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: 10358603
• 负责人: Donna G Albertson
• 金额: $ 62.74万
• 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/10358603
• 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; Lead; Malignant Neoplasms; Measurable; Measures; Mediator of activation protein; 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; Proteins; Reporting; Research; Rodent Model; Sampling; Sensory; Signal Transduction; Spinal Ganglia; Stains; Stimulus; Stromal Cells; Structure of trigeminal ganglion; TRPV channel; Testing; Tissues; Trigeminal System; afferent nerve; angiogenesis; attenuation; base; cancer cell; cancer pain; cancer therapy; carcinogenesis; chronic pain; cohort; density; experience; extracellular vesicles; immunoreactivity; improved; innovation; malignant mouth neoplasm; mechanical allodynia; member; migraine treatment; 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.

项目总结