Function and Behavior Phenotype of Inflammatory Arthritis in the Rat Knee and TMJ

描述（由申请人提供）：退行性关节疾病，如关节炎，影响相当大比例的美国人口，并造成重大经济负担。疾病修饰药物和组织再生细胞策略的集中使用为治疗这些疾病提供了巨大的潜力;然而，这些治疗策略的安全性和有效性必须首先在临床前模型中进行评估。本提案的目的和主要研究者的职业目标是创建和完善技术，以评估关节炎临床前动物模型中的关节功能和症状，并研究疾病改善疗法的潜力，以改善与关节炎相关的功能和症状后遗症。该建议从指导阶段开始，其中膝关节中的白细胞介素1 p（IL-lp）过表达将用作单侧炎性关节炎的大鼠模型。将使用定制设计的步态和疼痛敏感性测试来评价这种关节炎的功能和症状后遗症。此外，将评价两种ILIp拮抗剂，白细胞介素1受体拮抗剂（111 Ra）和可溶性白细胞介素1受体II型（slHRII），其改变与膝关节炎相关的功能和症状性后遗症的能力。然后，PI将在指导阶段获得的技能和知识过渡到颞下颌关节（TMJ）疾病及其功能和症状后遗症的研究。在独立的阶段，技术和方法，以评估颞下颌关节紊乱病的后遗症将开发啮齿动物模型，包括系统，以评估口面敏感性，咬合力，饮食习惯和睡眠模式。然后将调整关节内ILip过表达模型以启动TMJ关节炎，并应用所开发的技术并评估其改变相关功能和神经后遗症的能力。该提案涉及膝关节炎和TMJ疾病的新型治疗和评估策略的开发，主要借鉴了PI在TMJ研究方面的经验以及指导机构在骨关节炎和药物输送方面的专业知识。此外，该研究计划将协助PI过渡到教师职位，并建立一个独立的研究项目，评估TMJ疾病和变性的治疗干预措施。

DESCRIPTION (provided by applicant): Degenerative joint disorders, such as arthritis, affect a substantial percentage of the US population and have a significant economic burden. The focused use of disease modifying drugs and cellular Strategies for tissue regeneration offer great potential to treat these disorders; however, the safety and efficacy of these treatment strategies must first be evaluated in pre-clinical models. The purposes of this proposal, and the career aims of the principal investigator, are to create and refine techniques to evaluate joint function and symptoms in pre-clinical, animal models of arthritis and to investigate the potential for disease-modifying therapeutics to modify functional and symptomatic sequelae associated with arthritis. This proposal begins with the mentored phase where interleukin 1p (IL-lp) overexpression in the knee joint will be used as a rat model of unilateral inflammatory arthritis. The functional and symptomatic sequelae of this arthritis will be evaluated using custom-designed gait and pain sensitivity tests. Moreover, two ILIp antagonists, interleukin 1 receptor antagonist (111 Ra) and soluble interleukin 1 receptor type II (slHRII), will be evaluated for their ability to modify functional and symptomatic sequelae associated with knee arthritis. The PI will then transition skills and knowledge gained during the mentored phase to the study of temporomandibular joint (TMJ) disorders and their functional and symptomatic sequelae. In the independent stage, techniques and methods to assess the sequelae of TMJ disorders will be developed for rodent models, including systems to evaluate orofacial sensitivity, bite force, dietary habits, and sleep patterns. The intra-articular ILip over-expression model will then be adapted to initiate TMJ arthritis, and the developed technologies will be applied and assessed for their ability to modify the associated functional and symptomal sequelae. This proposal addresses the developments of novel treatment and assessment strategies for knee arthritis and TMJ disorders, drawing significantly on the PI's experience in TMJ research and the mentor institution's expertise in osteoarthritis and drug delivery. Moreover, this research plan will assist the PI in transitioning to a faculty position and establish an independent research program evaluating therapeutic interventions for TMJ disorders and degeneration.