Dissecting the heterogeneity of oral cancer pain

项目总结/摘要 该提案提出了一个为期五年的研究职业发展计划，重点是神经生物学 口腔癌疼痛的机制。候选人是一名临床科学家，坚定地致力于 从事儿科患者口面疼痛神经生物学的转化研究。概述的 提案建立在候选人以前的基础和临床研究技能，通过整合以患者为导向的 翻译研究在纽约大学布莱恩施密特博士的指导下，候选人将 我有机会与一个研究项目，定义了疼痛的口面的临床表型 条件，并开发了一种范式，允许研究人员测试伤害性机制负责 疼痛状态的表型特征。拟议的研究和职业发展计划将 为候选人提供一套独特的跨学科技能，使其能够过渡到独立 作为一名专注于儿科患者口面疼痛临床管理的转化科学家。 口腔癌的发病率在美国迅速上升。越来越多的患者患有口腔癌 比黑色素瘤、宫颈癌或卵巢癌更严重。口面部疼痛是最常见的初始症状之一 口腔癌的早期症状，并经常导致口腔癌的诊断。然而，性格，严重性和独特性 口腔癌疼痛的特征在患者之间差异很大。目前没有有效和持久的治疗方法 可缓解口腔癌疼痛。临床和临床前数据表明， 疼痛通过介质的分泌，激活和敏化伤害感受器;然而，特定的 伤害感受介质的作用及其作用机制（即，责任受体）是未知的。 这项建议的基础是基于初步研究表明，口腔癌患者 经历对辣椒素的术前敏感性（即，化学敏感性）并报告更大的功能性（即， 机械敏感性）疼痛。概述的实验将测试这样一个假设，即所经历的疼痛的质量 口腔癌患者的疼痛依赖于伤害感受器上特定通道的激活水平。整体 该提案的目标是：1）开发和验证测定，以定量机械和化学敏感性， 口腔癌患者，并与健康受试者比较敏感性，以及2）确定受体亚型 负责口腔癌小鼠模型中的伤害感受行为。从建议中获得的知识 研究为开发新的非阿片类药物治疗策略提供了相当大的希望， 专门针对个别患者所经历的独特疼痛。圆满完成拟议的 培训计划将为候选人提供必要的技能和经验，以指导一个综合的临床 和实验室研究计划，以解决儿童牙科患者的疼痛相关的挑战。

PROJECT SUMMARY/ABSTRACT This proposal presents a five-year research career development program focused on the neurobiologic mechanisms responsible for oral cancer pain. The candidate is a clinician-scientist and is firmly committed to a career in translational research studying the neurobiology of orofacial pain in pediatric patients. The outlined proposal builds on the candidate’s previous basic and clinical research skills by integrating patient-oriented translational research. Under the mentorship of Dr. Brian Schmidt at New York University, the candidate will have the opportunity to work with a research program that defined the clinical phenotype of a painful orofacial condition, and developed a paradigm that allows investigators to test nociceptive mechanisms responsible for the phenotypic features of the painful condition. The proposed research and career development plan will position the candidate with a unique set of cross disciplinary skills that will enable her transition to independence as a translational scientist focused on the clinical management of orofacial pain in pediatric patients. The incidence of oral cancer is rapidly increasing in the United States. More patients are afflicted with oral cancer than melanoma, cervical cancer, or ovarian cancer. Orofacial pain is one of the most common initial symptoms of oral cancer and often leads to the diagnosis of oral cancer. However, the character, severity, and unique features of oral cancer pain widely differ between patients. There is currently no effective and lasting treatment available to alleviate suffering from oral cancer pain. Clinical and preclinical data suggest that cancer causes pain through the secretion of mediators that activate and sensitize nociceptors; however, the specific contributions of nociceptive mediators and their mechanisms of action (i.e., responsible receptors) are unknown. The foundation for this proposal is based on preliminary studies demonstrating that oral cancer patients experience preoperative sensitivity to capsaicin (i.e., chemosensitivity) and report greater functional (i.e., mechanosensitivity) pain. The outlined experiments will test the hypothesis that the quality of pain experienced by oral cancer patients is dependent on the level of activation of specific channels on nociceptors. The overall objectives of this proposal are to 1) develop and validate assays to quantify mechano- and chemosensitivity in oral cancer patients, and compare the sensitivities to healthy subjects, and 2) determine the receptor subtypes responsible for nociceptive behavior in an oral cancer mouse model. The knowledge gained from the proposed research holds considerable promise for the development of novel, non-opioid treatment strategies that specifically address the unique pain experienced by individual patients. Successful completion of the proposed training plan will provide the candidate with the skills and experience necessary to direct an integrated clinical and laboratory research program to address pain-related challenges in pediatric dental patients.