A Novel Model of TMJ Osteoarthritis to Define Glial Reactivity in Chronic Pain

一种新的颞下颌关节骨关节炎模型来定义慢性疼痛中的神经胶质反应

基本信息

批准号：
7244043
负责人：
Beth A Winkelstein
金额：
$ 17.35万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7244043
关键词：
Adjuvant Aging Animals Arthralgia Arthritis Award Back Behavioral Biochemical Biological Assay Biomedical Engineering Brain Stem Cartilage Cell Separation Cells Cervical spinal cord structure Chronic Clinical Condition Data Degenerative polyarthritis Dependence Development Disease Etiology Foundations Frequencies Funding Future Goals Healthcare Systems Healthy People 2010 Hypersensitivity Immunophenotyping Incidence Inflammation Inflammatory Injury Interleukin-6 Interleukins Invasive Joints Lesion Maintenance Measures Mechanics Mediator of activation protein Methods Modeling Molecular Profiling Neuraxis Neuroglia Neurons Oral cavity Orofacial Pain Osteoarthrosis Deformans Pain Pathogenesis Pattern Physiological Polymerase Chain Reaction Population Production Rattus Research Research Personnel Research Project Grants Research Proposals Role Spinal Symptoms Synovitis Techniques Temporomandibular Joint Temporomandibular Joint Disorders Temporomandibular joint osteoarthritis Time Tissue Engineering Tissues Tumor Necrosis Factor-alpha United States United States National Institutes of Health Work allodynia base behavior test caN protocol career cartilage development cell type chronic pain cytokine experience in vivo in vivo Model instrument novel response

项目摘要

DESCRIPTION (provided by applicant): Chronic pain associated with temporomandibular joint (TMJ) disorders is a major problem in the United States, with poorly defined pathophysiological mechanisms. It is the long-term objective of this application to develop a novel in vivo model of painful mechanically-induced TMJ osteoarthritis in the rat and utilize this model to define mechanisms of glial reactivity and cytokine expression that contribute to TMJ pain. In this proposed research plan, we will integrate bioengineering approaches, behavioral test instruments and biochemical assays to define mechanisms of painful osteoarthritis (OA) in the TMJ. We have preliminary data supporting steady mouth-opening as producing sustained mechanical allodynia in the rat. In this proposal we extend those studies to define the pathogenesis of persistent behavioral sensitivity associated with the development of cartilage degeneration in the TMJ. The goals of the proposed research project are to develop a novel pain model of osteoarthritis in the TMJ via non-invasive and non-adjuvant methods, and to utilize this model to understand the relationship between osteoarthritic changes, behavioral sensitivity, and glial activation in the CMS. We hypothesize that a repeated mouth-opening protocol can induce permanent osteoarthritic changes in TMJ cartilage that depend on loading frequency and applied force. Further, such changes in TMJ cartilage give rise to elevated glial pro-inflammatory cytokine expression in the CNS which contribute to the initiation and maintenance of sustained allodynia, mimicking persistent orofacial pain symptoms. The specific aims of this research are to: (1) develop an in vivo rat model of repeated mouth-opening which produces TMJ osteoarthritic lesions and persistent behavioral sensitivity; and (2) utilize immunophenotyping and cell sorting techniques to separate glial and neuronal cell populations, and real-time PCR to probe cytokine expression profiles in those cells during the onset and maintenance of chronic behavioral sensitivity. Findings from this developmental research project will establish a novel rat model for defining the etiology of TMJ pain and potential future treatment strategies. Relevance: The incidence of TMJ osteoarthritis continues to rise due to the aging United States population. This places growing strain on the United States healthcare system, making it difficult to achieve the objective of 'Healthy People 2010.' This research proposal lays the foundation for defining the cellular mechanisms in the joint and central nervous system associated with chronic pain in the TMJ. It also identifies the time course of physiologic mechanisms of these disorders, and will provide the basis for future studies to investigate potential pharmacologic therapies for chronic TMJ pain.

描述（由申请人提供）：与颞下颌关节（TMJ）疾病相关的慢性疼痛是美国的主要问题，病理生理机制差。这是该应用的长期目标，是开发大鼠中疼痛机械诱导的TMJ骨关节炎的新型体内模型，并利用该模型来定义有助于TMJ疼痛的神经胶质反应性和细胞因子表达的机制。在该提出的研究计划中，我们将整合生物工程方法，行为测试工具和生化测定法，以定义TMJ中疼痛骨关节炎（OA）的机制。我们有初步的数据支持稳定的张开，因为在大鼠中产生了持续的机械性异常性疾病。在此提案中，我们扩展了这些研究，以定义与TMJ软骨变性有关的持续行为敏感性的发病机理。拟议的研究项目的目标是通过非侵入性和非助剂方法开发出一种新型的TMJ骨关节炎疼痛模型，并利用该模型来了解骨关节炎的变化，行为敏感性和CMS中的胶质激活之间的关系。我们假设重复的张开方案可以诱导TMJ软骨的永久性骨关节炎变化，该方案取决于负载频率和施加力。此外，TMJ软骨的这种变化会导致中枢神经系统中神经胶质促炎细胞因子的表达升高，这有助于持续性异常性疾病的启动和维持，从而模仿持续的口面疼痛症状。这项研究的具体目的是：（1）开发一个重复张开的体内大鼠模型，该模型会产生TMJ骨关节炎病变和持续的行为敏感性；（2）在慢性行为敏感性的发作和维持过程中，利用免疫表型和细胞分选技术将这些细胞中的细胞因子表达谱分开，并实时PCR探测这些细胞中的细胞因子表达谱。该发展研究项目的发现将建立一个新的大鼠模型，以定义TMJ疼痛和潜在的未来治疗策略的病因。相关性：由于美国老龄化，TMJ骨关节炎的发生率继续升高。这使美国医疗保健系统的压力越来越大，因此很难实现“健康人2010”的目标。该研究提案为定义与TMJ慢性疼痛相关的关节和中枢神经系统中的细胞机制奠定了基础。它还确定了这些疾病的生理机制的时间过程，并将为未来的研究提供基础，以研究慢性TMJ疼痛的潜在药理疗法。