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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

基本信息

批准号：
10440385
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440385
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

项目摘要

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.

项目总结