Molecular Bases of Cilia Orientation

描述（由申请人提供）：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）产生沿着沿着腔表面运输生物材料的有力流体流。多纤毛细胞遍布呼吸道、生殖道和脑室，它们产生的气流对人类健康有重要意义。实现定向流动的一个关键过程是使跳动的纤毛沿着一个共同的平面轴对齐，这需要在每个纤毛的基部定向基体的旋转轴的机制。已知该过程由平面细胞极性途径启动，并且涉及基于流动的线索和细胞骨架的元素，但是排列纤毛方向的机制在很大程度上是未知的。为了解决这个问题，一种方法是定义驱动多纤毛细胞分化的遗传途径，并使用这些途径来 确定纤毛定向的新因素。具体来说，这种方法解决了fct，在一个多纤毛细胞的基体是高度专业化相比，在其他纤毛细胞中发现的，但这些专业化的分子基础仍然不确定。使用这种方法，将确定纤毛定向所涉及的基体因素，并将其在产生定向流体流动中的作用的特点。研究的因素包括一个新的基体相关的蛋白质所需的成熟纤毛方向，蛋白质，包括一个基体附属物称为纤毛根，和候选蛋白质已被确定的基础上，其结构特征，以及事实上，他们的表达与multicilate细胞分化。拟议的研究将产生新的见解，让多纤毛细胞中的基底体介导定向流体流动的细胞特异性成分，并为理解流动如何在人类疾病（如原发性纤毛运动障碍）中失败奠定基础。

DESCRIPTION (provided by applicant): 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 fct 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 foundatio for understanding how flow can fail in human diseases such as primary ciliary dyskinesia.