Photoreceptor Disk Formation and Retinal Degenerations

感光盘形成和视网膜变性

• 批准号: 10513271
• 负责人: Alecia K Gross
• 金额: $ 3.67万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10513271
• 关键词: Affect; Architecture; Cell Maintenance; Cells; Cellular biology; Cilia; Confocal Microscopy; Data; Development; Disease; Dynein ATPase; Electron Microscopy; F-Actin; Functional disorder; Genes; Goals; HSP 90 inhibition; Heat-Shock Proteins 90; Hereditary Disease; Knockout Mice; Leber' s amaurosis; Lipids; Maintenance; Mediating; Membrane; Microtubules; Mitochondria; Mitotic; Molecular; Movement; Mutation; Neuroprotective Agents; Neurosciences; Nuclear; Organelles; Parents; Pathway interactions; Photoreceptors; Process; Proliferating; Protein C; Protein Sortings; Proteins; Recombinant adeno-associated virus (rAAV); Regulation; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Role; Signal Transduction; Structure; intervertebral disk degeneration; novel; photoreceptor disc; protein distribution; protein transport; retinal rods; rod outer segment disc

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.

项目摘要/摘要 - 父级R01 分子神经科学和细胞生物学中最基本的过程之一是适当的组装 信号传递机制，包括蛋白质成分的运输和分选。主要原因 视网膜变性和其他遗传性疾病是蛋白质的定位不当和组织 脂质。这项研究的总体目的是了解调节调节的细胞机制 基础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。 在光感受器磁盘中发现蛋白质的基因突变通常会诱导异常磁盘的形成 导致视网膜变性并表现为视网膜炎色素炎或Leber的视网膜疾病 我们的长期目标是了解两极分化所需的机制 感光细胞的生长和维护，这两个过程需要蛋白质在整个纤毛上运输。 我们最近发现，动力蛋白介导的调节剂在增殖或分裂细胞中的运动，核 分布蛋白C（NUDC）在感光磁盘组件和维护中具有关键功能。这是 该发育蛋白在非运动后有丝分裂后光感受器细胞中的新作用。我们的初步 结果强烈表明NUDC参与了调节和维持F-肌动蛋白的分子途径 磁盘结构所需的结构，包括蛋白质Cofilin1和热激蛋白90（HSP90）。 我们的数据显示，NUDC调节Cofilin1（CFL1）以维护磁盘所需的F-肌动蛋白结构 结构。我们的初步数据还表明，NUDC会影响内部内部的线粒体大小和定位 杆细胞的片段，很可能是由于NUDC对这些细胞中微管网络的调节。在 此外，我们已经确定了NUDC在残余疾病中的神经保护剂的新作用，大多数 可能通过抑制HSP90。