Endoplasmic Reticulum Stress Responses in Pain
疼痛中的内质网应激反应
基本信息
- 批准号:10579846
- 负责人:
- 金额:$ 39.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcetic AcidsAcute PainAddressAffectBehaviorBehavioralBioinformaticsBiological AssayBiologyCellsCluster AnalysisCommunitiesDevelopmentDinoprostoneElectrophysiology (science)Endoplasmic ReticulumExhibitsFoundationsGene ExpressionGenesGenetic TranscriptionHumanHypersensitivityImmuneImmunologyIn SituIncidenceIndividualInflammationInflammatoryInjuryKnockout MiceLabelLeucocytic infiltrateLeukocytesLigationMedicalModelingMolecularMusNanotechnologyNerve DegenerationNeuroimmuneNeuronsNociceptorsOperative Surgical ProceduresOutcomePainPatientsPatternPattern recognition receptorPeripheralPeripheral nerve injuryPersistent painPhenotypePhosphotransferasesPhysical assessmentPositioning AttributePreventiveProcessProductionProstaglandinsProtein BiosynthesisProteinsQuality of lifeRecoveryRecovery of FunctionRegulationResolutionRoleSignal TransductionSocial ImpactsSurgical incisionsTechnologyTestingTherapeuticTissuesToll-like receptorsXBP1 genearmbiological adaptation to stresschronic inflammatory diseasechronic neuropathic painchronic painchronic pain managementclinically relevantconditional knockoutcytokineeconomic impacteffective therapyendoplasmic reticulum stressgain of functiongenetic signaturegenome-wideimmune activationimmune cell infiltrateimprovedin vivoinflammatory paininhibitorinjuredinnovationloss of functionmisfolded proteinmouse modelnerve injuryneurobiotinnovelpainful neuropathypartial recoverypharmacologicpreventprogramsrecruitresponsesciatic nervesingle-cell RNA sequencingsmall moleculetooltranscriptomics
项目摘要
Summary
Peripheral nerve injury activates pattern recognition receptors (i.e. Toll-like receptors) in immune cells, thus
triggering and maintaining inflammation, and ultimately determining the perpetuation of pain. Immune cell
activation demands high levels of protein synthesis, folding and secretion, which are regulated by the
endoplasmic reticulum (ER). An excessive demand in protein handling can evoke ER stress (accumulation of
misfolded proteins) and consequently trigger robust activation of the unfolded protein response (UPR). IRE1α-
XBP1 is the most evolutionarily conserved arm of the UPR and can be directly activated via Toll-like receptor
engagement to promote the expression of pro-inflammatory factors. We have unveiled that conditional knockout
(cKO) mice devoid of IRE1α/XBP1 in immune cells (Ern1/Xbp1f/f-Vav1cre), display decreased PGE2 production
in vivo, reduced nociceptor responsiveness, and faster resolution of non-reflexive pain-related behaviors
following paw incision. Similarly, these cKO mice exhibit improved recovery after partial sciatic nerve ligation
(PSNL). Through unbiased genome-wide transcriptomic analyses we found that IRE1α-XBP1 signaling in
leukocytes is critically required for the induction of prostanoids, cytokines and other novel factors such as Nupr1
(associated with chronic inflammatory diseases in humans). Of note, IRE1α-XBP1 overactivation has been
correlated with painful or inflammatory conditions in humans. Therefore, we hypothesize that IRE1α-XBP1
signaling in leukocytes governs peripheral neuro-immune interactions and the development of chronic
pain. Using cutting-edge experimental approaches, we will accomplish the following specific aims: 1) Determine
how IRE1α-XBP1 signaling dictates the dynamics of immune cell infiltration and molecular changes that drive
behavioral non-reflexive hypersensitivity following peripheral nerve injury. We postulate that the IRE1α-XBP1
arm operates as a key modulator of pro-algesic factors in immune cells, and that Nupr1 is a novel XBP1-
dependent factor (using ChIP PCR) implicated in PSNL. 2) Establish how IRE1α-XBP1 activation governs
individualized immune cellular reprogramming and how this drives the cross-talk with nociceptor afferents
following peripheral nerve injury. Our hypothesis is that the reduced hypersensitivity observed in our cKO mice
following PSNL is determined by discrete gene signatures in specific injury-infiltrating leukocyte subsets (using
single cell RNA sequencing), and by the acquisition of a less responsive phenotype in nociceptors (via in vivo
intracellular DRG recordings). 3) Define the therapeutic potential of inhibiting IRE1a to accelerate recovery from
PSNL. We posit that pharmacological inhibition of IRE1α using MKC8866 (RNAase domain inhibitor) or KIRA6
(kinase domain inhibitor) will prevent or treat chronic neuropathic pain. Our team has expertise in pain biology
and neuroimmune interactions (Romero-Sandoval), immunology and ER stress biology (Cubillos-Ruiz), in vivo
electrophysiology (Boada), and scRNAseq and bioinformatics (Miller). Thus, we are uniquely positioned to test
our innovative hypothesis and contribute to the development of novel non-narcotic treatments for chronic pain.
总结
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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Mario Danilo Boada其他文献
Mario Danilo Boada的其他文献
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{{ truncateString('Mario Danilo Boada', 18)}}的其他基金
Oxytocin-mediated modulation of peripheral mechanical sensibility after injury
催产素介导的损伤后外周机械敏感性调节
- 批准号:
10609949 - 财政年份:2022
- 资助金额:
$ 39.63万 - 项目类别:
Oxytocin-mediated modulation of peripheral mechanical sensibility after injury
催产素介导的损伤后外周机械敏感性调节
- 批准号:
10332263 - 财政年份:2022
- 资助金额:
$ 39.63万 - 项目类别:
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