Neurobehavioral phenotypes of mouse models of Osteogenesis Imperfecta

成骨不全小鼠模型的神经行为表型

基本信息

批准号：
10416072
负责人：
Matthew L Warman
金额：
$ 23.13万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-02 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10416072
关键词：
Adult Affect Age Anabolism Analgesics Animals Anxiety Assessment tool Behavior Behavioral Biological Assay Blinded Bone Resorption Boston Buprenorphine Catabolism Child Clinical Clinical Research Clinical Trials Cognitive Deformity Disease Environment Exploratory Behavior FDA approved Fracture Genes Genetic Genotype Human Human Activities Incidence Individual Insurance Knowledge Leg Life Experience Measures Mediating Modeling Monoclonal Antibodies Movement Mus Mutation Operative Surgical Procedures Opioid Analgesics Osteoclasts Osteogenesis Imperfecta Outcome Pain Pain quality Pathway interactions Patient Self-Report Patients Pediatric Hospitals Phenotype Physical therapy Physiology Property Provider Psychology Quality of life Reporting Research Personnel Resolution Severities Shapes Signal Pathway TNFSF11 gene Testing Therapeutic Time Transforming Growth Factor beta Variant WNT Signaling Pathway animal pain bisphosphonate bone bone fragility bone mass bone strength bone turnover central pain chronic pain cohort double-blind placebo controlled trial experimental study fracture risk improved mouse model neurobehavioral novel therapeutics off-label use open label pain perception pain reduction pain signal peripheral pain placebo controlled trial prevent skeletal skeletal disorder spine bone structure treatment group

项目摘要

Osteogenesis Imperfecta (OI), which affects nearly 20,000 US citizens, is a genetically heterogeneous disorder that causes skeletal fragility. Patients with OI live with significant chronic pain, which also affects their level of activity and quality of life. Bisphosphonates are currently used off-label in children with OI to improve bone mass and reduce skeletal deformity. Yet, despite improvements in bone mass, double-blind placebo- control trials have not found reduced fracture rates in OI patients who have received bisphosphonates. A suggested explanation for this apparent lack of efficacy is that bisphosphonate-induced increases in bone mass also reduce pain and as a consequence increase patient activity. Thus, it is the increased activity that paradoxically causes bisphosphonate-treated OI patients to fracture at the same rate as untreated patients. However, the ability to robustly assess pain and activity in OI patients is limited by several factors. OI patients have a range of clinical severity that is influenced by their specific mutation, genetic background, age, and environment. In addition, non-physiological factors such as cognitive, behavioral, and spiritual components affect how OI patients self-report pain, activity, and quality of life. We found that the automated Holeboard assay reveals significant differences in activity and exploratory behavior between the Jrt mouse model of moderate OI and wild-type littermates, independent of fracture. We now want to determine if therapies that increase bone mass, such as promoting bone anabolism by enhancing Wnt signaling and preventing catabolism by inhibiting osteoclast activity, improve activity and increase exploratory behavior in the Jrt mice, and we want to extend our studies to AGA2 mice, a more severe model of OI. We will also determine if the opioid analgesic Buprenorphine-SR increases activity and behavior in mouse models of OI, independent of fracture or increasing bone mass. Even though mice are not humans, peripheral and central pain perception pathways are highly conserved between these species. Moreover, cohorts of mice with the same mutation on a fixed genetic background can be housed and handled similarly, evaluated at the same age, time of day, and in a consistent order and spacing between tests. Successful completion of these experiments will inform us whether therapies that affect bone mass and bone properties provide additional benefits, such as increased activity and reduced anxiety. If these additional benefits occur in OI mice, they are likely to occur in OI patients as well.

成骨不全症 (OI) 影响近 20,000 名美国公民，是一种遗传异质性疾病导致骨骼脆弱的疾病。成骨不全患者患有严重的慢性疼痛，这也影响了他们的生活活动水平和生活质量。目前，双膦酸盐在 OI 儿童中超适应症使用，以改善病情骨量并减少骨骼畸形。然而，尽管骨量有所改善，双盲安慰剂对照试验尚未发现接受双磷酸盐治疗的成骨不全患者骨折率降低。一个对于这种明显缺乏功效的建议解释是双膦酸盐诱导的骨密度增加肿块还可以减轻疼痛，从而增加患者的活动量。因此，活动的增加矛盾的是，接受双膦酸盐治疗的成骨不全患者的骨折率与未经治疗的患者相同。然而，稳健评估成骨不全患者疼痛和活动的能力受到多种因素的限制。成骨不全患者具有一系列临床严重程度，受其特定突变、遗传背景、年龄和影响环境。此外，非生理因素，如认知、行为和精神成分影响成骨不全患者自我报告疼痛、活动和生活质量的方式。我们发现自动化 Holeboard 检测揭示了活性和探索性的显着差异中度 OI 的 Jrt 小鼠模型和野生型同窝小鼠之间的行为，与骨折无关。我们现在想确定是否有增加骨量的疗法，例如通过增强骨量来促进骨合成代谢通过抑制破骨细胞活性、提高活性和增加 Wnt 信号传导并防止分解代谢 Jrt 小鼠的探索行为，我们希望将我们的研究扩展到 AGA2 小鼠，这是一种更严重的模型哎呀。我们还将确定阿片类镇痛药丁丙诺啡-SR 是否会增加小鼠的活动和行为 OI 模型，与骨折或骨量增加无关。尽管老鼠不是人类，但外围中枢疼痛感知通路在这些物种之间高度保守。此外，小鼠群体在固定遗传背景上具有相同突变的情况可以进行类似的安置和处理，并在相同的年龄、一天中的时间、以及测试之间的顺序和间隔一致。这些实验的成功完成将告诉我们是否有影响骨量和骨骼特性提供了额外的好处，例如增加活动和减少焦虑。如果这些额外的成骨不全小鼠身上出现了这种益处，但成骨不全患者也可能会出现这种情况。