Dissecting the heterogeneity of oral cancer pain

项目摘要/摘要 这份提案提出了一项为期五年的研究生涯发展计划，重点是神经生物学 口腔癌疼痛的机制。候选人是一名临床医生兼科学家，并坚定地致力于 从事翻译研究，研究儿童患者口腔面部疼痛的神经生物学。概述 方案建立在候选人以前的基础和临床研究技能的基础上，结合了以患者为中心的 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 有机会参与定义口腔面部疼痛临床表型的研究项目 条件，并开发了一种范式，允许研究人员测试负责 疼痛状态的表型特征。拟议的研究和职业发展计划将 让候选人具备一套独特的跨学科技能，这将使她能够过渡到独立 作为一名转化型科学家，他专注于儿童患者口腔面部疼痛的临床治疗。 在美国，口腔癌的发病率正在迅速增加。更多的患者患有口腔癌 黑色素瘤、宫颈癌或卵巢癌。口面部疼痛是最常见的首发症状之一。 这是口腔癌的一种常见疾病，通常导致口腔癌的诊断。然而，特征、严重性和独一无二的 口腔癌疼痛的特点在不同患者之间有很大的不同。目前还没有有效和持久的治疗方法。 可用于缓解口腔癌疼痛的痛苦。临床和临床前数据表明，癌症导致 疼痛通过分泌介质来激活和敏化伤害感受器；然而，特定的 伤害性介质的作用及其作用机制(即负责的受体)尚不清楚。 这项建议的基础是初步研究表明，口腔癌患者 经历了术前对辣椒素的敏感性(即，化疗敏感性)，并报告了更多的功能(即， 机械敏感)疼痛。概述的实验将检验疼痛质量经历的假设 口腔癌患者所受的影响取决于伤害性感受器上特定通道的激活程度。整体而言 这项建议的目标是：1)开发和验证检测方法，以量化机械和化疗敏感性。 2)确定受体亚型 负责口腔癌小鼠模型的伤害性行为。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 具体解决个别患者所经历的独特疼痛。圆满完成拟议中的 培训计划将为应聘者提供必要的技能和经验，以指导综合临床 和实验室研究计划，以解决儿童牙科患者与疼痛相关的挑战。

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.