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

基本信息

批准号：
10434397
负责人：
Norman Taylor
金额：
$ 41.11万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434397
关键词：
Address American Animal Model Animals Anxiety Area Behavioral Characteristics Chronic Clinical Clinical Trials Clinical effectiveness Cognitive Dahl Hypertensive Rats Data Development Dexamethasone Diagnosis Diagnostic Diet Disease Drug Screening Endocrine Evaluation Exhibits FDA approved Face Fatigue Female Fibromyalgia Functional disorder Genetic Genetic Predisposition to Disease Goals Healthcare Human Hyperalgesia Immune Impaired cognition Impairment Individual Indomethacin Inflammation Institutes Intervention Measurement Measures Mechanics Mental Depression Methods Modeling Moods Muscle Outcome Pain Pain Measurement Pain management Pathogenesis Persistent pain Pharmaceutical Preparations Pharmacology Phase Phenotype Plant Roots Play Productivity Public Health Quality of life Rat Strains Rattus Rattus norvegicus Research Research Personnel Reserpine Risk Rodent Rodent Model Scandinavian Signs and Symptoms Sleep Sleep disturbances Sodium Chloride Sprague-Dawley Rats Stimulus Symptoms Syndrome System Testing Therapeutic Effect Translations Twin Multiple Birth Validation affective disturbance allodynia analog animal pain associated symptom biological adaptation to stress chronic widespread pain clinical pain clinical phenotype clinical predictors cohort cost estimate debilitating pain diffuse noxious inhibitory control disability drug development duloxetine experience experimental study functional disability gabapentin human disease improved indexing innovation male mechanical allodynia mechanical pressure midalcipran normotensive novel novel therapeutics pain model pre-clinical pregabalin pressure relating to nervous system response salt sensitive salt sensitive hypertension secondary endpoint therapeutic effectiveness therapeutic evaluation trait

项目摘要

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.

项目概要数以百万计的美国人患有纤维肌痛综合征 (FMS)，并经历严重的残疾和减退生活质量。这种慢性广泛性疼痛综合征伴有一系列症状，包括慢性疼痛疲劳、非恢复性睡眠、功能障碍以及认知和情绪障碍。目前使用的动物 FMS 模型在表面、构造和预测有效性方面存在缺陷，这导致了翻译差距;在动物模型中看似有希望的新疗法在人体临床试验中却失败了。一个策略为了提高 FMS 动物模型的面部评估和构建有效性，需要测量几个与同一动物的人类疾病相关的症状。因此，我们将开发一种纤维肌痛模拟模型（FAM）将作为类似于临床使用的诊断指标。我们假设该指数将提高动物 FMS 模型的面部和预测有效性评估，并提供定义方法来比较它们。次要终点是已建立的利血平之间的比较 FMS 模型和创新模型：Dahl 盐敏感（SS）大鼠。我们的初步研究表明 SS 大鼠是自发性异常性疼痛的模型，因为它们在没有外部刺激的情况下表现出机械压力敏感性促发干预。随着机械阈值的降低，这些大鼠也无法安装对疼痛刺激的弥漫性有害抑制控制反应。该菌株表现出额外的表型与 FMS 一致，例如焦虑、全身和神经炎症以及应激反应功能障碍系统（构建有效性）。这些大鼠还证明了加巴喷丁的预测有效性，但吲哚美辛则不然或地塞米松可改善痛觉过敏>30%。我们假设 FAM 指数将允许我们确定 SS 菌株作为 FMS 模型的适用性。 R61 阶段将包括三个实验。 (1) 六个行为终点将测试接受利血平治疗的同一女性 Sprague 的 FMS 特征道利鼠；疲劳、肌肉压痛、睡眠中断、广泛疼痛、焦虑等行为方面沮丧。然后将在严格的多元框架内使用回归模型对结果进行分析定义可观察的临床表型之间的关系以开发 FAM 指数。该数据也将被使用最大化测量的内部有效性。（2）我们将验证FAM指数的外部有效性使用另外两种品系：雌性 SS 大鼠和棕色挪威 (BN) 大鼠。 (3) 我们将在男性中重复研究所有三种菌株。五个统计里程碑将决定是否继续进行进一步的实验。在 R33阶段，我们将外部验证SS模型和FAM指数，并通过以下方式检查其预测有效性三组实验：（1）在其他大鼠品系中外部验证FAM指数； (2)建立SS 另一个机构的模特； (3)测试吲哚美辛、普瑞巴林、度洛西汀对多种疾病的治疗效果症状域。该提案建立了一个指数来评估面孔、构造和预测的有效性：以及一种新颖的FMS模型。该模型对于药物筛选和药理学测试非常理想。