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.

每年诊断出全球范围内近40万例口腔癌。大多数接受放疗，这可以挽救患者的寿命，但会导致辐射引起的并发症，例如静脉，严重牙列崩溃和咀嚼功能的丧失。目前对放射后牙列的理解辐射引起的静态症的崩溃被认为是最重要的病因因素，不是充分解释观察到的放射后病变特征，并在加载时具有初始搪瓷损失和弯曲部位（颈/切口/cuspal）。我们最近的临床研究数据首次表明直接牙齿级辐射剂量与单个牙齿病变的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分解的改进取决于对辐射引起的牙齿损伤的基本机制。解释辐射引起的机制目前未知牙齿水平的故障。潜在的解释可以与体外报告有关辐射引起的搪瓷和牙本质物理特性的变化。但是，牙列崩溃放射疗法往往会在第一年开始，并且随着时间的流逝变得更加严重。我们提出了这一点辐射可能会导致牙齿结构直接改变，但还必须考虑其他因素才能解释放射疗法和牙列分解之间的经过的时间。一个重要的因素可以是环状咬合负荷。我们期望放射治疗对牙齿结构的影响变得更多随着时间的推移，咀嚼功能可见。另一个机械因素可能是辐射引起的激活牙本小管中的基质金属蛋白酶（MMP）以及胶原基质。 MMP激活其次是胶原蛋白降解可能有助于财产和结构变化，也部分解释经过的时间。我们的中心假设是放疗可能导致胶原蛋白直接变化，矿物结构和可能的间接变化通过增加牙齿相关的MMP的活性额外的胶原基质降解。累积地，这些影响可能导致属性/结构变化牙本质，搪瓷和DEJ的功能下将对应力分布模式产生不利影响加载中。具体目的将确定1）放射治疗是否改变了牙本质的机械性能，搪瓷和dej; 2）生成的机械性能差异与化学组成/结构变化； 3）咬合/功能载荷进一步改变机械性能和结构辐射牙齿； 4）辐射诱导的性质/结构变化对DEJ的负载转移负面影响通过有限元建模预测； 5）放射疗法增加了牙齿相关酶（如MMP）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疗法对牙列的影响以及改变的结构/功能特征辐射牙齿可改善放射后口腔癌患者的预防和恢复性治疗。

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.

DOI：
10.1007/s10853-012-6693-7
发表时间：
2012-12
期刊：
JOURNAL OF MATERIALS SCIENCE
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.

Safety considerations for IMRT: Executive summary.

DOI：
10.1016/j.prro.2011.04.008
发表时间：
2011-07
期刊：
Practical radiation oncology
影响因子：
3.3
作者：
Moran JM;Dempsey M;Eisbruch A;Fraass BA;Galvin JM;Ibbott GS;Marks LB
通讯作者：
Marks LB

Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline.

DOI：
10.1016/j.prro.2011.12.004
发表时间：
2012-07
期刊：
Practical radiation oncology
影响因子：
3.3
作者：
Tsao, May N;Rades, Dirk;Wirth, Andrew;Lo, Simon S;Danielson, Brita L;Gaspar, Laurie E;Sperduto, Paul W;Vogelbaum, Michael A;Radawski, Jeffrey D;Wang, Jian Z;Gillin, Michael T;Mohideen, Najeeb;Hahn, Carol A;Chang, Eric L
通讯作者：
Chang, Eric L

Radiotherapy effect on nano-mechanical properties and chemical composition of enamel and dentine.