing nociceptors. Together, these
data show that heightened catecholamine tone leads to chronic pain via peripheral Adrb3 and its downstream
effectors. However, the cell types that express Adrb3 and mediate pain still need to be identified and the
molecular mechanisms determined. We hypothesize that activation of Adrb3 on adipocytes (fat cells that
surround peripheral nociceptor and sympathetic nerve terminals) drives chronic COMT-dependent pain via
increases in cytokines and MAPKs that promote inflammation and nociceptor activation. Further, we
hypothesize that stress-induced catecholamine release amplifies the effects of Adrb3 signaling on inflammation
and pain. Preliminary data reveal that COMT-dependent increases in pro-inflammatory cytokines are mediated
by Adrb3 located on adipocytes. Additional data reveal that sustained activation of Adrb3 leads to decreased
levels of miR-133a, a microRNA expressed in adipocytes that is able to block MAPK signaling. The proposed
studies will extend this work to directly determine 1) Adrb3 and miR-133a expression patterns in adipose vs
other peripheral tissues over time and their relationship to COMT-dependent functional pain, 2) the role of
peripheral Adrb3 and miR-133a in mediating COMT-dependent inflammation and neuroinflammation, 3) the
role of peripheral Adrb3 and miR-133a in mediating COMT-dependent increases in the activity of
mechosensitive and thermosensitive nociceptors, and 4) how these molecular and behavioral phenotypes are
influenced by stress. Results from these studies will advance our knowledge about the mechanisms whereby
peripheral Adrb3 drives chronic pain and elucidate new targets for the development of peripherally-restricted
therapies with improved specificity and side-effect profiles for the treatment of functional pain syndromes.
抽象的
功能性疼痛综合征会影响超过1亿人,但由于原因而保持无效治疗
在很大程度上未知。积累的证据表明,这些综合症在很大程度上是由于低的
儿茶酚-O-甲基转移酶(COMT)的活性,一种代谢儿茶酚胺的酶。估计
66%的功能性疼痛综合征患者(例如纤维肌痛)在COMT基因中具有变异性
导致COMT酶的活性低。具有“低COMT活动”基因型的人报告更大的疼痛
在压力事件发生后,基线和增加的疼痛,潜在的儿茶酚胺从
交感神经。与临床综合征一致,我们的实验室表明,药物抑制
啮齿动物中的COMT会在多个身体部位产生疼痛,并在反复的压力后增强疼痛。在
随后的研究,我们证明了依赖COMT的疼痛是由外周肾上腺接收器引发的
β-3(ADRB3)通过在局部组织中释放促炎细胞因子。疼痛由
随后脊柱组织中促炎细胞因子的随后增加和有丝分裂原活化的激活
细胞体和中央末端的蛋白激酶(MAPK)。在一起,这些
数据表明,升高的儿茶酚胺张力会导致外围ADRB3及其下游导致慢性疼痛
效果。但是,表达ADRB3和介导疼痛的细胞类型仍需要识别
分子机制确定。我们假设ADRB3在脂肪细胞上的激活(脂肪细胞
环绕周围的伤害感受器和交感神经终端)通过
促进注射和伤害感受器激活的细胞因子和MAPK的增加。此外,我们
假设应力诱导的儿茶酚胺释放放大器ADRB3信号对炎症的影响
和痛苦。初步数据表明,促炎细胞因子的COMT依赖性增加是介导的
由ADRB3位于脂肪细胞上。其他数据表明,ADRB3的持续激活导致精制
miR-133a的水平,一种在脂肪细胞中表达的microRNA,能够阻止MAPK信号传导。提议
研究将把这项工作扩展到直接确定1)脂肪中的ADRB3和miR-133a表达模式
随着时间的推移,其他周围组织及其与COMT依赖性功能疼痛的关系,2)
外围ADRB3和miR-133a在介导COMT依赖性炎症和神经炎症中,3)
外周ADRB3和miR-133a在介导COMT依赖性增加的活性中的作用
机电敏感和热敏性伤害感受器,以及4)这些分子和行为表型如何
受压力的影响。这些研究的结果将提高我们对机制的了解
外围ADRB3驱动慢性疼痛并阐明了新目标,以发展外围限制性
具有改进性和副作用谱的治疗疗法,用于治疗功能疼痛综合征。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
Andrea G Nackley其他文献
Andrea G Nackley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('Andrea G Nackley', 18)}}的其他基金
A novel clinically-relevant mouse model of chronic overlapping pain conditions for screening analgesics
用于筛选镇痛药的新型临床相关慢性重叠疼痛小鼠模型
- 批准号:
10821681 - 财政年份:2022
- 资助金额:
$ 52.47万 - 项目类别:
A novel clinically- relevant mouse model of chronic overlapping pain conditions for screening analgesics
用于筛选镇痛药的慢性重叠疼痛的新型临床相关小鼠模型
- 批准号:
10434449 - 财政年份:2022
- 资助金额:
$ 52.47万 - 项目类别:
A novel clinically- relevant mouse model of chronic overlapping pain conditions for screening analgesics
用于筛选镇痛药的慢性重叠疼痛的新型临床相关小鼠模型
- 批准号:
10732571 - 财政年份:2022
- 资助金额:
$ 52.47万 - 项目类别:
Resolving functional pain by complementary approaches
通过补充方法解决功能性疼痛
- 批准号:
9703534 - 财政年份:2020
- 资助金额:
$ 52.47万 - 项目类别:
Defining the role of peripheral Adrb3 in chronic pain and inflammation
定义外周 Adrb3 在慢性疼痛和炎症中的作用
- 批准号:
10442436 - 财政年份:2019
- 资助金额:
$ 52.47万 - 项目类别:
Defining the role of peripheral Adrb3 in chronic pain and inflammation
定义外周 Adrb3 在慢性疼痛和炎症中的作用
- 批准号:
10669732 - 财政年份:2019
- 资助金额:
$ 52.47万 - 项目类别:
Defining the role of peripheral Adrb3 in chronic pain and inflammation
定义外周 Adrb3 在慢性疼痛和炎症中的作用
- 批准号:
10216371 - 财政年份:2019
- 资助金额:
$ 52.47万 - 项目类别:
Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments (Vestibulodynia: UPDATe)
前庭痛:了解病理生理学并确定适当的治疗方法(前庭痛:UPDATe)
- 批准号:
10649404 - 财政年份:2018
- 资助金额:
$ 52.47万 - 项目类别:
Persistent COMT-dependent Pain: Role of beta-adrenergic Receptors
持续性 COMT 依赖性疼痛:β-肾上腺素能受体的作用
- 批准号:
8543772 - 财政年份:2011
- 资助金额:
$ 52.47万 - 项目类别:
Persistent COMT-dependent Pain: Role of beta-adrenergic Receptors
持续性 COMT 依赖性疼痛:β-肾上腺素能受体的作用
- 批准号:
8725747 - 财政年份:2011
- 资助金额:
$ 52.47万 - 项目类别:
相似国自然基金
FTL+ALB+脂肪干细胞与CD36+EBF2-内皮细胞通过交互作用影响脂肪组织衰老的机制研究
- 批准号:82370884
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
白色脂肪组织HIF-1α/ATGL通路在心衰时对心肌细胞线粒体功能的影响及相关机制
- 批准号:82172159
- 批准年份:2021
- 资助金额:55.00 万元
- 项目类别:面上项目
白色脂肪组织HIF-1α/ATGL通路在心衰时对心肌细胞线粒体功能的影响及相关机制
- 批准号:
- 批准年份:2021
- 资助金额:55 万元
- 项目类别:面上项目
层粘连蛋白调控巨噬细胞和脂肪基质细胞影响肥胖脂肪组织重塑的机制
- 批准号:
- 批准年份:2019
- 资助金额:300 万元
- 项目类别:
糖尿病肾病外泌体miRNAs介导内脏脂肪组织巨噬细胞-系膜细胞crosstalk影响肾脏自噬功能及丹酚酸B的作用
- 批准号:81974531
- 批准年份:2019
- 资助金额:55 万元
- 项目类别:面上项目
相似海外基金
Lipid storage and utilization in physiology and obesity
生理学和肥胖中的脂质储存和利用
- 批准号:
10663760 - 财政年份:2023
- 资助金额:
$ 52.47万 - 项目类别:
Role of SIK3 in PKA/mTORC1 regulation of adipose browning
SIK3 在 PKA/mTORC1 调节脂肪褐变中的作用
- 批准号:
10736962 - 财政年份:2023
- 资助金额:
$ 52.47万 - 项目类别:
Regulation of beige adipocyte plasticity in inguinal white adipose tissue.
腹股沟白色脂肪组织中米色脂肪细胞可塑性的调节。
- 批准号:
10563617 - 财政年份:2023
- 资助金额:
$ 52.47万 - 项目类别:
Mechanisms of mitochondrial-ER communication during dietary and thermal induced stress
饮食和热应激期间线粒体-内质网通讯的机制
- 批准号:
10663603 - 财政年份:2023
- 资助金额:
$ 52.47万 - 项目类别: