Molecular Bases of Cilia Orientation

描述(申请人提供)：在许多器官系统中，投射出数百个跳动的纤毛的细胞，称为多纤毛细胞，产生强劲的液体流动，沿着管腔表面运输生物材料。多纤毛细胞分布在呼吸道、生殖道和脑室，它们在这些地方产生的流量对人类健康有重大影响。实现定向流动的一个关键过程是将跳动的纤毛沿着共同的平面轴排列，这需要在每个纤毛的底部定位基本体的旋转轴的机构。已知这一过程是由平面细胞极性途径启动的，并涉及基于流动的信号和细胞骨架元素，但排列纤毛方向的机制在很大程度上尚不清楚。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 确定纤毛取向背后的新因素。具体地说，这种方法解决了FCT，即与其他纤毛细胞中发现的相比，多纤毛细胞中的基底高度特化，但这些特化的分子基础仍未确定。使用这种方法，将识别与纤毛定向有关的基本身体因素，并将表征它们在产生定向流体流动中的作用。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，包括被称为纤毛根的基体部附属物的蛋白，以及根据其结构特征确定的候选蛋白，以及它们的表达与多纤毛细胞分化相关的事实。这项拟议的研究将对细胞特有成分产生新的见解，这些成分允许多纤毛细胞中的基底体介导流向流，并为理解流如何在原发纤毛运动障碍等人类疾病中失灵奠定基础。

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.