Functional consequences of sensory neuronal invasion in oral cancer pain and carcinogenesis

感觉神经元侵袭对口腔癌疼痛和癌变的功能影响

• 批准号: 10200764
• 负责人: Nicole N Scheff
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200764
• 关键词: 3-Dimensional; 4-Nitroquinoline-1-oxide; Ablation; Afferent Neurons; Animal Model; Animals; Atlas of Cancer Mortality in the United States; Axotomy; Behavior; Cancer Biology; Cancer Patient; Cell Culture Techniques; Cellular biology; Closure by clamp; Communication; Coupled; Data; Denervation; Development; Electrophysiology (science); Etiology; Excision; Exhibits; Fiber; Gene Expression; Goals; Growth; Histopathology; Immune; Immune response; Immunofluorescence Immunologic; Immunosuppression; In Vitro; Inflammation; Injections; Knowledge; Label; Link; Literature; Local Anesthetics; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Measures; Mediating; Mediator of activation protein; Membrane Potentials; Mentors; Microscopy; Modeling; Mus; Nerve; Nerve Block; Nerve Fibers; Neurons; Neurotransmitters; Nociception; Optics; Oral; Oral cavity; Pain; Peripheral Nerves; Phase; Phenotype; Population; Research; Resolution; Rest; Role; Sensory; Signal Transduction; Structure of trigeminal ganglion; Testing; Thick; Time; Tongue; Training; Training Programs; Trigeminal System; Tumor-infiltrating immune cells; Work; Xenograft Model; Xenograft procedure; afferent nerve; axon growth; cancer cell; cancer pain; carcinogenesis; career; chemical carcinogenesis; chemical genetics; chronic pain; experimental study; genetic manipulation; lingual nerve; malignant mouth neoplasm; malignant stomach neoplasm; malignant tongue neoplasm; mouse model; mouth squamous cell carcinoma; nerve supply; neurotransmitter release; neurotrophic factor; novel therapeutic intervention; oral carcinogenesis; oral sensory; programs; sciatic nerve; skills; spatiotemporal; targeted treatment; tissue culture; treatment response; tumor microenvironment; two-dimensional

PROJECT SUMMARY Oral cancer pain results from activation of primary afferent neurons by cancer-secreted mediators. My previous work demonstrated that mice bearing tongue cancers induced by 4-nitroquinoline-1-oxide (4NQO)- carcinogenesis exhibit nociceptive behavior and trigeminal ganglia neurons (TGNs) innervating the tongue become hyperexcitable. Oral cancer cells also secrete neurotrophic factors that induce neuronal sprouting into the cancer, while local neurotransmitter release from TGNs innervating the cancer has been linked to carcinogenesis. I hypothesize that oral cancer and sensory neurons interact, such that, oral cancer induces sensitization, sprouting and plasticity in neurons, and efferent neuronal activity promotes oral carcinogenesis. In support of my hypothesis, I demonstrated, using an oral cancer xenograft model that nerve axotomy suppressed oral squamous cell carcinoma growth in the hindpaw. To test my hypothesis and to prepare me for an independent research career, I propose in the K99 phase to gain skills in high-resolution microscopy, quantitative analysis, cancer cell biology and oral histopathology. Specifically, I will characterize the type, distribution, sprouting features and development over time of sensory nerves innervating the oral cancer microenvironment during 4NQO-carcinogenesis (Aim 1). In Aim 2, I will determine the reciprocal impact of neuron-cancer communication using cell cultures in vitro. I propose to use these skills in the R00, to study the differential impact of primary afferent neurons on oral cancer pain and carcinogenesis through inhibition of cancer-induced neuronal sprouting and ablation of TGN subpopulations in an oral cancer mouse model. The successful completion of the proposed experiments and training program will further my knowledge in the relationship between sensory neurons and cancer, as well as develop skills I need to pursue an independent research career.

项目摘要 口腔癌疼痛是由癌症分泌的介体激活原发性传入神经元的原因。我的 先前的工作表明，轴承舌癌诱导的小鼠由4-硝基喹啉-1-氧化物（4NQO） - 癌变表现出伤害性行为和三叉神经元神经元（TGNS）支配舌头 变得过度兴奋。口腔癌细胞还分泌诱导神经元发芽到中的神经营养因素 癌症，而局部神经递质从TGN释放了癌症的癌症 致癌作用。我假设口腔癌和感觉神经元相互作用，以便口腔癌 在神经元中诱导敏化，发芽和可塑性，以及传出的神经元活动促进口服 致癌作用。为了支持我的假设，我使用口腔癌异种移植模型证明了神经 轴突切开术抑制了后爪口腔鳞状细胞癌的生长。检验我的假设和 我为独立的研究职业做好准备，我在K99阶段提出建议，以获得高分辨率的技能 显微镜，定量分析，癌细胞生物学和口腔组织病理学。具体来说，我会描述 感觉神经的感觉，分布，发芽特征和发展 癌症微环境在4NQO-癌发生期间（AIM 1）。在AIM 2中，我将确定倒数 在体外使用细胞培养物进行神经元癌通信的影响。我建议在R00中使用这些技能 研究原发性传入神经元对口腔癌疼痛和致癌作用的差异影响 抑制癌症引起的神经元发芽和口腔癌小鼠中TGN亚群的消融 模型。拟议的实验和培训计划的成功完成将进一步了解我的知识 在感觉神经元与癌症之间的关系以及发展技能中，我需要追求 独立研究职业。