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

胸腺素 Beta 4：一种治疗创伤后骨关节炎的新型生物疗法

• 批准号: 8784910
• 负责人: Ann Duskin Chauffe
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784910
• 关键词: Acute; Analgesics; Analysis of Variance; Animals; Apoptosis; Arthritis; Behavior; Biological Response Modifier Therapy; Blinded; Cartilage; Cartilage injury; Chondrocytes; Cicatrix; Clinical Trials; Controlled Study; Cornea; Data; Degenerative polyarthritis; Development; Disease; Dose; Ensure; Evaluation; Fibrosis; Goals; Healed; Health; Health system; Heart; Human; Hypertrophy; Inflammation; Injury; Intervention; Intra-Articular Injections; Investigational New Drug Application; Joints; Journals; Knee; Knee Osteoarthritis; Laser Scanning Confocal Microscopy; Lead; Measures; Mechanics; Medial meniscus structure; Microbubbles; Modality; Modeling; Mus; Myocardial Infarction; Nature; Operative Surgical Procedures; Orthotic Devices; Pain; Pharmaceutical Preparations; Postoperative Period; Process; Property; Proteins; Rattus; Recurrence; Rehabilitation therapy; Replacement Arthroplasty; Research Personnel; Rodent Model; Sclerosis; Skin; Statistical Data Interpretation; Surface; Surgical Models; Tactile; Techniques; Technology; Testing; Thymosin; Tissues; Training; Translating; Trauma; Ultrasonography; United States Food and Drug Administration; Veterans; Work; Wound Healing; allodynia; arm; bone; cardiac repair; disability; efficacy evaluation; experience; functional outcomes; gait examination; healing; human disease; improved; improved functioning; joint destruction; joint injury; joint loading; joint stress; mouse model; neurotensin mimic 2; novel; prevent; public health relevance; response; thymosin beta(4); tissue repair; translational study

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.

描述 该研究的总体目标是通过使用胸腺素 ¿4 (tb4) 改善患有骨关​​节炎 (OA) 的退伍军人的长期功能结果。 Tb4 是一种在细胞外抑制炎症并促进组织修复的蛋白质，多项动物研究和多项人类研究都证明了这一点。该提案包含两个具体目标，每个目标都使用不同的 OA 小鼠模型来测试以下假设：tb4 将通过防止软骨变性、软骨细胞肥大和细胞凋亡、软骨下骨硬化和滑膜纤维化来预防创伤后 OA 的发展。在第一个模型中，通过手术使膝关节失稳来诱发 OA。第二种模型是非侵入性的，利用机械关节加载。当单独发生时，所使用的力不会导致关节损伤。然而，当力量持续存在时，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压力后形成的创伤后骨关节炎。在该研究的内侧半月板不稳定手术中（具体目标 1），tb4 将在超声引导下每周注射一次，持续 16 周，从而模拟急性损伤和康复过程。关节加载臂（具体目标 2）模拟因反复关节应力而导致的 OA。同样，tb4 将在超声引导下每周注射到右膝，持续 8 周。在该研究的两个组中，对照小鼠将接受 PBS。 tb4的疗效评估将通过组织病理学评分、激光扫描共聚焦显微镜和微泡超声评估等多方面进行。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性疼痛反应来评估 OA 的症状后果以及 tb4 治疗的影响。在整个研究过程中，研究人员将对治疗不知情。数据的统计分析将包括使用方差分析的重复测量。为了与 RR&D CDA-1 的目标保持一致，Chauffe 博士将获得重要的研究经验。这将使她能够成功地成为一名独立调查员，重点关注预防关节炎引起的残疾。该提案中概述的培训计划包括实验室和教学中的广泛教育内容，以确保实现这一目标。