Photoreceptor Disk Formation and Retinal Degenerations

项目摘要/摘要-父R01 分子神经科学和细胞生物学中最基本的过程之一是正确地组装 信号传导膜，包括蛋白质组分的运输和分类。一个主要原因是 视网膜变性和其他遗传性疾病是蛋白质的不正确定位和组织 脂类。这项研究的总体目标是了解参与调控的细胞机制。 支持蛋白质和细胞器定位以及光感受器盘形成的细胞骨架网络。 在光感受器视盘中发现的编码蛋白质的基因突变经常导致视盘的异常形成 导致视网膜退化，并表现为视网膜色素变性或Leber‘s等致盲疾病 先天性黑猩猩。我们的长期目标是理解极化所需的机制 光感受器细胞的生长和维持，这两个过程需要蛋白质通过纤毛运输。 我们最近发现，在增殖或分裂细胞中，动力蛋白介导的运动的一个调节器，核 分布蛋白C(NUDC)在光感受器盘的组装和维护中起着关键作用。这是 这种发育蛋白在无运动的有丝分裂后光感受器细胞中的新作用。我们的预赛 结果有力地表明NUDC参与了调节和维持F-肌动蛋白的分子途径 磁盘结构所必需的结构，包括蛋白质cofilin1和热休克蛋白90(HSP90)。 我们的数据显示，NUDC调节cofilin1(CFL1)以维持磁盘所需的F-肌动蛋白体系结构 结构。我们的初步数据还表明，NUDC影响线粒体的大小和内部的定位 杆状细胞的节段，很可能是由于NUDC对这些细胞中的微管网络的调节。在……里面 此外，我们已经确定了NUDC作为视网膜退行性变的神经保护剂的新作用，大多数 可能是通过抑制HSP90来实现的。

Project Summary/Abstract – Parent R01 One of the most fundamental processes in molecular neuroscience and cell biology is the proper assembly of signal-transducing membranes including the transport and sorting of protein components. A major cause of retinal degenerations and other inherited disorders is the improper localization of proteins and organization of lipids. The overall goal of this study is to understand the cellular mechanisms involved in regulation of the cytoskeletal network that underpins protein and organelle localization and photoreceptor disk formation. Mutations in genes encoding proteins found in photoreceptor disks often induce abnormal disk formation resulting in retinal degeneration and manifest as blinding diseases such as retinitis pigmentosa or Leber’s congenital amaurosis. Our long-term goal is to understand the mechanisms required for polarized photoreceptor cell growth and maintenance, two processes that require protein trafficking across the cilium. We have recently found that a regulator of dynein-mediated movement in proliferating or dividing cells, nuclear distribution protein C (NUDC), has a critical function in photoreceptor disk assembly and maintenance. This is a novel role for this developmental protein in non-motile post-mitotic photoreceptor cells. Our preliminary results strongly indicate NUDC is involved in a molecular pathway that regulates and maintains the F-actin architecture necessary for disk structure, including the proteins cofilin1 and heat shock protein 90 (HSP90). Our data show NUDC regulates cofilin1 (CFL1) to maintain the F-actin architecture necessary for disk structure. Our preliminary data also show that NUDC affects mitochondria size and localization within the inner segment of rod cells, most likely due to NUDC’s regulation of the microtubule network in these cells. In addition, we have identified a novel role of NUDC as a neuroprotective agent in retinal degenerations, most likely through the inhibition of HSP90.