A Model for Nephronophthisis in Caenorhabditis elegans

秀丽隐杆线虫肾结核模型

• 批准号: 9142705
• 负责人: MAUREEN M BARR
• 金额: $ 10.08万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142705
• 关键词: Address; Alleles; Animal Model; Binding; Caenorhabditis elegans; Cilia; Cilium Microtubule; Cystic Kidney Diseases; Deacetylase; Defect; Disease; Enzymes; Etiology; Fluorescence Recovery After Photobleaching; Genes; Health; Histone Deacetylase; Human; Human Biology; Human Development; Logic; Mediating; Medical; Microtubules; Modeling; Motor; Motor Activity; Mus; Mutation; Nematoda; Nephronophthisis; Nerve Degeneration; Organelles; Pathogenesis; Pathway interactions; Pattern; Physiological; Plastics; Play; Post-Translational Protein Processing; Proteins; Regulation; Research; Role; Signal Transduction; Structure; Testing; Tubulin; Work; base; ciliopathy; cilium biogenesis; combat; gene function; in vivo; insight; kinetosome; mutant; scaffold; therapeutic target; tyrosyltubulin ligase

 DESCRIPTION (provided by applicant): Cilia are cellular organelles that are essential for human development and health. It has long been known that cilia are organized into structurally and functionally distinct compartments known as the basal body, the transition zone, and the cilia shaft. Nephronophthisis-related ciliopathy (NPHP-RC) proteins localize to subregions within the previously known compartments, revealing a hidden structural complexity. For example, NPHP2/Inversin localizes to a proximal region of the ciliary shaft called the Inversin Compartment (InvC) that is not identifiable by any ultrastructural features. Despite the profound medical importance of cilia in human health and disease, how this region of the cilium is spatially and functionally organized remains poorly understood. Identifying mechanisms controlling cilia shaft compartmentalization and understanding the physiological relevance of ciliary territories will be important in identifying therapeutic targets to combat cystic kidney diseases and other ciliopathies associated with ciliary defects. The InvC is conserved in the nematode C. elegans, suggesting that the logic underlying the establishment of the InvC and ciliary compartmentalization is similar in worm and human cilia. In C. elegans, we found that the InvC and microtubule (MT) doublet region genes function in modules to regulate ciliogenesis, MT patterning, and tubulin glutamylation. nphp-2 genetically interacts with the transition zone NPHP-RC modules, indicating inter-compartmental crosstalk between the InvC and transition zone components. In this competing renewal application, we use C. elegans, an exceptional model for ciliary biology and human ciliopathies, to address the question of how the cilium is spatially and functional organized. First, we will define the origin and function of the Inversin compartment. To this end, we will study InvC temporal and spatial regulation; ascertain how the InvC is established and determine whether tubulin glutamylation plays a role; and determine how the deacetylase HDAC-6 antagonizes InvC- and MT doublet region component-mediated ciliogenesis. Second, we determine how ciliary stability regulated by tubulin polyglutamylation may be involved in NPHP-RCs. We will test the hypothesis that NPHP- RC transition zone, InvC, and doublet region components regulate ciliary access and localization of tubulin glutamylases and deglutamylases. We will determine how tubulin polyglutamylation regulates ciliary motor- based transport and MT ultrastructure. We will identify suppressors of ciliary degeneration in the tubulin deglutamylase mutant ccpp-1. This research will address the medically relevant question of how cilia are structurally and functionally organized in healthy and diseased states, and will provide fundamental insight to the molecules, mechanisms, and functions of ciliary compartmentalization and tubulin post-translational modifications. These studies have direct implications for cystic kidney disease research because many of the genes and pathways explored in our work are associated with ciliopathies.

 描述（由申请人提供）：纤毛是对人类发育和健康至关重要的细胞器。人们早就知道，纤毛被组织成结构和功能不同的隔室，称为基体，过渡区和纤毛轴。肾结石相关纤毛病变（NPHP-RC）蛋白定位于以前已知的车厢内的亚区，揭示了隐藏的结构复杂性。例如，NPHP 2/反转蛋白定位于睫状体的近端区域，称为反转蛋白复合体（InvC），其不能通过任何超微结构特征识别。尽管纤毛在人类健康和疾病中具有深刻的医学重要性，但纤毛的这一区域在空间和功能上是如何组织的仍然知之甚少。确定控制纤毛轴区室化的机制和了解纤毛领土的生理相关性将是重要的，在确定治疗目标，以打击囊性肾病和其他纤毛缺陷相关的纤毛病。InvC在线虫C中是保守的。这表明InvC和纤毛区室化的建立背后的逻辑在蠕虫和人类纤毛中是相似的。In C.在线虫中，我们发现InvC和微管（MT）双联体区基因在模块中起调节纤毛发生、MT模式化和微管蛋白谷氨酰化的作用。nphp-2在遗传上与过渡区NPHP-RC模块相互作用，表明InvC和过渡区组分之间的隔室间串扰。在这个竞争更新应用程序中，我们使用C。elegans，纤毛生物学和人类ciliopathies的一个特殊的模型，以解决纤毛是如何空间和功能组织的问题。首先，我们将定义反转子区室的起源和功能。为此，我们将研究InvC的时间和空间调节;确定InvC是如何建立的，并确定微管蛋白谷氨酰化是否起作用;并确定去乙酰化酶HDAC-6如何拮抗InvC和MT双联体区域组件介导的纤毛发生。其次，我们确定如何纤毛的稳定性调节微管蛋白polyglutamylation可能参与NPHP-RCs。我们将检验NPHP-RC过渡区、InvC和双重区成分调节纤毛通路和微管蛋白谷氨酰化酶和脱谷氨酰化酶的定位的假设。我们将确定微管蛋白多聚谷氨酰化如何调节纤毛运动为基础的运输和MT超微结构。我们将鉴定微管蛋白脱谷氨酰胺酶突变体ccpp-1中纤毛变性的抑制因子。这项研究将解决医学相关的问题，纤毛是如何在结构和功能上组织在健康和 疾病的状态，并将提供基本的见解的分子，机制和功能的纤毛区室化和微管蛋白的翻译后修饰。这些研究对囊性肾病研究有直接的影响，因为我们工作中探索的许多基因和途径与纤毛病有关。