Effect of inflammation on recovery and pain after spinal cord injury
炎症对脊髓损伤后恢复和疼痛的影响
基本信息
- 批准号:9212209
- 负责人:
- 金额:$ 18.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-02-01 至 2019-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdenosineAdverse effectsAffectAfferent NeuronsAffinityApoptosisApoptoticAstrocytesAttenuatedBehavioralBinding SitesBiomedical ResearchCASP1 geneCASP3 geneCASP8 geneCalciumCapsaicinCell DeathCell SeparationCellsChemicalsChestCollaborationsContusionsCoupledCytolysisDataDevelopmentDrug CombinationsEnvironmentEventExtracellular FluidFeedbackFiberFosteringGoalsImmunohistochemistryImpairmentInflammasomeInflammationInflammatoryInjuryInterleukin-1Interleukin-1 betaInterleukin-18InterruptionIon ChannelIrritantsLeadLocomotor RecoveryMediatingMethodsMicrogliaModelingMolecular ProfilingMultiprotein ComplexesNeurogliaNeuronsNociceptionPainPathway interactionsPeripheralPharmaceutical PreparationsPharmacotherapyPhaseProbenecidProceduresProcessPurinoceptorRNA InterferenceRattusRecoveryRegimenRegulationResearchResearch PersonnelRodentRoleSecondary toShockSignal TransductionSiteSpinalSpinal Cord PlasticitySpinal InjuriesSpinal cord injuryStretchingSystemTNF geneTRPV1 geneTactileTechniquesTestingTexasTimeTissuesTranslatingWestern BlottingWithdrawalWorkallodyniacell typecentral sensitizationchronic painclinical practicecytokineds-DNAeffective therapyextracellularindexinginhibitor/antagonistinjuredinnovationnerve injurynovelprotective effectprotein profilingpublic health relevancereceptorrelating to nervous systemresearch facilityresponsesuccesstripolyphosphate
项目摘要
DESCRIPTION (provided by applicant): The tissue damage caused by a spinal cord injury (SCI) breaks down cellular barriers and alters the composition of the extracellular fluid, initiatig a chemical wave that impacts uninjured cells in the surrounding region, inducing a state that primes the cells to die through a form of pro-inflammatory programmed cell death (pyroptosis). In addition, damage to descending pathways disrupts the regulation of lower (caudal) spinal systems, allowing afferent signals to induce a state of neural over-excitation (central sensitization) that can foster chronic pain and promote cell death. Supporting this, research has shown that pain (nociceptive) input soon after SCI enhances tissue loss, undermines behavioral function, and promotes the development of chronic pain. It is hypothesized that nociceptive stimulation undermines recovery after SCI because it promotes the induction of pyroptosis and thereby enhances secondary tissue damage. Pyroptosis is mediated by a multi-protein complex called the inflammasome, which initiates the proteolytic cleavage of pro-caspase-1 to form caspase 1. Caspase 1 engages cellular signals that cause the release of pro- inflammatory cytokines (e.g., interleukin 1-ß [IL-1ß] and tumor necrosis factor [TNF]). Activation of the inflammasome is tied to a membrane channel (pannexin-1) and the adjoining P2X7 receptor (P2X7R). When engaged, the pannexin-1 channel allows IL-1ß and TNF to flow out of the cell. Calcium entry through the pannexin-1 channel initiates intracellular processes that lead to cell death through lysis. The current project will evaluate whether nociceptive input engages these processes and thereby leads to greater cell loss. A rodent (rat) model will be used. Subjects will
receive a thoracic contusion injury. Prior work has shown that the application of a peripheral irritant (capsaicin) undermines behavioral recovery and enhances pain reactivity to tactile stimulation (allodynia). Aim 1 will establish the circumstances under which this occurs and assess tissue damage. It is hypothesized that spinal systems are especially vulnerable during the first few days after injury. Preliminary data indicate that nociceptive stimulation engages cellular signals indicative of pyroptosis (caspase 1, IL-1ß, IL-18). Aim 2 will examine how these processes unfold over time and the cell types affected. It is proposed that the spread of pyroptosis can be halted by a drug combination (probenecid plus Brilliant Blue-G [BBG]) that inhibits both the pannexin-1 channel and the P2X7R. Aim 3 will verify that this drug treatment attenuates the induction of pyroptosis in the acute stage. We also predict that it will reduce behavioral and cellular signs of central sensitization. After an effective regimen is derived, we will test whether it has a protective effect that blocks the adverse effect of nociceptive stimulation on long-term recovery. By discovering treatments that reduce cell loss after SCI, we hope to promote recovery. Further, because activation of the pannexin-1 channel can contribute to the development of central sensitization, interrupting this process should reduce chronic pain after injury.
描述(由适用提供):由脊髓损伤(SCI)造成的组织损伤破坏细胞屏障并改变细胞外液的组成,Initiatig A化学波,影响周围地区未受伤的细胞,诱导一个状态,使细胞通过促炎性症状的细胞死亡形式死亡,以使细胞死亡。此外,降落途径的损害破坏了较低(尾部)脊柱系统的调节,从而使传入信号诱导神经过度兴奋状态(中心灵敏度),该状态可以促进慢性疼痛并促进细胞死亡。支持这一点,研究表明,SCI后不久,疼痛(伤害感受)的输入会增强组织损失,破坏行为功能并促进慢性疼痛的发展。假设伤害性刺激会破坏SCI后的恢复,因为它促进了诱导的诱导,从而增强了次要组织损伤。凋亡是由一种称为炎症体的多蛋白质复合物介导的,该复合物称为炎症体,该复合体启动pro-caspase-1的蛋白水解裂解形成caspase1。caspase 1参与细胞信号,引起促炎性细胞因子释放的细胞信号(例如,Ilthuukinkin 1-il-1- il-1-il-1-il-1 l-1ß]和tumor necrosis [tnf] [tnf]。炎性体的激活与膜通道(Pannexin-1)和相邻的P2X7受体(P2X7R)绑定。参与时,Pannexin-1通道允许IL-1ß和TNF从细胞中流出。通过Pannexin-1通道进入钙会引发细胞内过程,从而导致通过裂解导致细胞死亡。当前项目将评估伤害感受的输入是否与这些过程相关,从而导致更大的细胞损失。将使用啮齿动物(大鼠)模型。受试者会
受到胸骨挫伤。先前的工作表明,外周刺激物(辣椒素)的应用破坏了行为恢复,并增强了对触觉刺激的疼痛反应性(异常性疾病)。 AIM 1将确定发生这种情况并评估组织损伤的情况。假设脊柱系统在受伤后的头几天特别容易受到伤害。初步数据表明,伤害感受刺激会导致细胞信号指示了凋亡(caspase 1,IL-1ß,IL-18)。 AIM 2将检查这些过程如何随着时间的推移以及细胞类型的影响。有人提出,可以通过抑制Pannexin-1通道和P2X7R的药物组合(ProbEnecid和亮蓝色G [BBG])来阻止凋亡的扩散。 AIM 3将验证这种药物治疗会减弱急性阶段诱导的诱导。我们还预测,它将降低中心灵敏度的行为和细胞迹象。得出有效方案后,我们将测试它是否具有受保护作用,阻止伤害性刺激对长期恢复的不利影响。通过发现减少SCI后细胞损失的治疗方法,我们希望促进康复。此外,由于pannexin-1通道的激活可能有助于中枢灵敏度的发展,因此中断该过程应减少损伤后的慢性疼痛。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Pain Input After Spinal Cord Injury (SCI) Undermines Long-Term Recovery and Engages Signal Pathways That Promote Cell Death.
- DOI:10.3389/fnsys.2018.00027
- 发表时间:2018
- 期刊:
- 影响因子:3
- 作者:Turtle JD;Strain MM;Reynolds JA;Huang YJ;Lee KH;Henwood MK;Garraway SM;Grau JW
- 通讯作者:Grau JW
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James William Grau其他文献
James William Grau的其他文献
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{{ truncateString('James William Grau', 18)}}的其他基金
Nociceptive input after spinal cord injury (SCI) expands the region of secondary injury and undermines long-term recovery
脊髓损伤(SCI)后的伤害性输入会扩大继发性损伤的区域并破坏长期恢复
- 批准号:
10455530 - 财政年份:2018
- 资助金额:
$ 18.24万 - 项目类别:
Nociceptive input after spinal cord injury (SCI) expands the region of secondary injury and undermines long-term recovery
脊髓损伤(SCI)后的伤害性输入会扩大继发性损伤的区域并破坏长期恢复
- 批准号:
10213852 - 财政年份:2018
- 资助金额:
$ 18.24万 - 项目类别:
Influence of Environmental Stimulation and Learning on Recovery After Injury
环境刺激和学习对伤后恢复的影响
- 批准号:
7502211 - 财政年份:2007
- 资助金额:
$ 18.24万 - 项目类别:
Influence of Environmental Stimulation and Learning on Recovery After Injury
环境刺激和学习对伤后恢复的影响
- 批准号:
7663099 - 财政年份:2007
- 资助金额:
$ 18.24万 - 项目类别:
Influence of Environmental Stimulation and Learning on Recovery After Injury
环境刺激和学习对伤后恢复的影响
- 批准号:
7300500 - 财政年份:2007
- 资助金额:
$ 18.24万 - 项目类别:
Influence of Environmental Stimulation and Learning on Recovery After Injury
环境刺激和学习对伤后恢复的影响
- 批准号:
7900453 - 财政年份:2007
- 资助金额:
$ 18.24万 - 项目类别:
Learning Within the Spinal Cord: Clinical Implications
脊髓内的学习:临床意义
- 批准号:
6621602 - 财政年份:2001
- 资助金额:
$ 18.24万 - 项目类别:
Learning Within the Spinal Cord: Clinical Implications
脊髓内的学习:临床意义
- 批准号:
7261491 - 财政年份:2001
- 资助金额:
$ 18.24万 - 项目类别:
Learning Within the Spinal Cord: Clinical Implications
脊髓内的学习:临床意义
- 批准号:
7354777 - 财政年份:2001
- 资助金额:
$ 18.24万 - 项目类别:
Learning Within the Spinal Cord: Clinical Implications
脊髓内的学习:临床意义
- 批准号:
7754034 - 财政年份:2001
- 资助金额:
$ 18.24万 - 项目类别:
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