The molecular mechanisms by which mammalian Fused regulates motile cilia function

6.项目摘要/摘要 这项研究的长期目标是了解控制运动纤毛的分子机制。 装配和功能。活动纤毛在多种生理过程中起着重要作用，包括 呼吸系统中的粘液纤毛清除、脑脊液循环和精子活力。 运动纤毛和鞭毛功能障碍是人类原发性纤毛运动障碍综合征的基础 (PCD)。虽然活动纤毛的超微结构有很好的特征，但许多重要的方面 运动纤毛功能的生物发生和调节仍然知之甚少，部分原因是缺乏 了解控制这些流程的基本组件。我们对哺乳动物的研究 刺猬(HH)的信号导致了一个意想不到的发现，融合(FU)，一种可能的丝氨酸-苏氨酸 Kif27和Kif27是独立于HH调节纤毛运动功能的关键分子 发信号。因此，对FU和Kif27的研究为人类PCD提供了新的小鼠模型。更重要的是， 它们起到了弥合我们对转录因子之间步骤理解上的鸿沟的作用 纤毛发生和活动纤毛的构建和维持。我们提出了以下具体目标： 1)验证FU与中心蛋白相互作用以调节其定位和 在活动的纤毛生物发生过程中组装。2)阐明FU和Kif27之间的功能相互作用。 控制运动纤毛功能。3)明确FU在控制纤毛运动方向中的作用。4)识别 FU靶点结合候选基因和系统调控纤毛发生的研究 化学标记法。

6. Project Summary/Abstract The long-term goal of this study is to understand the molecular mechanisms that control motile cilia assembly and function. Motile cilia play essential roles in multiple physiological processes including mucociliary clearance in the respiratory system, cerebrospinal fluid (CSF) circulation and sperm motility. Dysfunction of motile cilia and flagella underlies the human syndrome of primary ciliary dyskinesia (PCD). While the ultrastructure of motile cilia is well characterized, many important aspects of the biogenesis and regulation of motile cilia function remain poorly understood, partly due to a lack of understanding of essential components that control these processes. Our studies on mammalian Hedgehog (Hh) signaling led to the unexpected finding that Fused (Fu), a putative serine-threonine kinase, and Kif27, a kinesin, are key players in regulating motile cilia function, independent of Hh signaling. Thus, studies on Fu and Kif27 provide new mouse models of human PCD. More importantly, they serve to bridge the gap in our understanding of the steps between transcription factors essential for ciliogenesis and construction and maintenance of the motile cilia. We propose the following specific aims: 1) Test the hypothesis that Fu interacts with central pair proteins to regulate their localization and assembly during motile cilia biogenesis. 2) Elucidate the functional interactions between Fu and Kif27 in controlling motile cilia function. 3) Define the role of Fu in controlling motile cilia orientation. 4) Identify Fu targets in controlling ciliogenesis through a combination of candidate gene approaches and systematic chemical labeling methods.