Thymosin Beta 4: A Novel Biologic Therapy for Post-traumatic Osteoarthritis

描述 这项研究的总体目标是通过使用胸腺肽4(TB4)来改善患有骨关节炎(OA)的退伍军人的长期功能结果。TB4是一种细胞外抑制炎症和促进组织修复的蛋白质，多项动物研究和几项人类调查研究表明。该提案包括两个特定的目标，每个目标都使用不同的OA小鼠模型来测试假设，即TB4将通过防止软骨退化、软骨细胞肥大和凋亡、软骨下骨硬化和滑膜纤维化来防止创伤后OA的发展。在第一个模型中，膝关节的手术失稳被用来诱发骨性关节炎。第二种模型是一种非侵入性的，使用机械关节加载。当单独发生时，所使用的力不会导致关节损坏。然而，当力量持续时，会导致OA型变化。这些模型模拟了退伍军人在遭受创伤或反复关节应激后发生的创伤后骨性关节炎。在本研究的内侧半月板手臂手术失稳(特定目标1)中，将在超声引导下每周注射TB4，持续16周，从而模拟急性损伤和康复过程。关节加载臂(特定目标2)模拟关节反复应力所导致的骨关节炎。同样，Tb4将在超声引导下每周一次注射到右膝关节，持续8周。在这项研究的两个手臂中，对照小鼠都将接受PBS。对TB4疗效的评估将结合组织病理学评分、激光扫描共聚焦显微镜和微泡超声评估。此外，对小鼠功能行为的评估将用于通过动态步态分析和触觉异常痛觉反应来评估OA的症状后果和TB4治疗的影响。在整个研究过程中，调查人员将对治疗视而不见。数据的统计分析将包括使用重复测量的方差分析。为了与RR&D CDA-1的目标保持一致，Chauffe博士将获得必要的研究经验。这最终将使她有能力成功地作为一名独立调查员工作，专注于预防因关节炎而导致的残疾。本建议中概述的培训计划包括广泛的教育内容，包括实验室和教学，以确保实现这一目标。

DESCRIPTION The overall objective of the study is to improve the long-term functional outcomes of Veterans suffering from osteoarthritis (OA) with the use of thymosin ¿4 (tb4). Tb4 is a protein found to extracellulary inhibit inflammation and promote tissue repair, as demonstrated in multiple animal studies and several investigational studies in humans. The proposal consists of two specific aims, each using a different mouse model of OA to test the hypothesis that tb4 will prevent the development of post-traumatic OA by preventing cartilage degeneration, chondrocyte hypertrophy and apoptosis, subchondral bone sclerosis, and synovial fibrosis. In the first model, surgical destabilization of the knee is used to induce OA. The second model is a non-invasive and utilizes mechanical joint loading. The force utilized does not lead to joint damage when it occurs individually. However, when the force is sustained leads to OA-type changes. These models mimic the post-traumatic OA Veterans develop either after sustaining trauma or after repeated joint stress. In the surgical destabilization of the medial meniscus arm of the study (Specific Aim 1), tb4 will be injected under ultrasound guidance at weekly intervals for 16 weeks, thereby mimicking acute injury and the rehabilitation process. The joint loading arm (Specific Aim 2) mimics the OA that results from recurrent joint stress. Similarly, tb4 will be injected unde ultrasound guidance into the right knee at weekly intervals for 8 weeks. In both arms of the study, control mice will receive PBS. Evaluation of the efficacy of tb4 will be multifaceted with histopathologic scoring, laser scanning confocal microscopy and microbubble ultrasound assessment. Additionally, evaluation of murine functional behaviors will be used to assess the symptomatic consequences of OA and impact of tb4 treatment with dynamic gait analysis and tactile allodynia response. Throughout the study, investigators will be blinded to treatment. Statistical analysis of the data will include the use repeated measures of ANOVA. In keeping with the goals of RR&D CDA-1, Dr. Chauffe will gain essential investigational experience. This will culminate with her ability to successfully work as an independent investigator with a focus on preventing disability due to arthritis. The training plan outlined in this proposal includes extensive educational components, both in the lab and didactic, ensuring this goal is achieved.