Cep290 function in photoreceptor structure and disease.

摘要 光感受器神经元是一种特殊的细胞，它具有精细的外节(OS)，其中包含 盘状结构，由连接纤毛(CC)固定。OS蛋白的描述 涉及光到电信号的转换已经很广泛，然而OS详述， 维护，以及维持这些过程的结构复合体还有待阐明。 因此，我的短期目标是确定CC驻留蛋白复合体和Y-link的作用 协调委员会内部的结构，特别是在外部部分的增长和组织方面。 这一目标具有临床意义，因为在OS组织和与Y-Y相关的蛋白质中存在缺陷。 链接结构导致了盲目性。我的最终目标是描述CC结构和交互的特征 并了解纤毛结构变化之间的机械联系 以及视网膜纤毛病变中的功能缺陷。这个应用程序的中心假设是 CEP290中的缺陷干扰了CC中Y-链的结构和功能，从而 破坏睫毛功能，导致OS形态发生异常。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。这项建议的具体目标是：1)将CEP290本地化 培养细胞的纤毛和杆状细胞的CC具有足够的分辨率以确定其结构 与Y链和睫状膜的关系，以及2)检验CEP290的假设 作为纤毛交易过滤器的一个组件。使用多种突变的动物模型 在CEP290或缺乏CEP290的情况下，我的目标是确定CEP290在光感受器中的确切位置 CC和确定CEP290‘S在滤入纤毛蛋白中的作用。这项研究将对 通过对Leber先天性巨结肠的机械知识库的贡献来促进健康领域的发展 其他与纤毛相关的视网膜退行性疾病，它将提供一个创造新的机会 这些疾病的治疗方法。

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.