Chibby and Wnt Signaling in Ciliated Cell Differentiation

纤毛细胞分化中的 Chibby 和 Wnt 信号转导

• 批准号: 8644869
• 负责人: KEN-ICHI TAKEMARU
• 金额: $ 44.07万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 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/8644869
• 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

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. PUBLIC HEALTH RELEVANCE: Motile cilia (tiny hair-like projections from ciliated cells) lining our respiratory tract wave back and forth to effectively remove inhaled debris and microorganisms entrapped in mucus, and human patients with dysfunctional cilia suffer from recurrent respiratory infections, leading to respiratory insufficiency. Therefore, understanding mechanisms of motile cilia formation and ciliated cell differentiation is critical for development of new therapies for diseases caused by dysfunctional cilia. Our research investigates roles of Chibby protein and Wnt signaling pathway in motile cilia formation and ciliated cell differentiation, and will most likely contribute to our better understanding of these important biological processes.

描述（由适用提供）：我们的呼吸道中的纤毛含量丰富，并在波浪中同步打击以促进粘液中掺入粘液的碎屑和病原体。这提供了针对呼吸道感染的重要先天防御机制。在呼吸上皮的纤毛细胞的顶部表面上，纤毛通常被发现为100至300的簇。纤毛运动功能障碍与人类疾病有关，尤其是原发性睫状运动障碍（PCD）。尽管它们的临床重要性，但对主题纤毛生成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制定新的治疗策略以预防和治疗PCD和其他纤毛疾病至关重要。 Chibby（CBY）最初被分离为Wnt/® -Catenin信号通路的进化保守拮抗剂。 CBY与关键下游共激活剂�-蛋白酶的物理相互作用，并抑制 - 帕宁蛋白介导的转录激活。有趣的是，由于完全没有粘膜纤毛转运活性，CBY敲除（CBY - / - ）小鼠患有复发性呼吸道感染，让人联想到PCD。我们的研究进一步表明，CBY - / - 小鼠的鼻腔和肺上皮中的纤毛细胞的分化很差，其特征是cilia的数量明显减少。与这种表型一致，我们发现内源性CBY蛋白定位在纤毛基础上。因此，我们的发现表明，CBY在呼吸道中纤毛的适当形成/功能中起着至关重要的作用。然而，CBY - / - 小鼠的纤毛缺陷背后的细胞和分子碱基在很大程度上仍然是出乎意料的。另外，CBY的纤毛生成功能是否与Wnt/¿-Catenin信号相关。该提案的目的是阐明CBY，CBY相互作用蛋白质和Wnt/® -catenin信号传导在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，我们提出以下特定目的：特定目的1。研究CBY在气管纤毛细胞分化中的作用；具体目标2。检查气管纤毛细胞分化时CBY基因的转录调节；特定的目标3。分离CBY结合伴侣并定义其在纤毛细胞分化中的作用。我们预计这些实验将有助于对纤毛生成和纤毛细胞分化的分子和细胞机制的基本了解。 公共卫生相关性：机动纤毛（来自纤毛细胞的小头发样突起）来回呼吸道波浪，以有效地消除粘液中的掺入的碎屑和微生物，以及患有纤毛功能失调的纤毛患者的呼吸道呼吸道感染，导致呼吸道感染，导致呼吸道不足。因此，了解母纤毛形成和纤毛细胞分化的机制对于开发由功能失调的纤毛引起的新疗法的发展至关重要。我们的研究调查了Chibby蛋白和Wnt信号通路在基纤维纤毛形成和纤毛细胞分化中的作用，并且很可能有助于我们更好地理解这些重要的生物学过程。