TRPV1 nociceptors in oral carcinogenesis and pain

TRPV1 伤害感受器在口腔癌发生和疼痛中的作用

• 批准号: 10600862
• 负责人: Donna G Albertson
• 金额: $ 60.57万
• 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: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600862
• 关键词: Afferent Neurons; Agonist; Attention; Attenuated; Behavior; Behavioral; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cancer Patient; Capsaicin; Cell Line; Cells; Chemicals; Clinical Trials; Data; Disseminated Malignant Neoplasm; Enrollment; Epithelial Cells; FDA approved; Foundations; Ganglia; Genes; Goals; Growth; Head and Neck Squamous Cell Carcinoma; Hyperalgesia; Incidence; Invaded; Malignant Neoplasms; Measurable; Measures; Mediator; MicroRNAs; Migraine; Modeling; Mus; Neoplasm Metastasis; Nerve; Neurons; Neuropeptides; Nociception; Nociceptive Stimulus; Nociceptors; Nodal; Nonmetastatic; Opioid; Pain; Pain Measurement; Painless; Patients; Peptide Signal Sequences; Phenotype; Proliferating; Proteins; Reporting; Research; Rodent Model; Sampling; Sensory; Signal Transduction; Spinal Ganglia; Stains; Stimulus; Stromal Cells; Structure of trigeminal ganglion; TRPV channel; TRPV1 gene; Testing; Tissues; Trigeminal System; afferent nerve; angiogenesis; attenuation; cancer cell; cancer pain; cancer therapy; carcinogenesis; chronic pain; cohort; density; experience; extracellular vesicles; immunoreactivity; improved; innovation; malignant mouth neoplasm; mechanical allodynia; member; mouse model; nerve supply; neuroregulation; novel strategies; oral carcinogenesis; oral pain; overexpression; perineural; prevent; prospective; response; spinal nerve posterior root; targeted treatment; tumor microenvironment

Project Summary Oral cancer pain is more severe than all other cancers. Patients with metastatic oral cancer experience the greatest pain. Oral cancers activate neurons and produce pain; however, the effect of nociceptors on oral cancer is largely unknown. The mechanisms of reciprocal interaction between oral cancer and neurons, and how the interactions promote cancer and pain, are not known. The long-term goal is to improve management of oral cancer patients and obviate opioids by identifying components of the cancer microenvironment that are viable targets to treat cancer and oral cancer pain. The overall objectives for this application are to (i) elucidate the phenotype and distribution of transient receptor potential channel, vanilloid subfamily member (TRPV1) + neurons innervating painful and metastatic oral cancers, (ii) measure sensitization and activation of TRPV1+ neurons by mediators secreted by oral cancer, and (iii) determine the contribution of TRPV1+ neurons to oral carcinogenesis. The central hypothesis is that oral cancers release mediators, including mediators carried in extracellular vesicles (EVs) that sensitize and activate nociceptors inducing oral cancer pain. The cancer- primed nociceptors, in turn, promote cancer. The rationale for the project is that identification of components of the cancer-nerve interaction provides the opportunity to develop approaches to treat oral cancer and oral cancer pain, thereby reducing use of opioids. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the type and density of innervation in oral cancers in relation to pain and metastasis; 2) Investigate sensitization of trigeminal (TG) neurons by cancer pain mediators; and, 3) Investigate cancer promotion by cancer activated and sensitized TRPV1+ neurons and evaluate the potential to stop cancer and alleviate cancer pain by antagonizing signaling via the sensory neuropeptide, calcitonin gene related peptide (CGRP). Under the first aim, neuronal innervation of the cancer will be evaluated in a retrospective patient cohort with known pain and nodal status, and testing for capsaicin (TRPV1 agonist) sensitivity and measurement of pain will be performed in prospectively enrolled oral cancer patients. For the second aim, a gene associated with pain and metastasis and miRNAs from EVs will be investigated as pain mediators. For the third aim a mouse oral carcinogenesis model will be used to investigate the impact of TRPV1 abundance on cancer incidence and phenotype, the impact of CGRP signaling on cancer promotion, and the potential for CGRP/CGRP receptor therapies for treating and preventing oral cancer and oral cancer pain. The research proposed is innovative because it is based on two new findings regarding oral cancer pain: (1) newly identified putative cancer pain mediators overexpressed in metastatic cancers from patients reporting high levels of pain, and (2) involvement of EVs in cancer induced nociceptive behavior. The proposed research is significant because these studies will lay the foundation for clinical trials to assess CGRP and CGRP receptor targeted therapies, which are FDA-approved for migraine, to treat cancer and attenuate cancer pain.

项目概要 口腔癌的疼痛比所有其他癌症都更严重。转移性口腔癌患者会经历以下情况 最大的痛苦。口腔癌会激活神经元并产生疼痛；然而，伤害感受器对口腔的影响 癌症在很大程度上是未知的。口腔癌和神经元之间相互作用的机制，以及 这种相互作用如何促进癌症和疼痛尚不清楚。长期目标是提高管理水平 通过识别癌症微环境的组成部分，对口腔癌患者进行治疗并避免使用阿片类药物 治疗癌症和口腔癌疼痛的可行目标。该应用程序的总体目标是 (i) 阐明 瞬时受体电位通道的表型和分布，香草酸亚家族成员（TRPV1）+ 神经元支配疼痛和转移性口腔癌，(ii) 测量 TRPV1+ 的敏化和激活 神经元通过口腔癌分泌的介质，以及（iii）确定 TRPV1+ 神经元对口腔的贡献 致癌作用。中心假设是口腔癌释放介质，包括携带的介质 细胞外囊泡（EV）可敏化并激活伤害感受器，从而诱发口腔癌疼痛。癌症—— 引发的伤害感受器反过来又会促进癌症。该项目的基本原理是识别组件 癌症与神经的相互作用为开发治疗口腔癌和口腔癌的方法提供了机会 癌症疼痛，从而减少阿片类药物的使用。中心假设将通过追求三个具体的 目标：1) 确定口腔癌中与疼痛和转移相关的神经支配类型和密度； 2） 研究癌痛介质对三叉神经 (TG) 神经元的敏化作用；以及，3) 研究癌症 癌症激活和敏化的 TRPV1+ 神经元的促进作用，并评估阻止癌症和 通过拮抗感觉神经肽、降钙素基因相关肽的信号传导来减轻癌症疼痛 （CGRP）。第一个目标是对癌症的神经元神经支配进行回顾性患者评估 已知疼痛和淋巴结状态的队列，并测试辣椒素（TRPV1 激动剂）敏感性和 将在前瞻性入组的口腔癌患者中进行疼痛测量。对于第二个目标， 与疼痛和转移相关的基因以及来自 EV 的 miRNA 将作为疼痛介质进行研究。为了 第三个目标将使用小鼠口腔癌模型来研究 TRPV1 丰度的影响 CGRP 信号对癌症发病率和表型的影响，以及 CGRP 信号对癌症促进的影响，以及 用于治疗和预防口腔癌和口腔癌疼痛的 CGRP/CGRP 受体疗法。研究 提议具有创新性，因为它基于关于口腔癌疼痛的两项新发现：（1）新发现 假定的癌症疼痛介质在来自报告高水平疼痛的患者的转移性癌症中过度表达， (2) EVs参与癌症诱发的伤害性行为。拟议的研究意义重大 因为这些研究将为评估CGRP和靶向CGRP受体的临床试验奠定基础 经 FDA 批准用于治疗偏头痛的疗法可治疗癌症并减轻癌症疼痛。