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

描述(申请人提供)：与工作相关的肌肉骨骼疾病占失去工作时间疾病的30%，然而，其发展和随时间持续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来识别和表征与重复和/或强力伸展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)确定长期暴露于中重复-低力(MRLF)和高重复-高力(HRHF)两种任务方案导致骨吸收和病理变化以及关节软骨损伤的机制，以及这些变化背后的机制是炎症、机械过度使用，还是两者兼而有之。2)确定长期暴露于两种任务方案(MRLF和HRHF)导致肌腱和神经组织纤维化和病理变性的机制，以及这些变化的机制是炎症、机械过度使用还是两者兼而有之。3)确定MRLF和HRHF两种任务方案暴露后，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。大鼠将被训练在MRLF(每分钟8次达到，5%最大自愿拉力，MPF)或HRHF(在60%MPF，每分钟达到12次)下执行自愿伸展和抓取任务。两个实验组将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，以阻止炎症。肌肉骨骼组织、周围神经和血清将采用后测试对照组设计，分析组织炎症和退化的细胞和生化标记物。正中神经功能也将采用后测对照组设计进行测试和分析。将使用重复测量设计分析表示伸展性能和运动协调性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联，将使用多元回归分析。两个实验组将进行16或22周的MRLF或HRHF任务。在每周结束时，所有动物将接受感觉运动能力测试，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(每组每种分析类型在每周结束时5-10次)。年龄、饮食和体重相匹配的训练有素的对照组将在匹配的时间点被处死，以与实验动物进行比较。这些实验将加深我们对长期暴露于各种危险因素组合(重复和力)对组织和功能的影响，以及这些反应(退化、疼痛和功能丧失)背后的机制(机械超负荷，或炎症诱导的分解代谢/纤维化)的理解。公共卫生相关性：这种WMSD大鼠模型能够唯一地在组织病理生理学和暴露于一系列具有临床意义的任务引起的行为反应之间找到相似之处，因为它们是从关于这一重要职业健康问题的临床和流行病学文献中衍生出来的。在大鼠身上进行的这些研究产生的数据最终将有助于开发有效预防和管理过度使用伤害的新策略，为未来的临床人群转化性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.