Chibby and Wnt Signaling in Ciliated Cell Differentiation

纤毛细胞分化中的 Chibby 和 Wnt 信号转导

基本信息

批准号：
8442395
负责人：
KEN-ICHI TAKEMARU
金额：
$ 42.8万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442395
关键词：
Address Affinity Chromatography Apical Back Binding Biological Phenomena Biological Process Breathing Cell Differentiation process Cell Line Cells Chronic Cilia Clinical Defect Defense Mechanisms Development Disease Epithelial Cells Epithelium Functional disorder Genes Goals Hair Human Infection Knockout Mice Knowledge Link Lung Mass Spectrum Analysis Mediating Molecular Mucociliary Clearance Mucous body substance Mus Nose Outcome Patients Pharyngeal structure Phenotype Physiological Play Prevention Prevention strategy Primary Ciliary Dyskinesias Proteins Recurrence Research Resources Respiratory Insufficiency Respiratory System Respiratory Tract Infections Respiratory tract structure Role Signal Pathway Signal Transduction Structure of respiratory epithelium Surface Therapeutic Transcriptional Activation Transcriptional Regulation Wnt proteins Work base cilium biogenesis clinically significant experience human disease in vivo microorganism novel therapeutics particle pathogen programs protein complex public health relevance research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): Motile cilia are abundant in our respiratory tract, and beat synchronously in waves to propel inhaled debris and pathogens entrapped in mucus to the pharynx. This provides an important innate defense mechanism against respiratory infections. Motile cilia are usually found as clusters of 100 to 300 on the apical surface of a ciliated cell in the respiratory epithelium. Dysfunction of motile cilia has been linked to human diseases, especially primary ciliary dyskinesia (PCD). Despite their clinical importance, little is known about the key molecules and signaling pathways that govern motile ciliogenesis and ciliated cell differentiation. Therefore, understanding these fundamental biological phenomena is crucial for developing novel therapeutic strategies for the prevention and treatment of PCD and other cilia-related disorders. Chibby (Cby) was originally isolated as an evolutionarily conserved antagonist of the Wnt/¿-catenin signaling pathway. Cby physically interacts with the pivotal downstream coactivator ¿-catenin and inhibits ¿-catenin-mediated transcriptional activation. Intriguingly, Cby-knockout (Cby-/-) mice suffer from recurrent respiratory infections due to a complete absence of mucociliary transport activity, reminiscent of PCD. Our studies further revealed that ciliated cells in the nasal and lung epithelia of Cby-/- mice are poorly differentiated characterized by a markedly decreased number of motile cilia. Consistent with this phenotype, we found that endogenous Cby protein localizes to the base of cilia. Our findings therefore establish that Cby plays an essential role in proper formation/function of motile cilia in the respiratory tract. However, the cellular and molecular bases underlying the ciliary defects of Cby-/- mice remain largely unexplored. In addition, whether the ciliogenic function of Cby relates to Wnt/¿-catenin signaling is unclear. The goal of this proposal is to elucidate the roles of Cby, Cby-interacting proteins and Wnt/ ¿-catenin signaling in motile ciliogenesis and tracheal ciliated cell differentiation. In order to achieve this goal, we propose the following Specific Aims: Specific Aim 1. Investigate the role of Cby in tracheal ciliated cell differentiation; Specific Aim 2. Examine transcriptional regulation of the Cby gene during differentiation of tracheal ciliated cells; Specific Aim 3. Isolate Cby-binding partners and define their roles in ciliated cell differentiation. We expect that these experiments will contribute to a fundamental understanding of the molecular and cellular mechanisms of ciliogenesis and ciliated cell differentiation.

描述（由申请人提供）：运动纤毛在我们的呼吸道中大量存在，并以波浪形式同步跳动，将吸入的碎片和粘液中的病原体推入咽部，这通常提供了针对呼吸道感染的重要先天防御机制。呼吸道上皮纤毛细胞顶端表面有 100 至 300 个簇，运动纤毛功能障碍与此有关。人类疾病，尤其是原发性纤毛运动障碍（PCD），尽管其临床重要性，但人们对控制运动纤毛发生和纤毛细胞分化的关键分子和信号通路知之甚少，因此，了解这些基本生物学现象对于开发新的治疗策略至关重要。预防和治疗 PCD 和其他纤毛相关疾病 Chibby (Cby) 最初是作为 Wnt/¿ 的进化上保守的拮抗剂被分离出来的。 -连环蛋白信号通路。Cby 与关键的下游共激活因子发生物理相互作用。 -连环蛋白并抑制 ¿有趣的是，Cby 基因敲除 (Cby-/-) 小鼠由于完全缺乏粘液纤毛转运活性而遭受反复呼吸道感染，这让人想起 PCD。 Cby-/-小鼠的上皮细胞分化差，其特征是运动纤毛数量显着减少，与这种表型一致，我们发现内源性Cby蛋白定位于上皮细胞的基部。因此，我们的研究结果表明，Cby 在呼吸道运动纤毛的正常形成/功能中发挥着重要作用，然而，Cby-/- 小鼠纤毛缺陷的细胞和分子基础仍然很大程度上未被探索。 Cby 的纤毛形成功能与 Wnt/¿ -连环蛋白信号传导尚不清楚。该提案的目的是阐明 Cby、Cby 相互作用蛋白和 Wnt/¿ - 连环蛋白信号在运动纤毛发生和气管纤毛细胞分化中的作用为了实现这一目标，我们提出以下具体目标：具体目标 1. 研究 Cby 在气管纤毛细胞分化中的作用。气管纤毛细胞分化过程中的 Cby 基因；具体目标 3. 分离 Cby 结合伴侣并确定其在纤毛细胞分化中的作用。这些实验将有助于对纤毛发生和纤毛细胞分化的分子和细胞机制的基本理解。