Cilia function in spine development and disease

摘要/项目摘要 特发性脊柱侧凸(IS)影响着全世界3%的儿童，但这种疾病的根本原因(S)是 人们对此知之甚少。青春期IS(AIS)通常发生在青春期的快速生长期， 导致毁容、肺功能减退和慢性疼痛。我们最近证明了 在斑马鱼模型中，脑脊液(CSF)流动缺陷是AIS发生的基础。中的缺陷 Ptk7基因突变是人类IS的原因，或者是纤毛运动的重要基因突变，扰乱了脑脊液流动。 在斑马鱼身上。这导致斑马鱼幼鱼在快速生长阶段形成脊柱侧弯曲线， 在人类身上模仿这种疾病的发病过程。我们证明在这个模型中预防脊柱侧弯可以 仅通过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 使用了一种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内恢复，则会出现脊柱侧弯。在这项提案中，我们将采用 下一个合乎逻辑的步骤是调查脑脊液流动是如何被感知的，以及鱼是如何对这一信息做出反应的。我们 将研究椎管内纤毛状脑脊液感觉神经元在脊柱侧弯发生发展中的作用 我们IS模型中的曲线。我们将确定最近在人类中发现的POC5基因是否会导致 脑脊液的产生或感觉，正如我们的模型所预测的那样。我们将描述以下方面的空间要求 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，我们将需要对开发背后的机制有深入的了解 以及脊椎弯曲度对脑脊液流量改变的反应。这些信息对探险至关重要。 限制或预防人类人工智能的策略。

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.