Photoreceptor dysfunction associated with rhodopsin mislocalization

与视紫红质错误定位相关的光感受器功能障碍

• 批准号: 9900015
• 负责人: Yoshikazu Imanishi
• 金额: $ 40.19万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2020-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900015
• 关键词: Ablation; Address; Affect; Autophagocytosis; Catabolism; Cell membrane; Disease; Dissection; Down-Regulation; Excision; Foundations; Functional disorder; Genetic; HCN1 channel; Homeostasis; Human; Imaging Techniques; Laboratories; Longevity; Lysosomes; Mediating; Membrane; Membrane Proteins; Modeling; Molecular; Mus; Mutation; Na(+)-K(+)-Exchanging ATPase; Neurons; Pathologic Processes; Phagocytes; Phagocytosis; Photoreceptors; Plant Roots; Process; Retina; Retinal Diseases; Retinitis Pigmentosa; Rhodopsin; Rod; Role; Signal Pathway; Structure; Structure of retinal pigment epithelium; Study Subject; Syndrome; TAC1 gene; Testing; Time; Vertebrates; Vesicle; Visual impairment; Visualization; Xenopus; base; ciliopathy; insight; mouse model; mutant; novel; photoreceptor degeneration; proteostasis; receptor; retinal rods; success; vesicular release

Title: Photoreceptor dysfunction associated with rhodopsin mislocalization Abstract: Rhodopsin mislocalization is observed in various blinding disorders including syndromic and non-syndromic retinitis pigmentosa. In most of these disorders rhodopsin mislocalizes to the inner segment (IS) plasma membrane (PM). Growing evidence suggests that PM mislocalization of rhodopsin is the root cause of photoreceptor degeneration, but how such mislocalization causes rod photoreceptor degeneration remains unknown. In this project, we will test the hypothesis that mislocalized rhodopsin disrupts PM homeostasis thereby causing dysfunction and degeneration of rod photoreceptor neurons. In rod photoreceptors, rhodopsin is synthesized at an extremely high rate and delivered to the base of the outer segments (OSs). This high rate of synthesis is balanced with a high rate of catabolism. Rhodopsin-containing disk membranes are shed at the tip of the OSs, engulfed, and digested by the retinal pigment epithelial (RPE) cells. When rhodopsin mislocalizes, a massive amount of rhodopsin is delivered to the PM of the ISs, where rhodopsin-containing membranes have no apparent contact with RPE cells. Nevertheless, we recently found that mislocalized rhodopsin is actively eliminated from the PM while new rhodopsin molecules are continuously delivered to this structure. The mechanism of elimination will be the subject of this study (Aim 1). Photoreceptor cells are terminally differentiated neurons that survive during the entire lifespan of vertebrates, including humans. Therefore, the contents of photoreceptor cells must be continuously renewed. How this renewal occurs for the OS structure is well-established, but has not been studied for the IS. We will address the renewal mechanism of IS PM proteins in rod photoreceptors and investigate the pathological process of disrupting the IS PM protein homeostasis by massive mistrafficking of rhodopsin there (Aim 2).

标题：与视紫红质错误定位相关的光感受器功能障碍 抽象的： 在各种致盲性疾病中观察到视紫红质错误定位，包括综合症和 非综合征性视网膜色素变性。在大多数这些疾病中，视紫红质错误定位到 内段 (IS) 质膜 (PM)。越来越多的证据表明，PM 视紫红质的错误定位是感光细胞退化的根本原因，但如何做到这一点 错误定位导致视杆光感受器变性的原因仍不清楚。在这个项目中，我们将 检验错误定位的视紫红质破坏 PM 稳态从而导致 视杆细胞感光神经元的功能障碍和变性。在杆状光感受器中，视紫质是 以极高的速率合成并传递到外部片段（OS）的底部。 这种高合成率与高分解代谢率相平衡。含视紫红质的盘 膜在操作系统的尖端脱落，被视网膜色素吞噬和消化 上皮（RPE）细胞。当视紫红质错误定位时，会释放大量视紫红质 到 IS 的 PM，其中含有视紫红质的膜与 视网膜色素上皮细胞。然而，我们最近发现错误定位的视紫红质被主动消除 当新的视紫红质分子不断地被输送到这个结构时，它就会从 PM 中释放出来。这 消除机制将是本研究的主题（目标 1）。感光细胞是 在脊椎动物的整个生命周期中存活的终末分化神经元，包括 人类。因此，感光细胞的内容必须不断更新。这怎么办 OS 结构的更新已经很成熟，但尚未针对 IS 进行研究。我们 将解决视杆光感受器中 IS PM 蛋白的更新机制并研究 通过大量错误运输来破坏 IS PM 蛋白稳态的病理过程 存在视紫红质（目标 2）。