Nephronophthisis-related ciliopathies and ciliary compartmentalization

肾结核相关纤毛病和纤毛区室化

• 批准号: 10078948
• 负责人: MAUREEN M BARR
• 金额: $ 34.7万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078948
• 关键词: Address; Animal Model; Biology; Caenorhabditis elegans; Carboxypeptidase; Cells; Cilia; Cilium Microtubule; Code; Cystic Kidney Diseases; Defect; Disease; Dynein ATPase; Etiology; Flagella; Gene Family; Genes; Goals; Health; Homeostasis; Human; Human Development; Human body; Instruction; Interphase Cell; Kidney; Kinesin; Language; Location; Logic; Malignant Neoplasms; Medical; Microtubules; Modeling; Motor; Mus; Mutation; Nematoda; Nephronophthisis; Organelles; Pathologic; Pathology; Pathway interactions; Pattern; Physiological; Play; Polycystic Kidney Diseases; Post-Translational Protein Processing; Proteins; Reader; Research; Retinal Degeneration; Role; Structure; Suppressor Genes; Sushi Domain; Syndrome; System; Testing; Tubulin; Work; base; cell type; ciliopathy; clinical phenotype; combat; combinatorial; extracellular vesicles; gene product; insight; kinetosome; nephronophthisis-related ciliopathy; nervous system disorder; progressive neurodegeneration; reconstitution; sperm cell; therapeutic target; tyrosyltubulin ligase

Project Summary 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 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 the ciliary shaft 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. 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 regulates microtubule patterning and tubulin glutamylation. We also discovered that the Tubulin Code – via tubulin isotypes and tubulin post-translational modifications – sculpts ciliary structure, ciliary motor-based transport, and ciliary functions including release of ciliary extracellular vesicles. In this new 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 InvC and examine the relationship between the InvC and tubulin glutamylation. Second, we determine how the Tubulin Code regulates microtubule ultrastructure, motor-based intraflagellar transport, and specialized ciliary functions. Finally, we will identify new genes and pathways that control ciliary homeostasis and protect against ciliary degeneration. 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 the Tubulin Code. 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.

项目概要 纤毛是对人类发育和健康至关重要的细胞器。 纤毛被组织成结构和功能不同的区室，称为基体、 过渡区和纤毛轴蛋白定位于肾痨相关纤毛病 (NPHP-RC)。 先前已知的分区内的子区域，揭示了隐藏的复杂性例如， NPHP2/Inversin 定位于称为“Inversin 室”(InvC) 的睫状干近端区域，该区域是 尽管纤毛对人类具有深远的医学重要性，但无法通过任何超微结构特征来识别。 对于健康和疾病，睫状干在空间和功能上的组织方式仍然知之甚少。 识别控制纤毛轴区室化的机制并了解其生理学 睫状体区域的相关性对于确定对抗囊性肾的治疗目标非常重要 InvC 在线虫中是保守的，这表明这一逻辑。 蠕虫和人类纤毛中 InvC 和纤毛区室化建立的基础是相似的。 在秀丽隐杆线虫中，我们发现 InvC 调节微管模式和微管蛋白谷氨酰化。 发现微管蛋白密码——通过微管蛋白同种型和微管蛋白翻译后修饰——塑造 睫状体结构、基于睫状运动的运输和睫状体功能，包括睫状体细胞外物质的释放 在这个新应用中，我们使用秀丽隐杆线虫，它是纤毛生物学和人类的特殊模型。 纤毛病，为了解决纤毛在空间和功能上如何组织的问题，首先，我们将定义。 研究了 InvC 的起源和功能，并检查了 InvC 与微管蛋白谷氨酰化之间的关系。 其次，我们确定微管蛋白代码如何调节微管超微结构、基于运动的鞭毛内 最后，我们将确定控制纤毛的新基因和途径。 这项研究将解决与医学相关的问题。 纤毛在健康和患病状态下如何在结构和功能上组织的问题，并将提供 对纤毛区室化的分子、机制和功能以及 这些研究对囊性肾病研究具有直接影响，因为许多 我们的工作中探索的基因和途径与纤毛病有关。