TRPA1 regulation of oral cancer nociception

TRPA1 调节口腔癌伤害感受

• 批准号: 10437911
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437911
• 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; Structure of trigeminal ganglion; TRP channel; Testing; Thermal Hyperalgesias; Vanilloid; Ventilatory Depression; Xenograft Model; afferent nerve; allodynia; antagonist; cancer cell; cancer pain; cancer site; chemical hypersensitivity; chronic pain; cohort; density; design; experience; innovation; malignant mouth neoplasm; mechanical allodynia; mechanical stimulus; 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.

项目总结