Biomarker of Tissue Tolerance and Behavior in a Rat Model of WMSD

描述（由申请人提供）：与工作相关的肌肉骨骼疾病占误工疾病的30%，然而，其发展和持续时间的病理生理机制尚不完全清楚。这项工作的长期目标是使用一种创新的大鼠上肢过度使用损伤模型，以识别和表征与重复性和/或强伸相关的组织变化和行为后遗症的细胞机制。该项目的具体目标是：1)确定长期暴露于两种任务方案，中重复-低力量（MRLF）和高重复-高力量（HRHF），导致骨吸收和病理变化以及关节软骨损伤的机制，以及这些变化的机制是炎症，机械过度使用，还是两者兼有。2)确定长期暴露于MRLF和HRHF两种任务方案导致肌肉肌腱和神经组织纤维化和病理性变性的机制，以及这些变化的潜在机制是炎症、机械过度使用，还是两者兼而有之。3)确定暴露于两种任务方案（MRLF和HRHF）后组织变化的生物标志物与感觉运动功能之间是否存在关系。大鼠将接受训练，以MRLF（每分钟8次，最大自愿拉力为5%）或HRHF（每分钟12次，最大自愿拉力为60%）的速度执行自愿伸手和抓握任务。两组实验组预防性接受抗肿瘤坏死因子α或白细胞介素-1受体拮抗剂，以阻断炎症。采用测试后对照组设计，分析肌肉骨骼组织、周围神经和血清中组织炎症和变性的细胞和生化标志物。正中神经功能测试和分析也采用测试后对照组设计。使用重复测量设计，分析可达到性能和动作协调的行为变量随时间的变化。为了确定血清和行为变量之间的关系，将使用多元回归分析。两个实验组分别执行MRLF或HRHF任务16周或22周。在每个每周终点，所有动物进行感觉运动性能测试，然后随机分为3个亚组进行显微镜检查、蛋白质分析和正中神经传导速度测试（在所有每周终点，每种分析类型每组n=5-10）。经过训练的对照组，年龄、饮食和体重匹配，将在匹配的时间点牺牲，与实验动物进行比较。这些实验将增强我们对长期暴露于危险因素组合（重复和力量）对组织和功能的影响的理解，以及这些反应（变性，疼痛和功能丧失）背后的机制（机械过载，或炎症诱导的分解代谢/纤维化）。公共卫生相关性：该WMSD大鼠模型独特地能够将暴露于一系列具有临床意义的任务所产生的组织病理生理学和行为反应联系起来，因为它们来源于有关这一重要职业健康问题的临床和流行病学文献。这些大鼠研究产生的数据将最终有助于制定有效预防和管理过度使用损伤的新策略，为未来临床人群的转化研究提供见解和框架。

DESCRIPTION (provided by applicant): Work-related musculoskeletal disorders account for 30% of lost work time illnesses, yet, the pathophysiological mechanisms underlying their development and persistence over time is incompletely understood. The long term goal of this work is to use an innovative model of upper limb overuse injury in the rat to identify and characterize cellular mechanisms underlying tissue changes and behavioral sequelae associated with the performance of repetitive and/or forceful reaching. The specific aims for this project are: 1) To determine the mechanisms whereby long-term exposure to two task regimens, medium repetition-low force (MRLF) and high repetition-high force (HRHF), leads to bone resorption and pathological changes, and articular cartilage damage, and if the mechanism underlying these changes is inflammatory, mechanical overuse, or both. 2) To determine the mechanisms whereby long-term exposure to two task regimens, MRLF and HRHF, leads to fibrosis and pathological degeneration in musculotendinous and neural tissues and if the mechanism underlying these changes is inflammatory, mechanical overuse, or both. 3) To determine if there is a relationship between biomarkers of tissue changes and sensorimotor function after exposure to two task regimens, MRLF and HRHF. Rats will be trained to perform a voluntary reaching and grasping task at MRLF (8 reaches per minute @ 5% maximum voluntary pulling force, MPF), or HRHF (12 reaches per minute at 60% MPF). Two experimental groups will receive either anti-tumor necrosis factor alpha or interleukin-1 receptor antagonist prophylactically in order to block inflammation. Musculoskeletal tissues, peripheral nerve and serum will be analyzed for cellular and biochemical markers of tissue inflammation and degeneration using a post-test control group design. Median nerve function will be tested and analyzed also using a post-test control group design. Behavioral variables indicative of reach performance and movement coordination will be analyzed for changes over time using a repeated measures design. To determine the association between serum and behavioral variables, a multiple regression analysis will be used. The 2 experimental groups will perform either the MRLF or HRHF task for 16 or 22 weeks. At each weekly endpoint, all animals will undergo sensorimotor performance testing and will then be split randomly into 3 subgroups for microscopic examination, protein analysis and median nerve conduction velocity testing (n=5-10 per group per analysis type at all weekly endpoints). Trained controls, matched by age, diet, and weight, will be sacrificed at matched time points for comparison to experimental animals. Forelimb tissues will be collected bilaterally and prepared for the various analyses These experiments will enhance our understanding of the effects of long-term exposure to combinations of risk factors (repetition and force) on tissue and function, as well as mechanisms (mechanical overload, or inflammation-induced catabolism/fibrosis) underlying those responses (degeneration, pain and loss of function). PUBLIC HEALTH RELEVANCE: This rat model of WMSD is uniquely able to draw parallels between tissue pathophysiology and behavioral responses resulting from exposure to a range of tasks that are clinically meaningful, because they have been derived from the clinical and epidemiological literature concerning this important occupational health problem. The data generated by these studies in the rat will ultimately contribute to the development of new strategies for effective prevention and management of overuse injuries by providing insights into and a framework for future translational studies of clinical populations.