Molecular Bases of Cilia Orientation

项目摘要 在许多器官系统中，投射数百根跳动纤毛的细胞，称为多纤毛细胞，产生一种 沿着沿着管腔表面输送生物材料的剧烈流体流动。多纤毛细胞分布于 呼吸道、生殖道和脑室，它们产生的气流在那里流动， 对人类健康的重大影响。实现定向流动的一个关键过程是调整跳动的纤毛 沿着共同的平面轴线，需要将基体的旋转轴线定向在 每根纤毛的基部。已知该过程由平面细胞极性途径启动， 涉及基于流动的线索和细胞骨架的元素，但调整纤毛方向的机制是 大部分未知。为了解决这个问题，一种方法是定义驱动基因的遗传途径。 多纤毛细胞的分化，并使用这些途径来识别纤毛基础的新因子 导向具体地说，这种方法解决了多纤毛细胞中的基体是 与其他纤毛细胞中发现的细胞相比，这些细胞高度特化，但这些细胞的分子基础 专业化尚未定义。使用这种方法，涉及纤毛定向的基体因素将被 识别，和他们的作用，在生产定向流体流动的特点。研究的因素包括 成熟纤毛定向所需的新的基底体相关蛋白，包括基底体的蛋白， 被称为纤毛根的身体附属物，以及基于其 结构特征，以及它们的表达与多纤毛细胞分化相关的事实。的 拟议的研究将产生新的见解，细胞的具体组成部分，使基体在 多纤毛细胞介导定向流体流动，并为理解流动如何失败奠定基础。 人类疾病如原发性纤毛运动障碍。

Project Summary In many organ systems, cells projecting hundreds of beating cilia, called multiciliate cells, produce a vigorous fluid flow that transports biological materials along luminal surfaces. Multiciliate cells populate the respiratory airways, the reproductive tract, and the ventricles of the brain, where the flow they produce has significant implications for human health. A key process in achieving directed flow is to align beating cilia along a common planar axis, requiring mechanisms that orient the rotational axis of the basal body at the base of each cilium. This process is known to be initiated by the planar cell polarity pathway, and to involve flow-based cues and elements of the cytoskeleton, but the mechanisms that align cilia direction are largely unknown. To address this issue, one approach is define the genetic pathways that drive the differentiation of multiciliate cells, and to use these pathways to identify novel factors that underlie cilia orientation. Specifically, this approach addresses the fact that the basal bodies in a multiciliate cell are highly specialized compared to those found in other ciliated cells, but the molecular bases of these specialization remain undefined. Using this approach, basal body factors involved in cilia orientation will be identified, and their role in producing directed fluid flow will be characterized. The factors studied include a new basal body associated protein required for maturating cilia orientation, proteins that comprise a basal body appendage called the ciliary rootlet, and candidate proteins that have been identified based on their structural features, and the fact that their expression is associated with multiciliate cell differentiation. The proposed studies will generate new insights into the cell specific components that allow basal bodies in multiciliate cells to mediate directed fluid flow, and lay the foundation for understanding how flow can fail in human diseases such as primary ciliary dyskinesia.