The Effect of Radiotherapy on Enamel Associated Proteins

描述(由申请人提供)：本建议书是雅各布·D·麦奎尔为鲁斯·L·基尔施斯坦国家研究服务奖个人博士后研究员(F-32)提交的初步意见书。这一奖项将作为他在密苏里大学堪萨斯城牙学院完成跨学科口腔生物学博士项目的博士教育的平台。此外，这一奖项将使他成为一名独立的牙科研究员，为他的高影响力研究生涯做好准备。这项建议的总体目标是表征放射治疗对牙釉质相关蛋白的影响。大多数口腔癌患者接受放射治疗是因为它具有抗癌和挽救生命的作用。照射后会出现许多负面的口腔后遗症，包括牙釉质丢失/剪切。病理性釉质丢失大大降低了患者的生活质量，限制了日常活动的表现； 并对一个人的心理和社会福祉产生负面影响。牙釉质丢失/剪切开始于放射治疗后，并随着时间的推移而发展，导致牙釉质从支持牙本质部分或完全剥离。如果没有保护性牙釉质，暴露的牙本质会迅速腐烂，并导致进一步的发病。釉质相关蛋白是釉质发育过程中的残留物，在牙本质-釉质交界处高度集中，位于切牙、牙尖、颈部和裂隙区域。根据它们在牙釉质中的位置，它们可以通过赋予DEJ和牙釉质本身的稳定性而起到“粘结材料”的作用。放射治疗后牙釉质在正常稳定的DEJ交界处发生牙釉质剪切的机制尚未阐明。一种可能的解释可能与大量集中在DEJ附近的釉质蛋白有关。我们假设放射治疗可能通过改变牙釉质的结构完整性和化学特征来改变或损伤与牙釉质相关的蛋白质。这些结构和化学变化可能会影响DEJ的稳定性，导致临床观察到的釉质丢失。具体目标将1)表征放射治疗前后釉质相关蛋白的结构完整性；2)表征放射治疗前后釉质相关蛋白的化学特征。拟议的研究结果有可能开始定位导致放射治疗后牙釉质丢失的机制，这将为开始指导放射治疗后患者预防性和恢复性治疗的发展提供至关重要的知识。 公共卫生相关性：大多数口腔癌患者接受放射治疗是因为它具有抗癌和挽救生命的作用。照射后会出现许多负面的口腔后遗症，包括牙釉质丢失/剪切。我们的研究将提供对放射治疗后釉质相关蛋白如何影响的理解，这反过来可能开始分离牙釉质丢失和牙本质-牙釉质连接不稳定的机制。

DESCRIPTION (provided by applicant): This proposal is an initial submission from Jacob D. McGuire, DDS for the Ruth L Kirschstein National Research Service Award (NRSA) for Individual Postdoctoral Fellows (F-32). This award will serve as the platform to complete his doctoral education in the interdisciplinary Oral Biology PhD program at the University of Missouri-Kansas City School of Dentistry. In addition, this award will equip him for a high impact research career as an independent dental researcher. The overall goal of this proposal is to characterize the effect of radiotherapy on enamel associated proteins. The majority of oral cancer patients receive radiotherapy for its anti-cancer and life saving effects. Following irradiation numerous negative oral sequelae develop including enamel loss/shearing. Pathologic enamel loss greatly diminish a patient's quality of life, limit performance of everyday activities; and negatively affect one's psychological and social well-being. Enamel loss/shearing initiates following radiotherapy and progresses over time resulting in partial to complete delamination of enamel from the supporting dentin. Without the protective enamel, exposed dentin decays rapidly and leads to further morbidity. Enamel associated proteins are remnants from developing enamel and are highly concentrated at the dentin-enamel junction (DEJ) in the incisal, cuspal, cervical, and fissure regions. Based on their intraenamel location, they may act as a 'cementing material' by imparting stability to the DEJ and enamel proper. A mechanism to explain why enamel shears at the normally stable junction of the DEJ following radiotherapy has not been elucidated. A potential explanation could be linked to enamel proteins heavily concentrated near the DEJ. We hypothesize that radiotherapy may alter or damage proteins associated with enamel by altering their structural integrity and chemical profile. These structural and chemical changes may affect the stability of the DEJ, resulting in enamel loss observed clinically. The specific aims will 1) characterize the structural integrity of enamel associated proteins before and subsequent to radiotherapy; 2) characterize the chemical profile of enamel associated proteins before and subsequent to radiotherapy. Outcomes of the proposed study have the potential to begin localizing a mechanism contributing to post-radiotherapy enamel loss, which would provide vital knowledge to begin directing development of preventative and restorative treatments for patients post-radiotherapy. PUBLIC HEALTH RELEVANCE: The majority of oral cancer patients receive radiotherapy for its anti-cancer and life saving effects. Following irradiation numerous negative oral sequelae develop including enamel loss/shearing. Our studies will provide understandings of how enamel associated proteins are affected subsequent to radiotherapy, which in turn could begin isolating a mechanism of enamel loss and dentin-enamel junction destabilization.