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.

抽象的 视网膜中的感光细胞是高度极化和分隔的神经元。大多数蛋白质 定位于感光器中的特定隔室，并定位于这种区室特异性蛋白质定位 对于光感受器的适当功能和存活至关重要。尽管进行了大量研究， 但是，我们对光感受器获得特定于隔室的机制的理解 蛋白质定位是有限的。与此相关的是，由 这些机制的破坏也没有充分理解。这部分是因为缺乏 易于使用的方法是监测患病感受器中蛋白质运输和限制。解决 这种需求，我们已经开发了两条转基因小鼠线，即irosrept（外部可诱导的报告基因 细分市场更新和蛋白质运输）和iratprox（可诱导的ABCA4贩运记者和 接近标签）。在拟议的研究中，我们将利用这些记者线和四个疾病模型 代表纤毛门的破坏，氟叶室内运输（IFT）和胞吐膜融合 机械和研究这些机制的确切要求 蛋白质定位在感光体中。我们预计这项研究的结果将大大进步 我们对获得光感受器室稳态的机制的理解以及 视网膜变性的病理生理学与蛋白质运输和监禁有缺陷有关。这 知识将建立基础，以开发用于纤毛相关的视网膜变性的治疗方法并评估 新开发的疗法的功效。