Compartmentalized protein localization in photoreceptors

光感受器中的区室化蛋白质定位

• 批准号: 10707229
• 负责人: Seongjin Seo
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707229
• 关键词: 220kDa rod outer segment rim protein; Address; Appearance; Binding Proteins; Cells; Chimeric Proteins; Cilia; Cone; Disease; Disease model; Estrogen Receptors; Excision; FLP recombinase; Foundations; Functional disorder; Genetic Recombination; Goals; Homeostasis; Impairment; Individual; Injections; Internal Ribosome Entry Site; Knowledge; Label; Link; Mediating; Membrane Fusion; Membrane Proteins; Molecular; Monitor; Neurons; Outcome Study; Photoreceptors; Protein Biosynthesis; Proteins; Reaction; Reporter; Reporter Genes; Research; Retina; Retinal Degeneration; Rod; Role; Signal Transduction; Tamoxifen; Testing; Therapeutic; Transgenic Mice; Variant; Vision; ciliopathy; efficacy evaluation; homologous recombination; inherited retinal degeneration; mosaic; novel; preservation; programs; protein transport; retinal rods; syntaxin 3; target SNARE proteins; therapy development; trafficking

ABSTRACT Photoreceptor cells in the retina are highly polarized and compartmentalized neurons. Most proteins localize to a specific compartment in photoreceptors, and such compartment-specific protein localization is essential for the proper function and survival of photoreceptors. Despite considerable research efforts, however, our understanding of the mechanisms by which photoreceptors achieve compartment-specific protein localization is limited. Related to this, the pathophysiology of retinal degenerations caused by the disruption of these mechanisms is also not sufficiently understood. This is partly because of the lack of easy-to-use means to monitor protein trafficking and confinement in diseased photoreceptors. To address this need, we have developed two transgenic mouse lines, iROSRePT (inducible Reporter for the Outer Segment Renewal and Protein Trafficking) and iRATProx (inducible Reporter for ABCA4 Trafficking and Proximity labeling). In the proposed studies, we will utilize these reporter lines and four disease models representing the disruption of the ciliary gate, intraflagellar transport (IFT), and exocytotic membrane fusion machinery and investigate the precise requirements of these mechanisms for the compartmentalized protein localization in photoreceptors. We anticipate that the outcome of this study will significantly advance our understanding of the mechanisms by which photoreceptor compartment homeostasis is attained and the pathophysiology of retinal degenerations linked to defective protein trafficking and confinement. This knowledge will build a foundation to develop treatments for cilia-related retinal degenerations and assess the efficacy of newly developed therapies.

摘要 视网膜中的光感受器细胞是高度极化和分隔的神经元。大多数蛋白质 定位于光感受器中的特定隔室，以及这种隔室特有的蛋白质定位 对光感受器的正常功能和生存至关重要。尽管做出了相当大的研究努力， 然而，我们对光感受器实现隔室特异性的机制的理解 蛋白质的定位是有限的。与此相关的是，视网膜退行性变的病理生理学 对这些机制的破坏也没有得到充分的理解。这部分是因为缺乏 易于使用的手段，以监测蛋白质的运输和限制疾病的光感受器。致信地址 在这种需要下，我们培育了两个转基因小鼠系，iROSRept(Inducable Reporter For The Exter) 分段更新和蛋白质贩运)和iRATProx(ABCA4贩运和蛋白质贩运的可诱导报告程序 邻近标记)。在拟议的研究中，我们将利用这些报道线和四种疾病模型 代表纤毛门、鞭毛内转运(IFT)和胞外膜融合的破坏 机械和调查这些机构的准确要求，以区分 光感受器中的蛋白质定位。我们预计，这项研究的结果将大大推进 我们对光感受器室内稳态的机制的理解和 视网膜退行性变的病理生理学与蛋白质运输和限制缺陷有关。这 知识将为开发纤毛相关性视网膜退行性变的治疗方法和评估 新开发的治疗方法的疗效。