Integrating Biomechanics and Cell Biology to Understand TMJ Pathology

描述(申请人提供)：颞下颌关节紊乱病(TMJD)是一个重要的国家健康问题，在美国有超过3500万人受到影响。TMJ关节盘机械功能障碍，尤其是组织退变导致的移位，是许多TMJ疾病的中心。一般认为，病理性机械负荷，例如持续咬合或错牙合，会触发一系列分子事件，导致TMJ盘退变。然而，人们对其机制知之甚少。正常的TMJ间盘是一个大的无血管结构，营养供应是维持间盘健康的关键。本项目的目标是开发一种非侵入性的集成动态测量系统(具有TMJ成像、颌骨跟踪和TMJ盘有限元模型)，以建立TMJ盘的颌骨负荷(模式和大小)、营养浓度分布(氧/葡萄糖/乳酸)和代谢率(氧/葡萄糖利用和ATP/乳酸生产)之间的定量关系。我们假设TMJ盘中的营养物质浓度和细胞代谢率对颌骨功能过程中机械负荷的模式和大小很敏感，因此可以作为评估机械负荷对TMJD影响的早期生物学指标。我们将追求四个具体目标来检验这一假说。目的1：测定与机械应变有关的猪TMJ圆盘的传输特性。目的2：测定猪颞下颌关节盘细胞能量代谢率与营养浓度的关系。目的3：研制一种无创综合动态测量系统，用于测定TMJ盘内营养素浓度和细胞代谢率的分布。目的：测试机械加载方式和大小对TMJ盘中营养物质浓度和细胞代谢率的影响，并根据其机械敏感性确定潜在的生物指标。颌骨功能(AIM 4)期间特定受试者的营养环境和相应的TMJ细胞代谢率将使用机械电化学信号分析器(即验证的有限元模型)来确定，输入来自AIM 3的动态TMJ解剖以及来自AIM 1的组织运输特性和来自AIM 2的细胞能量代谢率。拟议的AIMS的成功完成将1)建立一种新的途径来理解与关节负荷、组织营养和细胞代谢相关的TMJ病理；2)识别潜在的TMJ早期退变的生物指标；3)建立一种新的动态测量系统，用于患者特异性地检测早期诊断的生物指标；4)由于营养是软骨组织工程的关键前提，为TMJ的组织再生提供基础的运输和能量代谢数据；5)论证采用这种多尺度方法研究关节力学生物学的可行性和重要性。尽管我们的重点将放在猪模型上，但由于它是最接近人类TMJ特性的，因此生物指标和测量系统都将在未来直接转化为人体研究，展示这一拟议项目在TMJ研究中的长期和重大影响。

DESCRIPTION (provided by applicant): Temporomandibular joint disorders (TMJD) are an important national health problem affecting more than 35 million people in the United States. Mechanical dysfunction of TMJ disc, especially displacement due to tissue degeneration, is central to many TMJ disorders. It is generally believed that pathological mechanical loadings, e.g. sustained jaw clenching or malocclusion, trigger a cascade of molecular events leading to TMJ disc degeneration. However, the mechanism is poorly understood. The normal TMJ disc is a large avascular structure and nutrient supply is crucial for maintaining disc health. The objective of this project is to develop a non-invasive integrated dynamic measuring system (with TMJ imaging, jaw tracking, and TMJ disc finite element model) to establish quantitative relationships between jaw loading (pattern and magnitude), nutrient concentration profiles (oxygen/glucose/lactate), and metabolic rates (oxygen/glucose use and ATP/Lactate production) in TMJ disc. We hypothesize that the nutrient concentrations and cell metabolic rates in TMJ disc are sensitive to the pattern and magnitude of the mechanical loading during jaw function and are therefore potential early bio-indicators for evaluating the impact of mechanical loading on TMJD. Four specific aims will be pursued to test this hypothesis. Aim 1: Determine transport properties of porcine TMJ discs in relation to mechanical strains. Aim 2: Determine porcine TMJ disc cell energy metabolic rates in relation to nutrient concentrations. Aim 3: Develop a non-invasive integrated dynamic measuring system to determine the profiles of nutrient concentrations and cell metabolic rates in TMJ disc. Aim 4: Test the impact of mechanical loading pattern and magnitude on nutrient concentrations and cell metabolic rates in TMJ disc and identify potential bio-indicators based on their mechanical sensitivities. Subject-specific nutrient environment and corresponding cell metabolic rates in TMJ disc during jaw function (Aim 4) will be determined using a mechano-electrochemical signal analyzer (i.e., validated finite element model) with inputs of dynamic TMJ anatomy from Aim 3 as well as tissue transport properties from Aim 1 and cell energy metabolic rates from Aim 2. Successful completion of the proposed aims will 1) establish a new approach to our understanding of TMJ pathology related to joint loading, tissue nutrition, and cell metabolism; 2) identify potential bio-indicators of early TMJ disc degeneration; 3) establish a novel dynamic measuring system to patient-specifically determine those bio-indicators for early diagnosis; 4) provide foundational transport and energy metabolic data for TMJ disc tissue regeneration since nutrition is a key prerequisite for cartilaginous tissue engineering; and 5) demonstrate the feasibility and importance to take this multiscale approach to study joint mechanobiology in general. Although our focus will be on the porcine model, since it is the closest to human TMJ properties, the bio-indicators and measuring systems will all be directly translated to human studies in the future, demonstrating the long term and significant impact of this proposed project in TMJ research.