TRPA1 regulation of oral cancer nociception

TRPA1 调节口腔癌伤害感受

• 批准号: 10288005
• 负责人: Aditi Bhattacharya
• 金额: $ 15.85万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288005
• 关键词: Acids; Afferent Neurons; Anatomy; Animals; Ankyrin Repeat; Cancer Model; Cancer Patient; Carcinogens; Chemicals; Constipation; Data; Dependence; Development; Dose; Eating; Fiber; Foundations; Functional disorder; Goals; Head and Neck Cancer; Human; Hyperalgesia; Hypersensitivity; Knowledge; Lead; Malignant Neoplasms; Measurable; Measures; Mechanics; Mediating; Mediation; Mediator of activation protein; Molecular; National Institute of Dental and Craniofacial Research; Nerve; Neurobiology; Neuronal Plasticity; Neurons; Nociception; Nociceptors; Non-Malignant; Opioid; Oral; Orofacial Pain; Outcome; Pain; Pain management; Painless; Patients; Pharmaceutical Preparations; Quality of life; Regulation; Reporting; Research; Retrospective cohort; Role; Sampling; Sensory; Spinal Ganglia; Stimulus; Structure of trigeminal ganglion; TRP channel; Testing; Thermal Hyperalgesias; Vanilloid; Ventilatory Depression; Xenograft Model; afferent nerve; allodynia; cancer cell; cancer pain; cancer site; chemical hypersensitivity; chronic pain; cohort; density; design; experience; innovation; malignant mouth neoplasm; mechanical allodynia; mouse model; mustard oil; nerve supply; non-opioid analgesic; novel therapeutics; oral pain; pain score; prospective; receptor; relating to nervous system; response; side effect; tumor microenvironment

Project summary Oral cancer patients suffer persistent and severe pain at the primary site of the cancer. Oral cancer pain is poorly managed with opioids. A small subset of cancer patients do not report pain. Oral cancer pain is initiated and maintained in the tumor microenvironment (TME). Mediators released from the cancer sensitize primary afferent neurons (nociceptors) and may also increase neuronal density in the TME to produce mechanical, thermal and chemosensory hyperalgesia. Oral cancer patients report mechanical and functional allodynia, as well as thermal and chemical hypersensitivity. These findings have been replicated in oral cancer mouse models. Transient receptor potential (TRP) channels on neurons have been implicated in orofacial pain. TRP vanilloid 1 (TRPV1) responds to acid and heat, but not mechanical stimuli. By contrast, TRP ankyrin repeat 1 (TRPA1), which is co-expressed with TRPV1 on a subset of nociceptors, has been implicated in mechanical allodynia. Cancer pain is associated with increased density of nerves in the cancer microenvironment, suggesting that increased TRPA1+ neuronal density in the TME of painful oral cancers mediates the mechanical and functional allodynia experienced by patients. There is a gap in our knowledge, however, regarding the neurobiological role of TRPA1 in mediation of oral cancer pain. The long-term goal is to define the molecular anatomy of the oral cancer microenvironment, and the associated mechanisms that contribute to oral cancer pain. The overall objectives of this application are to; 1) determine whether density of TRPA1+ fibers in the TME is greater in oral cancers from patients who report high levels of pain and 2) determine the contribution of TRPA1 to mechanical allodynia and thermal hyperalgesia evoked by mediators released from oral cancer cells in a mouse model of oral cancer pain. The central hypothesis is that oral cancer induced pain (mechanical allodynia and thermal hyperalgesia) is mediated by sensitization of TRPA1 on sensory neurons. The rationale for this project is that identification of specific receptors on sensory neurons sensitized by oral cancer pain mediators provides the opportunity to develop novel therapies for oral cancer pain to reduce dependence on opioids. The central hypothesis will be tested by pursuing two specific aims: 1) Evaluate TRPA1 expression in a retrospective cohort of oral cancer patients with painful and non-painful cancers 2) Evaluate the impact of TRPA1 on oral cancer nociception in a mouse model. Under the first aim TRPA1+ neuronal density in the TME will be measured in a retrospective patient cohort with highest and lowest pain scores. For the second aim impact of TRPA1 on mechanical and thermal hypersensitivity will be measured in a mouse model of oral cancer pain. The proposed research is innovative because the impact of TRPA1 on oral cancer pain has not been studied. The proposed study is significant, because the results will determine whether antagonism of the TRPA1-oral cancer axis could be beneficial in mitigation of oral cancer pain.

项目摘要 口腔癌患者在癌症的主要部位遭受持久和严重的疼痛。口腔癌疼痛是 阿片类药物管理不佳。一小部分癌症患者不会报告疼痛。口腔癌疼痛开始 并保持在肿瘤微环境（TME）中。癌症释放的介体敏感 传入神经元（伤害感受器），也可能增加TME中的神经元密度，以产生机械性， 热和化学感应痛觉过敏。口腔癌患者报告机械和功能性异常性症，AS 以及热和化学超敏反应。这些发现已在口腔癌小鼠中复制 型号。神经元上的瞬时受体电位（TRP）通道已与口面疼痛有关。 trp 香草酸1（TRPV1）对酸和热量反应，但没有机械刺激。相比之下，trp Ankyrin重复1 （TRPA1）与TRPV1在伤害感受器的子集上共表达，已经与机械有关 异常性。癌症疼痛与癌症微环境中神经密度的增加有关， 表明疼痛口服癌症TME中TRPA1+神经元密度增加了 患者经历的机械和功能性异常。但是，我们的知识存在差距 关于TRPA1在口腔癌疼痛中的神经生物学作用。长期目标是定义 口腔癌微环境的分子解剖学以及有助于 口腔癌疼痛。该应用程序的总体目标是； 1）确定trpa1+的密度是否 TME中的纤维在口服癌症的口服癌症中更大 TRPA1对机械性异常性痛和热痛觉过敏的贡献 口腔癌疼痛的小鼠模型中的口腔癌细胞。中心假设是口腔癌引起疼痛 （机械性异常性症和热痛觉过敏）是通过在感觉神经元上的TRPA1敏化介导的。 该项目的基本原理是鉴定口服敏感的感觉神经元上的特定受体 癌症止痛介质提供了开发口腔癌疼痛的新疗法以减少的机会 对阿片类药物的依赖。中心假设将通过追求两个具体目标来检验：1）评估 TRPA1在回顾性的口腔癌患者中表达，患有疼痛和非疾病的癌症2） 评估TRPA1对小鼠模型中口腔癌伤害感受的影响。在第一个目标trpa1+下 TME中的神经元密度将在回顾性患者队列中测量，最高和最低疼痛 分数。对于TRPA1对机械和热超敏反应的第二个目标影响，将在A中测量 口腔癌疼痛的小鼠模型。拟议的研究具有创新性，因为TRPA1对口服的影响 尚未研究癌症疼痛。拟议的研究很重要，因为结果将决定 TRPA1-口腔癌轴的拮抗作用是否对缓解口腔癌疼痛有益。