Photoreceptor Disk Formation and Retinal Degenerations

感光盘形成和视网膜变性

基本信息

批准号：
10415996
负责人：
Alecia K Gross
金额：
$ 39.99万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415996
关键词：
Actins Affect Animal Model Animals Architecture Biological Assay C-Microtubule Carrier Proteins Cell Maintenance Cells Cellular biology Cilia Cone Confocal Microscopy Cryoelectron Microscopy Cytoskeleton Data Defect Development Disease Disease Progression Dynein ATPase Electron Microscopy Electroretinography F-Actin Face Functional disorder Genes Goals HSP 90 inhibition Health Heat-Shock Proteins 90 Hereditary Disease Immunohistochemistry Knock-out Knockout Mice Leber&apos s Hereditary Optic Neuropathy Leber&apos s amaurosis Lipids Longevity Maintenance Mediating Membrane Microtubules Mitochondria Mitotic Modeling Molecular Molecular Abnormality Monitor Morphology Movement Mus Mutation Neuroprotective Agents Neurosciences Nuclear Optic Atrophy Organelles Oxygen Consumption Pathway interactions Photoreceptors Play Preparation Process Production Proliferating Protein C Protein Sortings Proteins Publishing Recombinant adeno-associated virus (rAAV)Regulation Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rhodopsin Rod Role Scanning Electron Microscopy Signal Transduction Structural defect Structure Testing Transgenic Model Transgenic Organisms Usher Syndrome Vertebrate Photoreceptors Viral experimental study intervertebral disk degeneration mutant new therapeutic target novel overexpression photoreceptor disc protein distribution protein transport retinal rods rod outer segment disc therapeutic target trafficking

项目摘要

Project Summary/Abstract 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化感光器所需的机制细胞的生长和维护，这两个过程需要蛋白质在整个纤毛上进行。我们最近有发现在增殖或分裂细胞中，动力蛋白介导的运动的调节剂，核分布蛋白 C（NUDC）在光感受器磁盘组件和维护中具有关键功能。这是一个新颖的角色非运动后有丝分裂后感光细胞中的发育蛋白。我们的初步结果强烈表明 NUDC参与了调节和维持F-肌动蛋白结构所必需的F-肌动蛋白结构的分子途径盘结构，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）维持磁盘结构所需的F-肌动蛋白结构。我们的初步数据也显示 NUDC会影响杆细胞内部段内的线粒体大小和定位，很可能是由于 NUDC对这些细胞中微管网络的调节。此外，我们已经确定了NUDC的新作用作为残留变性的神经保护剂，最有可能通过抑制HSP90。