Cep290 function in photoreceptor structure and disease.

摘要 光感受器神经元是具有精细外节（OS）的特化细胞， 盘状结构，并通过连接纤毛（CC）锚定。OS蛋白的描绘 涉及光到电信号的转换已经广泛，尽管OS的阐述， 维持，和维持这些过程的结构复合体尚未阐明。 因此，我的短期目标是确定CC驻留蛋白复合物和Y连接的作用 CC内部的结构，特别是关于外部部分的增长和组织。 这一目标具有临床意义，因为OS组织和与Y细胞相关的蛋白质存在缺陷。 链接结构导致失明。我的最终目标是描述CC的结构和相互作用 并了解纤毛结构变化之间的机械联系 和视网膜纤毛病变的功能缺陷。本申请的中心假设是， CEP290中的缺陷干扰CC中Y形连接件的结构和功能，从而 破坏纤毛功能并导致异常OS形态发生。我的假设是 基于Cep290突变患者的初步数据以及分析 Cep290突变小鼠品系。本提案的具体目标是：1）将CEP290本地化， 培养细胞的纤毛和视杆细胞的CC具有足够的分辨率，以确定其结构 与Y形连接件和睫状膜的关系，以及2）检验CEP290 用作纤毛运输过滤器的组件。使用多个突变的动物模型 在Cep290或缺乏Cep290的情况下，我的目标是确定Cep290在感光细胞中的确切位置。 CC，并确定CEP290的蛋白质过滤到纤毛的作用。这项研究将影响 通过为Leber先天性黑蒙症的机械知识库做出贡献， 其他与睫状体相关的视网膜变性疾病，它将提供一个机会，创造新的 治疗这些疾病。

ABSTRACT Photoreceptor neurons are specialized cells that possess elaborated outer segments (OS) containing disc like structures and are anchored by connecting cilia (CC). The delineation of the OS proteins involved in the conversion of light to electrical signal has been extensive, nevertheless OS elaboration, maintenance, and the structural complexes sustaining these processes have yet to be elucidated. Therefore, my short-term goal is to define the role of CC-resident protein complexes and Y-link structures within the CC, specifically in regards to the growth and organization of the outer segment. This goal is of clinical significance as defects in OS organization and in proteins associated with the Y- link structures lead to blindness. My ultimate goal is to characterize the CC structure and interactions of proteins within it, and to understand the mechanistic connections between changes in cilia structure and functional defects in retinal ciliopathies. The central hypothesis of this application is that defects in CEP290 interfere with the structure and function of the Y-links in the CC, thereby disrupting ciliary function and resulting in aberrant OS morphogenesis. My hypothesis has been formed based on preliminary data from patients with mutations in Cep290, as well as from the analysis of Cep290 mutant mouse lines. The specific aims of this proposal are to 1) Localize CEP290 in primary cilia of cultured cells and the CC of rod cells with sufficient resolution to determine its structural relationship to the Y-links and the ciliary membrane, and 2) Test the hypothesis that CEP290 functions as a component of a ciliary trafficking filter. Using multiple animal models with mutations in Cep290 or lacking Cep290, my goal is to identify the exact location of CEP290 within photoreceptor CC and to determine CEP290’s role in the filtering of proteins into the cilium. This research will impact the health field by contributing to the mechanistic knowledge base for Leber Congenital Amaurosis and other cilia-related retinal degeneration diseases, and it will provide an opportunity to create novel treatments for these diseases.