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.

项目摘要 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 在以前已知的隔间，揭示了隐藏的复杂性。比如说， 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）， 不能通过任何超微结构特征识别。尽管纤毛在人体内具有深远的医学意义， 对于健康和疾病，睫状体在空间上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并了解生理学 睫状体区域的相关性在确定治疗目标以对抗囊性肾方面将是重要的 疾病和其他纤毛病。InvC在线虫C中是保守的。这表明， 在蠕虫和人类纤毛中，InvC和纤毛区室化的建立的基础是相似的。在 C.在elegans中，我们发现InvC调节微管图案化和微管蛋白谷氨酰化。我们也 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 纤毛结构、基于纤毛运动的转运和纤毛功能，包括纤毛细胞外 囊泡在这个新的应用程序中，我们使用C。线虫，纤毛生物学和人类的特殊模型 纤毛病，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 InvC的起源和功能，探讨InvC与微管蛋白谷氨酰化的关系。 其次，我们确定了微管编码如何调节微管超微结构，基于运动的鞭毛内 运输和专门的纤毛功能。最后，我们将确定新的基因和途径，控制纤毛 保持体内平衡和防止纤毛变性。这项研究将解决医学相关的 纤毛在健康和疾病状态下的结构和功能如何组织的问题，并将提供 对纤毛区室化的分子、机制和功能的基本见解， 微管蛋白编码。这些研究对囊性肾病的研究有直接的影响，因为许多 在我们的工作中探索的基因和途径与纤毛病有关。