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: 10088607
• 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/10088607
• 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.

项目概要 口腔癌疼痛是由癌症分泌的介质激活初级传入神经元引起的。我的 先前的工作表明，4-硝基喹啉-1-氧化物（4NQO）诱导小鼠患有舌癌- 癌变表现出伤害性行为和支配舌头的三叉神经节神经元（TGN） 变得极度兴奋。口腔癌细胞还分泌神经营养因子，诱导神经元萌芽 癌症，而支配癌症的 TGN 释放的局部神经递质与 致癌作用。我假设口腔癌和感觉神经元相互作用，因此，口腔癌 诱导神经元的敏化、萌芽和可塑性，传出神经元活动促进口腔 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 轴索切除术抑制了后爪口腔鳞状细胞癌的生长。为了检验我的假设并 为我的独立研究生涯做好准备，我建议在 K99 阶段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，我将描述 支配口腔的感觉神经的类型、分布、萌芽特征和随时间的发展 4NQO 致癌过程中的癌症微环境（目​​标 1）。在目标 2 中，我将确定倒数 使用体外细胞培养物对神经元-癌症通讯的影响。我建议在 R00 中使用这些技能， 研究初级传入神经元对口腔癌疼痛和癌变的不同影响 口腔癌小鼠中癌症诱导的神经元萌芽和 TGN 亚群消融的抑制 模型。成功完成拟议的实验和培训计划将进一步加深我的知识 感觉神经元与癌症之间的关系，以及培养我追求癌症所需的技能 独立的研究生涯。