Molecular Mechanisms of Connecting Cilium Function in the Vertebrate Eye

项目摘要 这个项目的长期目标是提高我们对遗传的分子机制的理解。 视网膜疾病(IRD)，并开发个性化治疗方法。令人惊讶的是，纤毛病已经被确定 作为IRDS的主要原因之一，25%的已知致病基因涉及适当的纤毛 光感受器细胞的形成和功能。然而，尽管有大量的视网膜疾病基因 与纤毛功能有关，确切的发病机制在很大程度上仍不清楚。我们最近做了 发现了连接纤毛(CC)的光感受器的一个新的亚区，称为光感受器- 特定过渡区(PSTZ)，它对CC的稳定性和功能起着至关重要的作用。委员会的设立 PSTZ依赖于已知的LCA疾病基因Spata7和RPGR复合体的其他成员。在这 提议，我们计划利用Spata7作为切入点，更好地了解这种新结构的功能 在感光细胞的连接纤毛中。我们的具体目标是： 具体目标1：调查PSTZ的建立机制 具体目标2：确定RPGR复合体成员在PSTZ结构和功能中的作用 具体目标3：确定Spata7在RPGR复合体组装和 CC结构和功能的建立和维护 这些研究将共同提供对PSTZ结构、关键蛋白质成分、 调节和功能，从而为蛋白质的分子机制提供了新的见解 通过光感受器细胞的连接纤毛运输。鉴于初级纤毛的核心作用不是 不仅在视网膜疾病中，而且在许多其他综合征病理中，这些目标有可能使 对我们诊断和治疗人类疾病的理解和能力产生了很大的影响。

Project Summary The long-term goal of this project is to improve our understanding of the molecular mechanisms of inherited retinal diseases (IRDs) and to develop personalized treatments. Strikingly, ciliopathies have been identified as one of the major causes of IRDs with 25% of the known disease-causing genes involved in proper cilia formation and function in photoreceptor cells. However, despite the large number of retinal disease genes related to cilium function, the precise disease mechanisms remain largely unknown. We have recently discovered a novel subdomain of the photoreceptor connecting cilium (CC), named the photoreceptor- specific transition zone (PSTZ), which plays a critical role in CC stability and function. Establishment of the PSTZ depends on Spata7, a known LCA disease gene, and other members of the RPGR complex. In this proposal, we plan to utilize Spata7 as an entry point to better understand the function of this novel structure in the connecting cilium of photoreceptor cells. Our Specific Aims are to: Specific Aim 1: Investigate the mechanism of PSTZ establishment Specific Aim 2: Determine the role of RPGR complex members in PSTZ structure and function Specific Aim 3: Determine the role of Spata7 in RPGR complex assembly and in establishment versus maintenance of CC structure and function Together these studies will provide a systematic evaluation of the PSTZ structure, key protein composition, regulation, and function, thereby providing novel insights concerning the molecular mechanisms of protein trafficking through the connecting cilium of photoreceptor cells. Given the central role primary cilia play not only in retinal disease, but also many other syndromic pathologies, these aims have the potential to make a high impact in our understanding of and ability to diagnose and treat human disease.