Exploration of the functions of the ciliopathy Arls in cilia.

描述（由申请人提供）：纤毛在大多数真核细胞表面充当运动或感觉装置，并在发育中多种器官的正确形成中发挥重要作用。通过鞭毛内运输（IFT）和感觉转导能力进行的纤毛组装在所有纤毛生物中都高度保守。随着过去十年人类疾病基因定位克隆的快速进展，多种疾病，如常染色体显性多囊肾病（ADPKD）、Joubert综合征（JBST）、Bardet-Biedl综合征（BBS）、肾结核（NPHP）、Meckel-Gruber综合征（MKS）和常染色体隐性多囊肾病（ARPKD），已被分子表征为纤毛相关疾病，现在统称为纤毛病。纤毛功能的建立和维持显然对于生物体的健康至关重要。与纤毛的普遍存在相一致，许多纤毛病作为影响多个器官的综合征性疾病发生，包括肾、肝、四肢、眼和中枢神经系统。尽管纤毛具有生理和临床相关性，但调节纤毛生物发生和功能的核心机制以及疾病基因功能和病理学之间的联系在很大程度上仍然难以捉摸。三种小 GTP 酶 Arls（ADP 核糖基化因子 (Arf) 样蛋白）Arl3、Arl6/Bbs3 和 Arl13B 与人类纤毛病或脊椎动物纤毛病模型有关，并且也被证实在所有检查的纤毛生物中是保守的纤毛蛋白。小 GTP 酶在多种膜和细胞骨架相关的细胞过程中充当关键分子开关。然而，Arl 家族成员的角色定义不明确。由于研究纤毛形成与感觉功能和疾病之间的联系在人类和哺乳动物模型生物中非常困难，因此需要替代的实验系统。秀丽隐杆线虫使得能够在活体动物中探索这些问题。高度保守的纤毛病候选者、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天然细胞环境中的生理作用的强大模型。该提议旨在检验纤毛病 Arls 在纤毛背景下以协调一致的方式发挥关键调节作用的中心假设。拟议的研究具有在不久的将来揭示纤毛研究突破的巨大潜力，并将提供关于纤毛生物发生和感觉功能如何在其原生环境中调节的开创性信息，揭示纤毛病的病因学，并有可能为疾病诊断和治疗提供新的靶点。 公共卫生相关性：纤毛生物发生或功能的缺陷导致多种人类疾病，现在统称为纤毛病。该提案旨在使用简单但强大的遗传模型线虫来表征三种纤毛病小 GTP 酶（Arl3、Arl6 和 Arl13B）在纤毛背景下的协同作用及其与人类纤毛病病理学的相关性。我们提出的研究将拓宽对正常和病理状态下纤毛发育和功能的理解，并为三个纤毛Arls及其效应器在疾病过程中的作用及其作为治疗靶点的潜力提供开创性的见解。

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.