The molecular mechanisms by which mammalian Fused regulates motile cilia function

描述（由申请人提供）：本研究的长期目标是了解控制运动纤毛组装和功能的分子机制。纤毛运动在呼吸系统纤毛黏液清除、脑脊液循环和精子运动等多种生理过程中发挥重要作用。运动纤毛和鞭毛的功能障碍是人类原发性纤毛运动障碍综合征（PCD）的基础。虽然运动纤毛的超微结构已经被很好地表征，但运动纤毛功能的生物发生和调节的许多重要方面仍然知之甚少，部分原因是缺乏对控制这些过程的基本成分的了解。我们对哺乳动物Hedgehog （Hh）信号传导的研究意外地发现，一种被认为是丝氨酸-苏氨酸激酶的fuse （Fu）和一种激酶蛋白Kif27是调节纤毛运动功能的关键角色，独立于Hh信号传导。因此，Fu和Kif27的研究提供了新的人类PCD小鼠模型。更重要的是，它们有助于弥合我们对纤毛发生和运动性纤毛的构建和维持所必需的转录因子之间步骤的理解的差距。我们提出以下具体目标：1)验证Fu与中心对蛋白相互作用调节其在运动性纤毛生物发生过程中的定位和组装的假设。2)阐明Fu与Kif27在控制纤毛运动功能中的功能相互作用。3)明确Fu在控制纤毛运动方向中的作用。4)通过候选基因方法和系统化学标记方法相结合，确定控制纤毛发生的Fu靶点。公共卫生相关性：影响纤毛运动功能的突变与人类原发性纤毛运动障碍（PCD）有关。确定控制这些过程的新成分和途径是进一步了解纤毛相关疾病病理生理学的关键，并为其诊断和治疗提供重要工具。这一知识对于理解与原发性非运动性纤毛缺陷相关的疾病具有更广泛的意义，因为可以采用类似的机制。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Mutations that affect motile cilia function are associated with human primary ciliary dyskinesia (PCD). Identifying new components and pathways that control these processes are key to further our understanding of the pathophysiology of cilia-related diseases and provide important tools for their diagnosis and treatment. This knowledge has an even wider implication for understanding diseases associated with defective primary nonmotile cilia since similar mechanisms could be employed.