Identifying non-opioid strategies to manage oral cancer pain
确定非阿片类药物策略来控制口腔癌疼痛
基本信息
- 批准号:10617001
- 负责人:
- 金额:$ 25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:Absence of pain sensationAdaptor Signaling ProteinAdjuvanticityAdvanced DevelopmentAgonistAnalgesicsAnatomyAntigen-Presenting CellsAwardBehavioralBone MarrowCellsChronicComplexConstipationDNADiseaseDoseDouble-Stranded RNAFormulationG-Protein-Coupled ReceptorsGene ActivationGenomicsGoalsHead and Neck CancerHead and Neck Squamous Cell CarcinomaHead and neck structureHumanIRF3 geneImmunizationImmunosuppressionImmunotherapyImplantInflammasomeInfrastructureInterferon Type IInterferon-betaInterferonsInterleukin-6Intrathecal InjectionsKRAS2 geneKnowledgeLeadLocationMalignant NeoplasmsMeasuresModelingMorphineMusMutationMyoclonusNauseaNociceptionNociceptorsOncogenesOncogenicOpioidOral cavityOrofacial PainPainPain managementParentsPathway interactionsPatient-Focused OutcomesPatientsPattern recognition receptorPersistent painPharmacologyPoly I-CPotassiumProgression-Free SurvivalsQuality of lifeReceptor ActivationRecurrenceRefractoryRegulationReproducibilityResistanceResistance developmentResolutionRestSedation procedureSeminalSeriesSignal TransductionSmokingSpecificityStimulator of Interferon GenesSurveysSymptomsTBK1 geneTLR2 geneTLR3 geneTLR4 geneTP53 geneTestingTongueTumor BurdenTumor-infiltrating immune cellsUnresectableXerostomiaaddictionanti-PD-L1anti-tumor immune responsebasebehavioral studycancer painchemotherapycytotoxic CD8 T cellsdebilitating paindeprivationhead and neck cancer patientimmune checkpoint blockadeimmunogenicityimplantationimprovedin vivoirradiationmacrophagemalignant mouth neoplasmmalignant oropharynx neoplasmmorphine tolerancemu opioid receptorsneoplastic cellnon-opioid analgesicnovelpain modelpain reliefprogramspublic health relevancereduce symptomsresponsereward circuitryside effectsingle cell technologytumortumor microenvironment
项目摘要
PROJECT SUMMARY
An almost universal symptom of head and neck squamous cell carcinoma (HNC) is cancer-related pain. Oral
cavity and oropharyngeal cancers are even more painful than the rest of the head and neck anatomic sites.
HNC-associated pain frequently develops resistance to morphine and few strategies are available for effective
pain management after they develop resistance. In addition, the inevitable morphine dose escalation leads to
constipation, nausea, sedation, dry mouth, and myoclonus, which substantially decrease the patient’s quality of
life. Recent studies have also shown that morphine has undesirable immunosuppressive features. Through the
support of the parent R01 award, we have found that type-I interferon signatures underpin the immunogenicity
of HNC and made seminal contributions to the understanding of oncogenic suppression of type-I interferons by
promoting the rapid turnover of an adaptor protein, stimulator of interferon genes (STING). In addition to the
potential of STING agonists in reprograming the antigen-presenting cells to cross prime CD8+ cytotoxic T-
lymphocytes more effectively, we recently uncovered an unexpected yet powerful function of STING agonists
in promoting analgesia. Hosts that are deficient in the STING-type-I interferon pathway show significantly
elevated nociceptor excitability. We have found that common driver oncogenes for HNC initiation suppress
STING and lead to type-I interferon deprivation in the tumor microenvironment. In this supplement proposal,
we will provide transformative evidence to leverage type-I interferons for the management of HNC-associated,
morphine-resistant pain. To achieve this goal, we have generated novel and rigorous HNC models with high
fidelity resemblance to human HNC mutational features. We will integrate comprehensive modeling, behavior
studies, and single-cell technologies to identify non-opioid agents for HNC pain management.
项目总结
头颈部鳞状细胞癌(HNC)的一个几乎普遍的症状是癌症相关的疼痛。口头的
口腔癌和口咽癌甚至比头颈部的其他解剖部位更痛苦。
HNC相关性疼痛经常对吗啡产生抵抗力,有效的治疗策略很少
在他们产生抵抗力后的疼痛管理。此外,不可避免的吗啡剂量增加会导致
便秘、恶心、镇静、口干和肌阵挛,这些都会显著降低患者的生活质量
生活。最近的研究还表明,吗啡具有不良的免疫抑制特性。通过
支持父母R01奖,我们发现I型干扰素签名支持免疫原性
并为理解HNC对I型干扰素的致癌抑制做出了开创性的贡献。
促进一种适配器蛋白的快速周转,即干扰素基因的刺激物(STING)。除
STING激动剂对抗原提呈细胞重新编程以跨越初始CD8+细胞毒T细胞的潜力
更有效的淋巴细胞,我们最近发现了一种意想不到的强大的刺痛激动剂的功能
在促进止痛方面。缺乏刺痛-I型干扰素途径的宿主显示出显著的
伤害性感受器兴奋性升高。我们已经发现HNC启动抑制的共同驱动癌基因
刺痛并导致肿瘤微环境中的I型干扰素缺失。在这份补充提案中,
我们将提供变革性的证据来利用I型干扰素来管理HNC相关的、
耐吗啡的疼痛。为了实现这一目标,我们生成了新的和严格的HNC模型,具有高
与人类HNC突变特征的保真度相似。我们将综合建模、行为
研究和单细胞技术,以确定用于HNC疼痛控制的非阿片类药物。
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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Christopher Ryan Donnelly其他文献
Christopher Ryan Donnelly的其他文献
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{{ truncateString('Christopher Ryan Donnelly', 18)}}的其他基金
Neuro-immune modulation of pain in health and disease
健康和疾病中疼痛的神经免疫调节
- 批准号:
10522386 - 财政年份:2022
- 资助金额:
$ 25万 - 项目类别:
Neuro-immune modulation of pain in health and disease
健康和疾病中疼痛的神经免疫调节
- 批准号:
10686995 - 财政年份:2022
- 资助金额:
$ 25万 - 项目类别:
Understanding the Function of GFL-Ret Signaling in the Development of the Periphe
了解 GFL-Ret 信号在外周发育中的功能
- 批准号:
8867869 - 财政年份:2014
- 资助金额:
$ 25万 - 项目类别:
Understanding the Function of GFL-Ret Signaling in the Development of the Periphe
了解 GFL-Ret 信号在外周发育中的功能
- 批准号:
8716461 - 财政年份:2014
- 资助金额:
$ 25万 - 项目类别:














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