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.

项目摘要 口腔癌疼痛比所有其他癌症都更严重。转移性口腔癌患者经历 最大的痛苦。口服癌症激活神经元并产生疼痛；但是，伤害感受器对口服的影响 癌症在很大程度上是未知的。口腔癌与神经元之间的相互相互作用的机制，以及 相互作用如何促进癌症和疼痛。长期目标是改善管理 通过鉴定癌症微环境的组成部分，口腔癌患者的患者并消除阿片类药物 可行的治疗癌症和口腔癌疼痛的靶标。此应用程序的总体目标是（i）阐明 瞬态受体电位通道的表型和分布，香草素亚家族成员（TRPV1） + 神经元支配疼痛和转移性口服癌症，（ii）测量TRPV1+的激活 口腔癌分泌的介质神经元，以及（iii）确定TRPV1+神经元对口服的贡献 致癌作用。中心假设是口服癌症释放介体，包括介导的介体 细胞外囊泡（EV），使伤害感受器诱发口腔癌疼痛。癌症 - 启动的伤害感受器反过来促进癌症。该项目的理由是确定组件 癌症的互动提供了开发口腔癌和口腔治疗方法的机会 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特定的特定 目的：1）确定与疼痛和转移有关的口服癌症中神经的类型和密度； 2） 通过癌症止痛介质研究三叉神经（TG）神经元的敏化； 3）研究癌症 癌症促进激活和敏化的TRPV1+神经元，并评估阻止癌症和 通过感觉神经肽，降钙素基因相关肽来减轻癌症疼痛 （CGRP）。在第一个目标下，将在回顾性患者中评估癌症的神经元神经 队列具有已知疼痛和淋巴结状态，并测试辣椒素（TRPV1激动剂）敏感性和 前瞻性招收的口腔癌患者将进行疼痛的测量。为了第二个目标 与电动汽车的疼痛，转移和miRNA相关的基因将作为止痛介质研究。为了 小鼠口服癌变模型将用于研究TRPV1丰度的影响 关于癌症的发生率和表型，CGRP信号对癌症促进的影响以及潜力 CGRP/CGRP受体疗法用于治疗和预防口腔癌和口腔癌疼痛。研究 提出的是创新的，因为它基于有关口腔癌疼痛的两个新发现：（1）新发现 假定的癌症止痛介质在来自报告高水平疼痛的患者的转移性癌症中过表达 （2）电动汽车参与癌症引起的伤害性行为。拟议的研究很重要 因为这些研究将为评估针对CGRP和CGRP受体的临床试验奠定基础 FDA批准用于偏头痛的疗法治疗癌症和减轻癌症疼痛。