Understanding the mechanism of radiotherapy-induced dentition breakdown

了解放射治疗引起的牙列破坏的机制

基本信息

批准号：
8721204
负责人：
MARY P WALKER
金额：
$ 37.13万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-03 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721204
关键词：
Affect Attention Behavior Brain Breast Cancer Patient Cervical Characteristics Chemical Structure Chemicals Clinical Clinical Research Collagen Collagen Fibril Colon Data Dental Dental Care Dental Enamel Dental caries Dentin Dentition Dentures Dose Elements Enzymes Exposure to Fracture Future Head and neck structure In Vitro Individual Knowledge Lead Lesion Life Link Lung Malignant - descriptor Matrix Metalloproteinases Mechanics Minerals Modeling Neoplasm Metastasis Oral cavity Oral mucous membrane structure Outcome Study Patients Pattern Preventive Property Proteins Protocols documentation Radiation Radiation Protection Radiation induced damage Radiation therapy Radiation-Induced Change Reporting Salivary Glands Severities Simulate Site Stress Structure Surface Testing Time Tooth Diseases Tooth structure Up-Regulation Xerostomia cancer diagnosis improved in vitro testing malignant mouth neoplasm matrix metalloproteinase 26 novel strategies physical property prevent research clinical testing restorative treatment

项目摘要

Worldwide nearly 400,000 cases of oral cancer are diagnosed annually. Most are treated with radiotherapy, which saves the life of the patient but results in radiation-induced complications such as xerostomia, severe dentition breakdown and loss of masticatory function. The present understanding of post-radiation dentition breakdown, with radiation-induced xerostomia considered the most significant etiological factor, does not adequately explain the observed post-radiation lesion characteristics with initial enamel loss at loading and flexure sites (cervical/incisal/cuspal). Our recent clinical study data indicate for the first time a direct and independent link between tooth-level radiation dose and the severity of the individual tooth lesion. Thus, future improvements for preventing and treating post-radiation dentition breakdown depend on new knowledge of the underlying mechanism of radiation-induced tooth damage. A mechanism explaining radiation-induced breakdown at the tooth level is currently unknown. A potential explanation could be linked to reports of in vitro radiation-induced changes in the physical properties of enamel and dentin. However, dentition breakdown following radiotherapy tends to start within the first year and become more severe with time. We propose that radiation may cause a direct change in tooth structure, but other factors must also be considered in order to explain the elapsed time between radiotherapy and dentition breakdown. One important contributing factor could be cyclic occlusal loading. We expect that effects of radiotherapy on the structure of teeth become more evident with masticatory function over time. Another mechanistic factor could be radiation-induced activation of matrix metalloproteinases (MMPs) in the dentinal tubules as well as the collagen matrix. MMP activation followed by collagen degradation could contribute to property and structure changes and also partially explain the elapsed time. Our central hypothesis is that radiotherapy could cause direct changes in collagen and mineral structures and possible indirect changes through increased activity of tooth-associated MMPs leading to additional collagen matrix degradation. Cumulatively, these effects could result in property/structure changes of dentin, enamel and the DEJ that would adversely affect the stress distribution pattern under functional loading. The specific aims will determine whether 1) radiotherapy changes the mechanical properties of dentin, enamel and the DEJ; 2) resultant mechanical property differences correlate with chemical composition/structure changes; 3) occlusal/functional loading further alters mechanical properties and structure of radiated teeth; 4) radiation-induced property/structure changes negatively affect load transfer at the DEJ as predicted by finite element modeling; 5) radiotherapy increases activity of tooth-associated enzymes like MMPs leading to additional collagen degradation. The proposed study outcomes should identify mechanism(s) responsible for radiotherapy effects on the dentition and the altered structure/function characteristics of radiated teeth leading to improved preventive and restorative treatments for oral cancer patients post-radiation.

全球每年诊断出近 400,000 例口腔癌病例。大多数都接受放射治疗，这挽救了患者的生命，但会导致辐射引起的并发症，例如口干症、严重的牙列损坏和咀嚼功能丧失。目前对放射后牙列的认识分解，辐射引起的口干症被认为是最重要的病因，但并不充分解释观察到的辐射后病变特征以及加载和初始牙釉质损失弯曲部位（宫颈/切端/牙尖）。我们最近的临床研究数据首次表明直接和牙齿水平辐射剂量与个体牙齿病变严重程度之间的独立联系。因此，未来预防和治疗放射后牙列损坏的改进取决于对以下方面的新认识：辐射引起的牙齿损伤的潜在机制。解释辐射诱发的机制牙齿层面的破坏目前尚不清楚。一个潜在的解释可能与体外实验的报告有关辐射引起的牙釉质和牙本质物理性质的变化。然而，牙列崩坏放疗后的症状往往在第一年内开始，并随着时间的推移变得更加严重。我们建议辐射可能会导致牙齿结构的直接变化，但还必须考虑其他因素解释放射治疗和牙列损坏之间经过的时间。一个重要的影响因素可能是循环咬合负荷。我们预计放射治疗对牙齿结构的影响会变得更大随着时间的推移，咀嚼功能明显。另一个机制因素可能是辐射诱导的激活牙本质小管和胶原蛋白基质中的基质金属蛋白酶（MMP）。基质金属蛋白酶激活随后的胶原蛋白降解可能会导致性质和结构的变化，并部分解释经过的时间。我们的中心假设是放射治疗可能会导致胶原蛋白和胶原蛋白的直接变化矿物结构和通过牙齿相关 MMP 活性增加可能产生的间接变化导致胶原蛋白基质进一步降解。累积起来，这些影响可能会导致属性/结构发生变化牙本质、牙釉质和 DEJ 的变化会对功能下的应力分布模式产生不利影响加载中。具体目标将决定：1）放射治疗是否会改变牙本质的机械性能，牙釉质和DEJ； 2) 由此产生的机械性能差异与化学性质相关成分/结构变化； 3) 咬合/功能负荷进一步改变机械性能和结构辐射齿； 4) 辐射引起的性能/结构变化会对 DEJ 处的载荷传递产生负面影响，如下所示通过有限元建模预测； 5) 放射治疗会增加与牙齿相关的酶（如基质金属蛋白酶）的活性导致额外的胶原蛋白降解。拟议的研究结果应确定机制负责放射治疗对牙列的影响以及牙列结构/功能特征的改变放射牙齿可以改善放射后口腔癌患者的预防和恢复治疗。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Distribution of Carbonate in Enamel and its Correlation with Structure and Mechanical Properties.

牙釉质中碳酸盐的分布及其与结构和力学性能的相关性。

DOI：
发表时间：
2012-12
期刊：
影响因子：
4.5
作者：
Xu, Changqi;Reed, Rachel;Gorski, Jeffrey P;Wang, Yong;Walker, Mary P
通讯作者：
Walker, Mary P

Stress analysis of irradiated human tooth enamel using finite element methods.

使用有限元方法对受辐射的人体牙釉质进行应力分析。

DOI：
发表时间：
2017-11
期刊：
影响因子：
1.6
作者：
Thiagarajan, Ganesh;Vizcarra, Bruno;Bodapudi, Venkata;Reed, Rachel;Seyedmahmoud, Rasoul;Wang, Yong;Gorski, Jeffrey P;Walker, Mary P
通讯作者：
Walker, Mary P

Enamel organic matrix: potential structural role in enamel and relationship to residual basement membrane constituents at the dentin enamel junction.

牙釉质有机基质：牙釉质中的潜在结构作用以及与牙本质牙釉质交界处残留基底膜成分的关系。

DOI：
发表时间：
2014-08
期刊：
影响因子：
2.9
作者：
McGuire, Jacob D;Walker, Mary P;Dusevich, Vladimir;Wang, Yong;Gorski, Jeff P
通讯作者：
Gorski, Jeff P

Characterization of elemental distribution across human dentin-enamel junction by scanning electron microscopy with energy-dispersive X-ray spectroscopy.

通过扫描电子显微镜和能量色散 X 射线光谱仪表征人体牙本质 - 牙釉质交界处的元素分布。

DOI：
发表时间：
2021-05
期刊：
影响因子：
2.5
作者：
Wang, Rong;Zhao, Donggao;Wang, Yong
通讯作者：
Wang, Yong

Safety considerations for IMRT: Executive summary.

IMRT 的安全注意事项：执行摘要。

DOI：
发表时间：
2011-07
期刊：
影响因子：
3.3
作者：
Moran, Jean M;Dempsey, Melanie;Eisbruch, Avraham;Fraass, Benedick A;Galvin, James M;Ibbott, Geoffrey S;Marks, Lawrence B
通讯作者：
Marks, Lawrence B