The Role of Chemokine Signaling in Sickle Cell Pain
趋化因子信号传导在镰状细胞疼痛中的作用
基本信息
- 批准号:8831817
- 负责人:
- 金额:$ 4.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-24 至 2016-09-23
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute PainAddressAdultAffectAfferent NeuronsAnimal ModelBehavioralBehavioral AssayBindingBlood VesselsCCL4 geneCalciumChronicComplexDataDevelopmentDiseaseElectrophysiology (science)ElementsErythrocytesEsthesiaExhibitsExtracellular Matrix ProteinsFiberFrequenciesGenerationsGlycoproteinsGoalsHereditary DiseaseHumanHyperalgesiaHypersensitivityHypoxiaImageImmune systemInflammation MediatorsIonsIsolectinLigandsLinkMaintenanceMechanicsMediatingMediator of activation proteinMentorsMethodsMissionMusNational Institute of Neurological Disorders and StrokeNerve FibersNeurologicNeuronsNursing FacultyPainPain DisorderPatch-Clamp TechniquesPathway interactionsPatientsPhenotypePhysiciansPopulationReportingResearchResearch ActivityRoleScientistSensorySeveritiesSickle CellSickle Cell AnemiaSignal TransductionSpinal GangliaStimulusSyndromeTechniquesTouch sensationTrainingUnderserved PopulationVanilloidWithdrawalbasebehavioral sensitizationchemokinechronic painexperiencein vivoinflammatory neuropathic paininsightmechanical drivemonocyte chemoattractant protein 1 receptormouse modelneuronal cell bodynovel therapeuticspain behaviorpainful neuropathypatch clamppreventpublic health relevancereceptorsickling
项目摘要
DESCRIPTION (provided by applicant): The overall goal of this project is to determine the contribution of the chemokine CCL2 to the sensation of pain in Sickle Cell Disease (SCD). SCD is a common genetic disorder that involves crippling pain during acute vaso-occlusive crises; moreover, approximately 50% of patients develop chronic pain by adulthood. This pain has elements of both neuropathic and inflammatory pain, and patients report pronounced hypersensitivity to both touch and cold. Previous evidence has shown that the chemokine CCL2 is elevated both during and between crises in sickle patients. Importantly, CCL2 has been linked to both cold and mechanical hypersensitivity in other animal models of neuropathic pain. However, there has been little research investigating how inflammatory mediators such as CCL2 may contribute to SCD pain. Thus, this proposal will explore mechanisms through which inflammatory mediators influence the generation and maintenance of pain in SCD. To achieve this goal, these studies will use a mouse model of sickle cell disease that closely mimics the human SCD pain phenotype. Just as human patients with SCD report cold pain and sensitized cold thresholds, sickle mice exhibit behavioral cold hypersensitivity and the sensory neurons from sickle mice are sensitized to cold. Aim 1 will determine whether the chemokine CCL2 acting at CCR2 is responsible for the increased cold sensitization in SCD. Previous research has also noted a strong mechanical hypersensitivity in sickle mice. Aim 2 will determine whether CCL2 drives the mechanical sensitization observed in SCD. To achieve these aims, patch clamp electrophysiology and teased nerve fiber recordings will be performed, along with calcium imaging and behavioral assays. These interrelated aims provide a directed, yet multifaceted, approach to address the role of CCL2 in the complex pain syndromes associated with SCD. By addressing the mechanisms underlying the frequent and severe pain of sickle cell disease, this proposal's aims align with the mission of the NINDS to reduce the burden of neurological and painful diseases.
描述(由适用提供):该项目的总体目标是确定趋化因子CCL2对镰状细胞疾病(SCD)的感觉的贡献。 SCD是一种常见的遗传疾病,涉及在急性血管结合性危机期间减轻疼痛;此外,大约50%的患者成年后会出现慢性疼痛。这种疼痛具有神经性疼痛和炎症性疼痛的元素,患者报告对触摸和冷的明显过敏。先前的证据表明,镰状患者期间和犯罪之间的趋化因子CCL2均升高。重要的是,在其他神经性疼痛的动物模型中,CCL2与冷和机械性超敏反应有关。但是,很少有研究研究炎症介质(例如CCL2)如何导致SCD疼痛。这是该提案将探索炎症介质会影响SCD疼痛的产生和维持的机制。为了实现这一目标,这些研究将使用镰状细胞疾病的小鼠模型,该模型紧密模仿了人类SCD疼痛表型。正如患有SCD的人类患者报告了冷疼痛和敏感的冷阈值一样,镰状小鼠暴露了行为冷的超敏反应,以及来自镰状小鼠的感觉神经元对感冒敏感。 AIM 1将确定在CCR2上作用的趋化因子CCL2是否导致SCD中的冷敏感性提高。先前的研究还指出,镰状小鼠的机械性超敏反应。 AIM 2将确定CCL2是否驱动SCD中观察到的机械感觉。为了实现这些目标,将进行贴片夹电生理学和嘲笑的神经纤维记录,以及钙成像和行为测定。这些相互关联的目的提供了一种定向但多方面的方法,可以解决CCL2在与SCD相关的复杂疼痛综合征中的作用。通过解决镰状细胞疾病经常和严重疼痛的基础机制,该提案的目的与Ninds的使命保持一致,以减少神经系统和疼痛疾病的燃烧。
项目成果
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Katherine Jahnelle Hendley Zappia其他文献
Katherine Jahnelle Hendley Zappia的其他文献
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