Nephronophthisis-related ciliopathies and ciliary compartmentalization

项目摘要 纤毛是人体发育和健康所必需的细胞器。很早以前就知道 纤毛被组织成结构上和功能上不同的隔室，称为基底体，即 过渡带和纤毛轴。肾病相关纤毛病变(NPHP-RC)蛋白定位于 在先前已知的隔间内的子区域，揭示了隐藏的复杂性。例如, NPHP2/Inversin定位于睫状干的近端区域，称为Inversin间隔(InvC)，即 不能通过任何超微结构特征识别的。尽管纤毛在人类中具有深远的医学意义 关于健康和疾病，睫状茎是如何在空间和功能上组织的，人们仍然知之甚少。 识别控制纤毛干区隔化的机制并理解生理 睫状区的相关性在确定抗击囊性肾的治疗靶点方面将是重要的 疾病和其他纤毛病。在线虫中，InvC是保守的，这表明 蠕虫和人的纤毛在InvC和纤毛区划的建立上是相似的。在……里面 在秀丽隐杆线虫中，我们发现InvC调节微管构型和微管蛋白谷氨化。我们也 发现微管蛋白编码-通过微管蛋白亚型和微管蛋白翻译后修饰-雕刻 纤毛结构、基于睫毛运动的运输和睫毛功能，包括纤毛细胞外的释放 水泡。在这个新的应用中，我们使用线虫，一种特殊的纤毛生物学和人类模型 纤毛病变，以解决纤毛如何在空间和功能上组织的问题。首先，我们将定义 探讨了InvC的起源和功能，并探讨了InvC与微管蛋白谷氨酰化的关系。 其次，我们确定了微管蛋白代码如何调节微管超微结构，即基于运动的鞭毛内 运输和特殊的纤毛功能。最后，我们将确定控制纤毛的新基因和途径。 动态平衡，防止纤毛退化。这项研究将解决与医学相关的 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 对睫状体区隔化的分子、机制和功能的基本认识 微管蛋白密码。这些研究对囊性肾脏疾病的研究有直接的影响，因为许多 我们工作中探索的基因和途径与纤毛疾病有关。

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.