The role of cell-specific TLR-4 signaling in oxaliplatin-induced peripheral neuropathy
细胞特异性 TLR-4 信号在奥沙利铂诱导的周围神经病变中的作用
基本信息
- 批准号:10194622
- 负责人:
- 金额:$ 43.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AVIL geneAction PotentialsAcuteAddressAdjuvant TherapyAdverse drug effectAfferent NeuronsAgonistAllelesAnimalsAntiepileptic AgentsAttenuatedBehaviorBehavior TherapyBehavioralBehavioral AssayBiological AssayCalciumCancer PatientCancer SurvivorCarboplatinCellsCharacteristicsChemotherapy-induced peripheral neuropathyChronicCisplatinClinicalClinical TreatmentClinical TrialsColorectal CancerCytosolDNADNA AdductsDataDevelopmentDiseaseDoseDose-LimitingDrug usageDysesthesiasEnterobacteria phage P1 Cre recombinaseEnzymesExcisionExposure toFDA approvedFutureGenderGenerationsGenesGoalsHMGB1 ProteinHypersensitivityImageImmuneIn VitroIncidenceInflammation MediatorsInterdisciplinary StudyInterleukin-1 ReceptorsInterruptionIon ChannelIonsLeadMaintenanceMeasuresMediatingMethodologyMethodsMotorMusNamesNational Cancer InstituteNerve FibersNeuritesNeuronsNociceptionNuclear ProteinNuclear TranslocationNumbnessPainParesthesiaPathway interactionsPatientsPerformancePeripheral Nervous System DiseasesPharmaceutical PreparationsPharmacologyPhysiologicalPhysiologyPlatinumPlatinum adductPoly(ADP-ribose) PolymerasesPopulationPre-Clinical ModelPreventionPropertyPublicationsQuality of lifeReceptor SignalingReflex actionReportingRodentRoleSignal TransductionSodium ChannelSpinal GangliaSymptomsTLR1 geneTLR4 geneTamoxifenTestingTherapeuticTimeToll-like receptorsToxic effectTranslationsVinca AlkaloidsWorkallodyniabasecancer cellchemotherapycolon cancer patientscolorectal cancer treatmentcrosslinkcytokinedrug developmentefficacy evaluationganglion cellin vivoinhibitor/antagonistinnovationnerve supplyneurotoxicnew therapeutic targetnovel therapeuticsoxaliplatinpain behaviorperipheral painphenotypic biomarkerpreventpromoterreceptorrelating to nervous systemsmall moleculesmall molecule inhibitortaxanetherapeutic targettumorvoltage
项目摘要
Oxaliplatin-associated Chemotherapy-induced Peripheral Neuropathy (CIPN) is a frequent, potentially
severe and dose-limiting toxicity of colorectal cancer treatment. The overall incidence of CIPN is estimated to be
approximately upwards of 40% in patients. CIPN can persist for months to years beyond chemotherapy
completion, causing significant challenges for cancer survivors due to its negative influence on quality of life
(QOL). CIPN represents an important challenge because of the lack of treatment that can effectively prevent or
mitigate this adverse drug effect. We have identified specific receptor-mediated pathways which contribute to
increases in ion current as a potential therapeutic target for the treatment or prevention of CIPN. Noteworthy,
several ion channel modulators central to CIPN treatment are FDA-approved drugs used for other disease
conditions. This proposal highlights a multidisciplinary research plan that builds upon our preliminary data to
explore both the mechanism of CIPN and the degree to which FDA-approved drugs can be repurposed for the
treatment or prevention of the condition. In Aim 1, we will examine the influence of platinum-DNA adducts and
release of high mobility group box-1 (HMGB1) in rodents following exposure to oxaliplatin. In Aim 2, we will
investigate whether the receptor Toll-like receptor (TLR4) is responsible for the development or maintenance of
CIPN across time. Finally, in Aim 3, we will conduct a proof of concept assessment of the efficacy of FDA-approved
antiepileptic drugs on both neuronal ion currents and CIPN behavioral characteristics. These proposed studies will provide new therapeutic targets which will likely alter the detrimental effects of oxaliplatin on sensory neurons.
奥沙利铂相关化疗引起的周围神经病变 (CIPN) 是一种常见的、潜在的
结直肠癌治疗的严重和剂量限制性毒性。 CIPN 的总体发生率估计为
患者中大约有 40% 以上。 CIPN 可以在化疗后持续数月至数年
由于其对生活质量的负面影响,给癌症幸存者带来了重大挑战
(生活质量)。 CIPN 是一个重要的挑战,因为缺乏可以有效预防或预防的治疗方法。
减轻这种药物的不良作用。我们已经确定了特定的受体介导的途径,这些途径有助于
离子电流的增加作为治疗或预防 CIPN 的潜在治疗靶点。值得注意的是,
几种对 CIPN 治疗至关重要的离子通道调节剂是 FDA 批准用于其他疾病的药物
状况。该提案强调了一项多学科研究计划,该计划以我们的初步数据为基础
探索 CIPN 的机制以及 FDA 批准的药物可以重新用于新用途的程度
治疗或预防该病症。在目标 1 中,我们将研究铂-DNA 加合物的影响和
啮齿类动物接触奥沙利铂后会释放高迁移率族蛋白盒-1 (HMGB1)。在目标 2 中,我们将
研究受体 Toll 样受体 (TLR4) 是否负责发育或维持
CIPN 跨越时间。最后,在目标 3 中,我们将对 FDA 批准的药物的功效进行概念验证评估
抗癫痫药物对神经元离子电流和 CIPN 行为特征的影响。这些拟议的研究将提供新的治疗靶点,可能会改变奥沙利铂对感觉神经元的有害影响。
项目成果
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{{ truncateString('FLETCHER A WHITE', 18)}}的其他基金
Novel treatments of chronic pain due to repetitive mild traumatic brain injury
重复性轻度创伤性脑损伤引起的慢性疼痛的新疗法
- 批准号:
10754128 - 财政年份:2023
- 资助金额:
$ 43.25万 - 项目类别:
The role of cell-specific TLR-4 signaling in oxaliplatin-induced peripheral neuropathy
细胞特异性 TLR-4 信号在奥沙利铂诱导的周围神经病变中的作用
- 批准号:
10442405 - 财政年份:2018
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$ 43.25万 - 项目类别:
Chemokine signaling in the transition from acute to chronic pain
从急性疼痛到慢性疼痛转变中的趋化因子信号传导
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8634938 - 财政年份:2014
- 资助金额:
$ 43.25万 - 项目类别:
Mechanisms of Neuropathic Pain in Demylenated Nerves
脱髓鞘神经中神经病理性疼痛的机制
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8005848 - 财政年份:2006
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$ 43.25万 - 项目类别:
Mechanisms of Neuropathic Pain in Demylenated Nerves
脱髓鞘神经中神经病理性疼痛的机制
- 批准号:
7387385 - 财政年份:2006
- 资助金额:
$ 43.25万 - 项目类别:
Mechanisms of Neuropathic Pain in Demylenated Nerves
脱髓鞘神经中神经病理性疼痛的机制
- 批准号:
7596188 - 财政年份:2006
- 资助金额:
$ 43.25万 - 项目类别:
Mechanisms of Neuropathic Pain in Demylenated Nerves
脱髓鞘神经中神经病理性疼痛的机制
- 批准号:
7212175 - 财政年份:2006
- 资助金额:
$ 43.25万 - 项目类别:
Mechanisms of Neuropathic Pain in Demylenated Nerves
脱髓鞘神经中神经病理性疼痛的机制
- 批准号:
7094854 - 财政年份:2006
- 资助金额:
$ 43.25万 - 项目类别:
Mechanisms of Neuropathic Pain in Demylenated Nerves
脱髓鞘神经中神经病理性疼痛的机制
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7795760 - 财政年份:2006
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