Understanding Photoreceptor Trafficking Pathways to the Outer Segment

了解光感受器外段运输途径

基本信息

项目摘要

ABSTRACT The first step of vision takes place in the retina where light is captured by the outer segment organelle of rod and cone photoreceptors. The outer segment is a modified primary cilium that contains a stack of flat disc-shaped membranes. This structural arrangement maximizes light detection by forcing photons to pass through hundreds of membrane layers densely packed with the light absorbing protein, opsin. A byproduct of light absorption is photooxidative damage, which the photoreceptor overcomes by continuously replacing its entire membrane-rich outer segment with new protein and lipid material. Defects in outer segment trafficking, formation, and function ultimately result in photoreceptor cell loss and cause a broad spectrum of inherited retinal dystrophies including retinitis pigmentosa, cone-rod dystrophy and Stargardt disease. It is now well established that photoreceptors utilize multiple trafficking pathways to deliver structural and signaling proteins to the light-sensitive outer segment organelle; however, how these pathways are coordinated, the molecular processes regulating delivery, why a cargo chooses a specific route remains largely unknown. The goals of our proposal are to investigate the trafficking pathways of outer segment membrane cargos that reside within the discs (rhodopsin), the disc rims (peripherin-2 and ABCA4) and the plasma membrane surrounding the discs (CNG channel). This comprehensive approach will allow us to understand shared and divergent features between specific trafficking pathways as well as build a complete overview of intracellular routes to the outer segment. Our aims utilize proximity labeling approaches to uncover transport partners in vivo as well as gene delivery techniques to rapidly screen candidates for targeting defects and uncover signals governing conventional and unconventional delivery to the outer segment in mouse rods. Completion of our aims will provide insight into how outer segment trafficking pathways cooperate to deliver the structural and functional proteins necessary to form the light-sensing outer segment organelle as well as how these processes fail during disease. Looking forward, our proposal aims to provide fundamental knowledge about membrane trafficking to sensory cilia in general as well as help to inform future therapeutic strategies for patients suffering from inherited blindness.
摘要 视觉的第一步发生在视网膜中,其中光被视网膜外节细胞器捕获。 视杆和视锥光感受器。外节是一个修改的初级纤毛,包含一堆扁平的 盘状膜。这种结构安排通过迫使光子 穿过数百层密集的光吸收蛋白质,视蛋白。一 光吸收的副产品是光氧化损伤,感光器通过以下方式克服光氧化损伤: 不断地用新的蛋白质和脂质物质替换其整个富含膜的外节。 外节运输、形成和功能的缺陷最终导致感光细胞的丧失 并引起广泛的遗传性视网膜营养不良,包括色素性视网膜炎、视锥-视杆细胞变性, 营养不良和Stargardt病。现在已经确定,光感受器利用多种运输 传递结构蛋白和信号蛋白到光敏感外节细胞器的途径; 然而,这些途径是如何协调的,调节递送的分子过程,为什么货物 选择一条特定的路线仍然是未知的。我们提案的目标是调查 存在于椎间盘内的外节膜货物(视紫红质)的运输途径,椎间盘 边缘(外周蛋白-2和ABCA 4)和围绕盘的质膜(CNG通道)。这 全面的方法将使我们能够了解具体的国家之间的共同和不同的特点, 运输途径,以及建立一个完整的概述细胞内的路线外节。我们 aims利用邻近标记方法来揭示体内转运伙伴以及基因递送 快速筛选目标缺陷的候选者并揭示控制常规缺陷的信号的技术 和非常规的递送到小鼠杆中的外节。完成我们的目标将提供 深入了解外段运输途径如何合作,以提供结构和功能 形成感光外节细胞器所必需的蛋白质以及这些过程如何失败 在疾病期间。展望未来,我们的建议旨在提供有关膜的基础知识 运输到感觉纤毛,以及帮助为患者提供未来的治疗策略 患有遗传性失明

项目成果

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Jillian Nydam Pearring其他文献

Jillian Nydam Pearring的其他文献

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{{ truncateString('Jillian Nydam Pearring', 18)}}的其他基金

Understanding Photoreceptor Trafficking Pathways to the Outer Segment
了解光感受器外段运输途径
  • 批准号:
    10364187
  • 财政年份:
    2022
  • 资助金额:
    $ 45.04万
  • 项目类别:
Understanding Photoreceptor Trafficking Pathways to the Outer Segment
了解光感受器外段运输途径
  • 批准号:
    9892591
  • 财政年份:
    2018
  • 资助金额:
    $ 45.04万
  • 项目类别:
Understanding Photoreceptor Trafficking Pathways to the Outer Segment
了解光感受器外段运输途径
  • 批准号:
    9115610
  • 财政年份:
    2015
  • 资助金额:
    $ 45.04万
  • 项目类别:
The Role of Arf4 in Sorting Photoreceptor Outer Segment Proteins
Arf4 在光感受器外节蛋白分选中的作用
  • 批准号:
    8311595
  • 财政年份:
    2012
  • 资助金额:
    $ 45.04万
  • 项目类别:
The Role of Arf4 in Sorting Photoreceptor Outer Segment Proteins
Arf4 在光感受器外节蛋白分选中的作用
  • 批准号:
    8456241
  • 财政年份:
    2012
  • 资助金额:
    $ 45.04万
  • 项目类别:
The Role of Arf4 in Sorting Photoreceptor Outer Segment Proteins
Arf4 在光感受器外节蛋白分选中的作用
  • 批准号:
    8650286
  • 财政年份:
    2012
  • 资助金额:
    $ 45.04万
  • 项目类别:

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