Cilia function in spine development and disease

纤毛在脊柱发育和疾病中的功能

• 批准号: 9899203
• 负责人: REBECCA D. BURDINE
• 金额: $ 45.73万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899203
• 关键词: Adolescence; Adolescent; Adolescent Development; Affect; Animal Disease Models; Area; Biological; Biology; Brain; Cells; Cerebrospinal Fluid; Child; Cilia; Congenital Abnormality; Data; Defect; Development; Disease; Esthesia; Fishes; Functional disorder; Generations; Genes; Genetic study; Goals; Human; Idiopathic scoliosis; Immune; Immune response; Infiltration; Knowledge; Lateral; Modeling; Mutation; Neuromuscular Diseases; Neurons; Onset of illness; Operative Surgical Procedures; Patients; Phase; Phenotype; Play; Prevention; Preventive treatment; Quality of life; Research; Role; Spinal; Spinal Canal; Spinal Cord; Spinal Curvatures; Temperature; Testing; Therapeutic; Time; Tumor-infiltrating immune cells; Variant; Vertebral column; Work; Zebrafish; base; cell motility; cerebrospinal fluid flow; chronic pain; cilium motility; fluid flow; gene product; human disease; insight; kinetosome; mutant; predictive modeling; prevent; pulmonary function; rapid growth; response; restorative treatment; scoliosis; teleost fish

Abstract/Project Summary Idiopathic scoliosis (IS) affects 3% of children worldwide, yet the underlying cause(s) of this condition are poorly understood. Adolescent IS (AIS) commonly develops during the rapid growth phase in adolescence, leading to disfigurement, reduced pulmonary functions and chronic pain. We recently demonstrated that defects in cerebrospinal fluid (CSF) flow underlie the development of AIS in a zebrafish model. Defects in ptk7, mutations in which are causative of IS in humans, or in genes important in cilia motility, disrupt CSF flow in zebrafish. This results in the formation of scoliotic curves during a rapid growth phase in juvenile zebrafish, mimicking the onset of this disorder in humans. We demonstrate that prevention of scoliosis in this model can be achieved by expressing wildtype genes products only in motile ciliated lineages in zebrafish. Importantly, we have used a temperature sensitive cilia motility mutant to demonstrate that zebrafish can recover from the onset of scoliotic curves if cilia motility is restored in a critical time window. In this proposal, we will take the next logical step by investigating how CSF flow is sensed and how the fish responds to this information. We will investigate the role of ciliated CSF sensing neurons in the spinal canal in the development of scoliotic curves in our IS model. We will determine if the recently identified POC5 gene in human IS causes defects in CSF generation or sensation as our model would predict. We will characterize the spatial requirements for motile cilia in our model, and determine if the immune response we detect impacts spinal curve progression. At the conclusion of this work, we will have needed insights into the mechanism underlying the development and progression of spinal curvatures in response to altered CSF flow. This information is crucial for exploration of strategies to limit, or prevent, human AIS.

摘要/项目摘要 特发性脊柱侧凸 (IS) 影响着全世界 3% 的儿童，但造成这种情况的根本原因是 不太了解。青春期 IS (AIS) 通常发生在青春期的快速生长期， 导致毁容、肺功能下降和慢性疼痛。我们最近证明了 斑马鱼模型中脑脊液 (CSF) 流动的缺陷是 AIS 发展的基础。缺陷于 ptk7 突变会导致人类 IS 或纤毛运动重要基因的突变，扰乱脑脊液流动 在斑马鱼中。这导致幼年斑马鱼在快速生长阶段形成脊柱侧凸曲线， 模仿人类这种疾病的发作。我们证明，在该模型中预防脊柱侧凸可以 通过仅在斑马鱼的活动纤毛谱系中表达野生型基因产物来实现。重要的是，我们 使用温度敏感的纤毛运动突变体来证明斑马鱼可以从 如果纤毛运动在关键时间窗口内恢复，则会出现脊柱侧弯。在本提案中，我们将采取 下一个合乎逻辑的步骤是研究如何感知脑脊液流量以及鱼如何响应此信息。我们 将研究椎管内纤毛脑脊液传感神经元在脊柱侧凸发展中的作用 IS 模型中的曲线。我们将确定最近在人类 IS 中发现的 POC5 基因是否会导致 正如我们的模型预测的那样，脑脊液的产生或感觉。我们将描述空间需求 在我们的模型中观察运动纤毛，并确定我们检测到的免疫反应是否会影响脊柱曲线的进展。 在这项工作结束时，我们将需要深入了解发展背后的机制 以及响应脑脊液流量改变的脊柱弯曲的进展。这些信息对于探索至关重要 限制或预防人类 AIS 的策略。