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: 8212390
• 负责人: Jinghua Hu
• 金额: $ 34.3万
• 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/8212390
• 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; public health relevance; 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）：纤毛作为大多数真核细胞表面的运动或感觉装置，在发育中各种器官的正确形成中发挥重要作用。通过鞭毛内转运（IFT）和感觉转导能力的纤毛组装在所有纤毛生物中是高度保守的。在过去的十年中，随着人类疾病基因的定位克隆的快速发展，各种各样的疾病，例如常染色体显性多囊肾病（ADPKD）、Joubert综合征（JBST）、Bardet-Biedl综合征（BBS）、肾单位营养不良（NPHP）、Meckel-Gruber综合征（MKS）和常染色体隐性多囊肾病（ARPKD），已经在分子上被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对于生物体的健康显然是必不可少的。与纤毛的普遍存在一致，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、肢体、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之间的联系在很大程度上仍然难以捉摸。三种小的GTP酶Ar 1（ADP-核糖基化因子（Arf）样蛋白）Ar 13、Ar 16/Bbs 3和Ar 113 B已经涉及人类纤毛病或脊椎动物纤毛病模型，并且也被证实是所有检查的纤毛生物体中的保守纤毛蛋白。小GTP酶作为关键的分子开关在不同的膜和细胞色素相关的细胞过程。然而，Arl家族成员的角色定义不明确。由于纤毛的形成和感觉功能和疾病之间的联系的研究在人类和哺乳动物模式生物中是非常困难的，替代实验系统是必要的。C.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ciliopathy候选人，ciliogenesis途径，和纤毛感觉功能，使秀丽隐杆线虫一个强大的模型，用于表征ciliopathy基因在其天然细胞环境中的生理作用。这个建议是为了测试的核心假设，纤毛Arls作为关键监管机构在一个协调一致的方式在纤毛的背景下。拟议的研究有很大的潜力在不久的将来揭开纤毛研究的突破，并将提供有关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，阐明纤毛病的病因，并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了广泛的人类疾病，现在统称为纤毛病。这个建议的目的是使用简单但功能强大的遗传模型C。elegans来表征三种纤毛病小GTP酶（Arl 3、Arl 6和Arl 13 B）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。我们提出的研究将扩大纤毛的正常和病理状态下的发展和功能的理解，并提供了开创性的见解的三个纤毛Arls和它们的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。