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:10442405
- 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 2024-06-30
- 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 DiseasesPersonsPharmaceutical 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 vivoinhibitorinnovationnerve 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.
奥沙利铂相关化疗所致周围神经病(CIPN)是一种常见的、潜在的
结直肠癌治疗的严重毒性和剂量限制性毒性。据估计,CIPN的总发病率为
患者中约有40%以上。CIPN可在化疗后持续数月至数年
完成,由于对生活质量的负面影响,给癌症幸存者带来了巨大的挑战
(QOL)。CIPN是一个重要的挑战,因为缺乏可以有效预防或
减轻这种药物的不良影响。我们已经确定了特定的受体介导的通路,这些通路有助于
增加离子电流作为治疗或预防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批准的用于其他疾病的药物
条件。这项建议强调了一个多学科研究计划,该计划建立在我们的初步数据基础上
探索CIPN的机制以及FDA批准的药物可以在多大程度上重新用于
疾病的治疗或预防。在目标1中,我们将研究铂-DNA加合物和
奥沙利铂对啮齿动物体内高迁移率族蛋白1(HMGB1)的释放在目标2中,我们将
探讨受体Toll样受体(TLR4)是否参与了Toll样受体的形成或维持
跨越时间的CIPN。最后,在目标3中,我们将对FDA批准的药物的有效性进行概念验证评估
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
期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Concentrations of HMGB1 and Hsp70 of healthy subjects in upper and lower airway: Literature Review and Meta-analysis.
- DOI:10.7150/ijms.53500
- 发表时间:2021
- 期刊:
- 影响因子:3.6
- 作者:Min HJ;Kim KS;Choi GJ;Kang H;White FA
- 通讯作者:White FA
The role of deficient pain modulatory systems in the development of persistent post-traumatic headaches following mild traumatic brain injury: an exploratory longitudinal study.
- DOI:10.1186/s10194-020-01207-1
- 发表时间:2020-12-03
- 期刊:
- 影响因子:0
- 作者:Naugle KM;Carey C;Evans E;Saxe J;Overman R;White FA
- 通讯作者:White FA
Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice.
- DOI:10.1111/epi.17069
- 发表时间:2021-12
- 期刊:
- 影响因子:5.6
- 作者:
- 通讯作者:
Dihydroceramides Derived from Bacteroidetes Species Sensitize TRPV1 Channels.
- DOI:10.3390/ijms24010877
- 发表时间:2023-01-03
- 期刊:
- 影响因子:5.6
- 作者:Ludwig, Nora;Demaree, Isaac S.;Yamada, Chiaki;Nusbaum, Amilia;Nichols, Frank C.;White, Fletcher A.;Movila, Alexandru;Obukhov, Alexander G.
- 通讯作者:Obukhov, Alexander G.
Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation.
- DOI:10.3390/cells11010018
- 发表时间:2021-12-22
- 期刊:
- 影响因子:6
- 作者:Munjuluri S;Wilkerson DA;Sooch G;Chen X;White FA;Obukhov AG
- 通讯作者:Obukhov AG
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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:
10194622 - 财政年份:2018
- 资助金额:
$ 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
- 批准号:
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
- 批准号:
8005848 - 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:
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:
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
- 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:
7795760 - 财政年份:2006
- 资助金额:
$ 43.25万 - 项目类别:
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