Exploration of the functions of the ciliopathy Arls in cilia.

纤毛病 Arls 在纤毛中的功能探索。

• 批准号: 8019251
• 负责人: Jinghua Hu
• 金额: $ 33.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019251
• 关键词: Abbreviations; Affect; Alleles; Anatomy; Animal Model; Animals; Arl proteins; Autosomal Dominant Polycystic Kidney; Autosomal Recessive Polycystic Kidney; Bardet-Biedl Syndrome; Behavior; Binding; Caenorhabditis elegans; Cell physiology; Cell surface; Cells; Chimeric Proteins; Cilia; Complex; Cystic kidney; Cytoskeleton; Data; Deacetylase; Defect; Development; Devices; Disease; Dominant-Negative Mutation; Dyes; Embryonic Development; Environment; Enzymes; Etiology; Eukaryotic Cell; Eye; Family member; Functional disorder; Future; GTPase Gene; Genes; Genetic; Genetic Models; Guanosine Triphosphate Phosphohydrolases; Histone Deacetylase; Homologous Gene; Human; Human Pathology; Individual; Joubert syndrome; Kidney; Letters; Life; Light; Limb structure; Liver; Maintenance; Mediating; Medical; Membrane; Modeling; Molecular; Monomeric GTP-Binding Proteins; Names; Nephronophthisis; Neuraxis; Nomenclature; Organ; Organelles; Organism; Partner in relationship; Pathology; Pathway interactions; Personal Satisfaction; Physiological; Play; Process; Proteins; Research; Role; Seminal; Sensory; Sensory Receptors; Signal Transduction; Structure; Syndrome; System; Testing; Transmission Electron Microscopy; Ubiquitin; Yeasts; ciliopathy; cilium biogenesis; clinically relevant; design; disease diagnosis; gene function; histone deacetylase 6; human disease; insight; kinetosome; male; mutant; novel; positional cloning; research study; therapeutic target; transmission process; yeast two hybrid system

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.

描述(由申请人提供)：纤毛在大多数真核细胞表面作为运动或感觉装置，在发育过程中各种器官的正确形成中发挥重要作用。纤毛组装通过鞭毛内运输(IFT)和感觉转导能力是高度保守的所有纤毛生物。随着人类疾病基因定位克隆的快速发展，许多疾病，如常染色体显性遗传性多囊肾病(ADPKD)、Joubert综合征(JBST)、Bardet-Biedl综合征(BBS)、肾病(NPHP)、Meckel-Gruber综合征(MKS)和常染色体隐性遗传性多囊肾病(ARPKD)在分子上被定性为纤毛相关疾病，现在统称为纤毛疾病。纤毛功能的建立和维持显然对生物体的健康至关重要。与无处不在的纤毛的存在相一致，许多纤毛疾病以综合征的形式出现，影响到多个器官，包括肾脏、肝脏、四肢、眼睛和中枢神经系统。尽管纤毛具有生理和临床相关性，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和病理之间的联系在很大程度上仍然难以捉摸。三个小的GTP酶Arl(ADP核糖化因子(Arf)样蛋白)，Ar13，Ar16/Bbs3和Ar13b，在人类纤毛疾病或脊椎动物纤毛疾病模型中都被发现，也被证实在所有被研究的纤毛生物中都是保守的纤毛蛋白。小分子GTP酶在不同的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家族成员的作用并不明确。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，因此有必要使用替代的实验系统。秀丽线虫的高度保守性、纤毛发生途径和纤毛感觉功能使秀丽线虫成为研究纤毛病基因在其天然细胞环境中的生理作用的有力模型。这一建议是为了检验中心假设，即纤毛病变ARL在纤毛环境中以一致的方式发挥关键调节作用。这些拟议的研究具有在不久的将来揭示纤毛研究的突破的巨大潜力，并将提供关于纤毛的生物发生和感觉功能在其自然环境中如何调节的开创性信息，阐明纤毛疾病的病因，并可能为疾病的诊断和治疗提供新的靶点。 与公共卫生相关：纤毛生物发生或功能缺陷导致了一系列人类疾病，现在统称为纤毛病。这项建议旨在利用简单但强大的线虫遗传模型来表征三种纤毛病小GTP酶(Ar13、Ar16和Ar13b)在纤毛环境中的协同作用及其与人类纤毛疾病病理的相关性。我们提出的研究将扩大对纤毛在正常和病理状态下的发育和功能的理解，并为三种纤毛ARL及其效应器在疾病过程中的作用以及它们作为治疗靶点的潜力提供开创性的见解。