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.

项目总结/摘要-父代R 01 分子神经科学和细胞生物学中最基本的过程之一是正确组装 信号转导膜，包括蛋白质成分的运输和分选。的主要原因 视网膜变性和其他遗传性疾病是蛋白质和组织的不适当定位， 脂质。本研究的总体目标是了解参与调节的细胞机制， 支持蛋白质和细胞器定位以及感光盘形成的细胞骨架网络。 在感光盘中发现的编码蛋白质的基因的突变经常诱导异常盘形成 导致视网膜变性并表现为致盲性疾病，如视网膜色素变性或Leber's 先天性黑蒙我们的长期目标是了解极化所需的机制， 感光细胞的生长和维持，这两个过程需要蛋白质运输穿过纤毛。 我们最近发现，在增殖或分裂细胞中，一种调节动力蛋白介导的运动的调节因子， 分布蛋白C（NUDC）在光感受器盘的组装和维持中具有关键功能。这是 一个新的作用，这种发展蛋白质在非运动后有丝分裂感光细胞。我们的初步 结果强烈表明NUDC参与调节和维持F-肌动蛋白的分子途径， 盘结构所必需的结构，包括蛋白质cofilin 1和热休克蛋白90（HSP 90）。 我们的数据显示NUDC调节cofilin 1（CFL 1）以维持磁盘所需的F-肌动蛋白结构 结构我们的初步数据还表明，NUDC影响线粒体的大小和内定位， 这可能是由于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作为视网膜变性的神经保护剂的新作用， 可能是通过抑制HSP 90。