Development and Validation of a Novel Rat Model of Fibromyalgia

新型纤维肌痛大鼠模型的开发和验证

• 批准号: 10732604
• 负责人: Norman Taylor
• 金额: $ 35.19万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732604
• 关键词: Development; Validation; Novel; Rat; Model

PROJECT SUMMARY Millions of Americans suffer from Fibromyalgia syndrome (FMS) and experience severe disability and diminished quality of life. This chronic widespread pain syndrome is accompanied by a range of symptoms including chronic fatigue, non-restorative sleep, functional disability, and cognitive and mood disturbances. Currently used animal models of FMS suffer from deficits in face, construct, and predictive validities, which has resulted in a translation gap; new therapies that appear to be promising in animal models have failed in human clinical trials. One strategy to improve the evaluation of face and construct validities of FMS animal models would be to measure several symptoms that correlate with the human disease in the same animal. We will therefore develop a Fibromyalgia Analog Model (FAM) that will serve as a diagnostic index similar to those used clinically. We hypothesize that this index will improve the evaluation of face and predictive validities of animal FMS models, and will provide a defined method to compare them. A secondary endpoint is a comparison between the established reserpine model of FMS and an innovative model: the Dahl salt-sensitive (SS) rat. Our preliminary studies show that SS rats are a model of spontaneous allodynia, as they exhibit mechanical pressure sensitivity without an external precipitating intervention. Accompanying the decrease in mechanical thresholds, these rats also fail to mount a diffuse noxious inhibitory control response to painful stimuli. This strain demonstrates additional phenotypes consistent with FMS such as anxiety, systemic and neural inflammation and dysfunction in stress response systems (construct validity). These rats also demonstrate predictive validity as gabapentin, but not indomethacin or dexamethasone provides >30% improvement in hyperalgesia. We hypothesize that the FAM index will allow us to determine the suitability of the SS strain as an FMS model. The R61 phase will comprise three experiments. (1) Six behavioral endpoints will test for FMS traits in the same individual female reserpine treated Sprague Dawley rat; behavioral aspects of fatigue, muscle tenderness, disrupted sleep, widespread pain, anxiety, and depression. The results will then be analyzed using regression modelling within a rigorous multivariate framework to define relationships in observable clinical phenotypes to develop the FAM index. The data will also be used to maximize the internal validity of the measurements. (2) We will certify the external validity of the FAM index using two additional strains, female SS and Brown Norway (BN) rats. (3) We will repeat the studies in males of all three strains. Five statistical milestones will determine whether to move forward with further experiments. In the R33 phase, we will externally validate the SS model and FAM index and examine its predictive validity via three sets of experiments: (1) externally validate the FAM index in additional rat strains; (2) establish the SS model in another institute; (3) test the therapeutic effect of indomethacin, pregabalin and duloxetine on multiple symptom domains. This proposal establishes an index to evaluate face, construct and predictive validities as well as a novel model of FMS. This model will be highly desirable for drug screening and pharmacologic testing.

项目摘要 数以百万计的美国人患有纤维肌痛综合征（FMS）并经历严重的残疾并减少 生活质量。这种慢性广泛的疼痛综合征伴随着一系列症状 疲劳，非儿童睡眠，功能障碍以及认知和情绪障碍。目前使用的动物 FM的模型遭受面部，构造和预测有效性的缺陷，这导致了翻译 差距;在人类临床试验中，在动物模型中似乎有希望的新疗法失败了。一种策略 为了改善FMS动物模型的面部和构造有效性的评估，将是测量几个 与同一动物中人类疾病相关的症状。因此，我们将开发纤维肌痛 模拟模型（FAM）将用作与临床上使用的指数相似的诊断指数。我们假设这一点 该指数将改善对动物FMS模型的面部和预测有效性的评估，并将提供 定义的方法比较它们。次要终点是已建立的优化 FMS和创新模型的模型：DAHL盐敏感（SS）大鼠。我们的初步研究表明SS 大鼠是自发异常性异常的模型，因为它们表现出机械压力灵敏度，而没有外部 沉淀干预。伴随机械阈值的降低，这些大鼠也无法安装 弥漫性有害抑制性控制对疼痛刺激的反应。该菌株展示了其他表型 与焦虑，全身性和神经炎症以及压力反应中功能障碍等FMS一致 系统（构造有效性）。这些大鼠还表现出预测性有效性为加巴喷丁，但不显示吲哚美辛 或地塞米松可提供超痛觉症的30％改善。我们假设FAM指数将允许 我们确定SS应变作为FMS模型的适用性。 R61相将包括三个实验。 （1）六个行为终点将在同一单个女性治疗sprague中测试FMS特征 道利·兰（Dawley Rat）；疲劳，肌肉压痛，睡眠中断，疼痛，焦虑和焦虑的行为方面 沮丧。然后将使用严格的多元框架内的回归建模来分析结果 定义可观察到的临床表型中的关系以发展FAM指数。数据也将使用 最大化测量的内部有效性。 （2）我们将证明FAM指数的外部有效性 使用另外两种菌株，雌性SS和棕色挪威（BN）大鼠。 （3）我们将重复对男性的研究 这三个菌株。五个统计里程碑将决定是否通过进一步的实验前进。在 R33阶段，我们将在外部验证SS模型和FAM指数，并通过 三组实验：（1）外部验证其他大鼠菌株中的FAM指数； （2）建立SS 另一家学院的模型； （3）测试吲哚美辛，前伽巴林和杜洛西汀对多种的治疗作用 症状领域。该建议建立了评估面部，构建和预测有效性的指数 以及一种新颖的FMS模型。对于药物筛查和药理测试，该模型将非常理想。