Exploration of the functions of the ciliopathy Arls in cilia.

描述（由申请人提供）：纤毛是大多数真核细胞表面的运动或感觉装置，在发育过程中多种器官的正确形成中起重要作用。纤毛通过鞭毛内运输（IFT）和感觉转导能力在所有纤毛生物中都是高度保守的。近十年来，随着人类疾病基因定位克隆技术的快速发展，许多疾病，如常染色体显性多囊肾病（ADPKD）、Joubert综合征（JBST）、Bardet-Biedl综合征（BBS）、肾病（NPHP）、Meckel-Gruber综合征（MKS）和常染色体隐性多囊肾病（ARPKD），在分子上被定性为与纤毛相关的疾病，现在统称为纤毛病。纤毛功能的建立和维持显然对生物体的健康至关重要。与普遍存在的纤毛一致，许多纤毛病以综合征性疾病的形式出现，影响多个器官，包括肾、肝、肢体、眼睛和中枢神经系统。尽管纤毛具有生理和临床意义，但调控纤毛生物发生和功能的核心机制以及疾病基因功能与病理之间的联系在很大程度上仍是难以捉摸的。三种小的GTPase Arls （adp -核糖基化因子（Arf）样蛋白），Arl3， ar16 / bs3和Arl13B与人类纤毛病或脊椎动物纤毛病模型有关，并且在所有被检测的纤毛生物中也证实是保守的纤毛蛋白。小gtpase在各种膜和细胞骨架相关的细胞过程中起着关键的分子开关作用。然而，Arl家庭成员的角色定义不清。由于在人类和哺乳动物模式生物中研究纤毛形成与感觉功能和疾病之间的联系是非常困难的，因此有必要采用其他实验系统。秀丽隐杆线虫使得在活体动物中探索这些问题成为可能。高度保守的纤毛候选者、纤毛发生途径和纤毛感觉功能使秀丽隐杆线虫成为表征纤毛病基因在其原生细胞环境中生理作用的有力模型。这一建议是为了验证在纤毛的背景下，纤毛病细胞以协调一致的方式起关键调节作用的中心假设。这些研究有可能在不久的将来揭开纤毛研究的新突破，为了解纤毛在自然环境中如何发生和调节感觉功能提供开创性的信息，揭示纤毛病的病因，并有可能为疾病的诊断和治疗提供新的靶点。

DESCRIPTION (provided by applicant): Cilia serve as motile or sensory devices on most eukaryotic cells surface and play an essential role in the proper formation of a diversity of organs in development. Ciliary assembly via intraflagellar transport (IFT) and sensory transduction capabilities are highly conserved in all ciliated organisms. With rapid advancements in the positional cloning of human disease genes in the past decade, a wide variety of disorders, such as autosomal dominant polycystic kidney disease (ADPKD), Joubert syndrome (JBST), Bardet-Biedl syndrome (BBS), nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS), and autosomal recessive polycystic kidney disease (ARPKD), have been characterized molecularly as cilia-related diseases, now known collectively as ciliopathies. The establishment and maintenance of ciliary function are clearly essential for the well-being of an organism. Consistent with the ubiquitous presence of cilia, many ciliopathies occur as syndromic disorders that affect multiple organs, including the kidney, liver, limb, eye, and central nervous system. Despite the physiological and clinical relevance of cilia, the core machinery that regulates cilia biogenesis and function as well as the connection between the disease gene function and pathology remain largely elusive. Three small GTPase Arls (ADP-ribosylation factor (Arf)-like proteins), Arl3, Arl6/Bbs3, and Arl13B, have been implicated in either human ciliopathies or vertebrate ciliopathy models, and also confirmed to be conserved ciliary proteins in all examined ciliated organisms. Small GTPases act as key molecular switches in diverse membrane- and cytoskeleton-related cellular processes. However, the roles of Arl family members are poorly defined. Because the study of the connections between cilia formation and sensory function and disease are prohibitively difficult in humans and in mammalian model organisms, alternative experimental systems are necessary. C. elegans enables the exploration of these questions in living animals., The highly conserved ciliopathy candidates, ciliogenesis pathway, and cilia sensory function make Caenorhabditis elegans a powerful model for characterizing the physiological roles of ciliopathy genes in their native cellular environments. This proposal is to test the central hypothesis that the ciliopathy Arls act as key regulators in a concerted manner in the context of cilia. The proposed studies have great potential to unveil breakthroughs in cilia research in the near future, and would provide seminal information about how cilia biogenesis and sensory function are regulated in their native environment, shed light on the etiologies of ciliopathies, and potentially provide novel targets for disease diagnosis and treatment. PUBLIC HEALTH RELEVANCE: Defects in cilia biogenesis or function contribute to a wide spectrum of human diseases, now collectively called as ciliopathies. This proposal is designed to use the simple but powerful genetic model C. elegans to characterize the concerted roles of three ciliopathy small GTPases (Arl3, Arl6, and Arl13B) in the context of cilia and their correlation to the pathology of human ciliopathies. Our proposed studies will broaden the understanding of cilia development and function in normal and pathological states and provide seminal insights into the roles of the three ciliary Arls and their effectors in disease processes, and their potential as therapeutic targets.