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中文摘要
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项目概要/摘要 分子神经科学和细胞生物学中最基本的问题之一是 信号转导膜的组装,包括蛋白质组分的运输和分选。 神经退行性疾病和其他遗传性疾病的主要原因是神经系统的不适当定位。 受体和其他信号或转运蛋白。 本研究的目的是鉴定在转运过程中与视紫红质相互作用的蛋白质, 参与视杆细胞外段盘膜的生物发生,然后确定 视紫红质与其他蛋白质的分子相互作用导致 形成健康的感光盘膜。这项工作将进一步了解 由受体和其他受体的不适当运输引起的神经退行性疾病的机制 膜蛋白拟议研究的重点是了解蛋白质-蛋白质相互作用 当视紫红质在其羧基末端缺乏适当的结构时,就有缺陷, 常染色体显性视网膜色素变性的几种最严重的形式。我们将使用强大的 我和我的同事开发的小鼠敲入模型,以及提出的新模型, 本文所 在目标1中,我们将鉴定与视紫红质的羧基末端相互作用以介导适当的蛋白质。 通过亲和捕获实验使用视网膜提取物的运输和盘膜组装 具有缺陷羧基末端的纯合子视紫红质突变体敲入动物。在目标2中,我们 首先在体外,然后在体内,表征突变视紫红质,Ter 349 Glu,含有羧基末端的 导致最严重形式的视紫红质介导的常染色体显性遗传的延伸 视网膜色素变性在目标3中,我们将开发一种新的工具,人视紫红质融合到光活化的 绿色荧光蛋白,其后面是视紫红质羧基末端的重复序列(rho-paGFP- 1D4)。这个结构将以两种不同的方式使用:首先,我们将测试假设, 无障碍的视紫红质羧基端足以在健康视杆细胞中形成适当的外节段, 敲入动物。其次,我们将研究特定蛋白质-蛋白质相互作用在视紫红质中的作用 运输后的GFP光活化,使我们能够跟踪亚群的运动, 细胞中的视紫红质。这为今后的体内贩运研究奠定了基础。项目叙述 这项研究的重点是了解蛋白质-蛋白质相互作用的缺陷 当弱光光感受器视紫红质在其羧基上缺乏适当的结构时, 末端,就像几种最严重的常染色体显性遗传病一样。 视网膜色素变性我们将研究视紫红质在视杆细胞形成中的作用, 退化,并监测其贩运,以更好地了解这些过程。
英文摘要
Project Summary/Abstract One of the most fundamental problems 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 neurodegenerative and other inherited disorders is the improper localization of receptors and other signaling or transport proteins. The goal of this study is to identify proteins that interact with rhodopsin during transport and those involved in the biogenesis of disk membranes in the outer segment of rod cells, and then determine the molecular mechanisms by which the molecular interactions of rhodopsin with other proteins lead to formation of healthy photoreceptor disk membranes. This work will further the understanding of the mechanisms of neurodegenerative disorders caused by improper trafficking of receptors and other membrane proteins. The focus of the proposed research is to understand protein-protein interactions that are defective when rhodopsin lacks the proper structure at its carboxy-terminus, as is the case in several of the most severe forms of autosomal dominant retinitis pigmentosa. We will use powerful mouse knock-in models that my co-workers and I have developed, as well as new models proposed herein. In Aim 1, we will identify proteins that interact with rhodopsin's carboxy-terminus to mediate proper transport and disk membrane assembly through affinity-capture experiments using retinal extracts from homozygote rhodopsin mutants with defective carboxyl-termini knock-in animals. In Aim 2, we will characterize, first in vitro, then in vivo, a mutant rhodopsin, Ter349Glu, containing a carboxyl-terminal extension that causes one of the most severe forms of rhodopsin-mediated autosomal dominant retinitis pigmentosa. In Aim 3, we will develop a new tool, human rhodopsin fused to photoactivatable green fluorescent protein that is followed by a repeat of rhodopsin's carboxyl terminus (rho-paGFP- 1D4). This construct will be used in two distinct ways: first, we will test the hypothesis that an unobstructed rhodopsin carboxy-terminus is sufficient to form proper outer segments in healthy rods in knock-in animals. Second, we will study the role of specific protein-protein interactions in rhodopsin trafficking after photoactivation of GFP, enabling us to track the movement of subpopulations of rhodopsin in cells for the first time. This sets the stage for in vivo trafficking studies in the future. Project Narrative The focus of this study is to understand protein-protein interactions that are defective when the dim light photoreceptor rhodopsin lacks the proper structure at its carboxy- terminus, as is the case in several of the most severe forms of autosomal dominant retinitis pigmentosa. We will study the role of rhodopsin in proper rod cell formation and degeneration, and monitor its trafficking to better understand these processes.
期刊论文(8)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1007/978-1-61779-848-1_11
发表时间: 2012-01-01
期刊: Methods in molecular biology (Clifton, N.J.)
影响因子: --
作者: [Sammons, Joshua, Gross, Alecia K]
通讯作者: Gross, Alecia K
DOI: 10.1016/j.visres.2013.10.008
发表时间: 2013-12-18
期刊: VISION RESEARCH
影响因子: 1.8
作者: [Sammons, Joshua D., Gross, Alecia K.]
通讯作者: Gross, Alecia K.
DOI: 10.1016/j.exer.2015.11.007
发表时间: 2016-09
期刊: Experimental eye research
影响因子: 3.4
作者: [Bales KL, Gross AK]
通讯作者: Gross AK
DOI: 10.1038/cddis.2014.539
发表时间: 2014-12-18
期刊: Cell death & disease
影响因子: 9
作者: []
通讯作者:
Photoreceptor Disk Formation and Retinal Degenerations
Photoreceptor Disk Formation and Retinal Degenerations
Photoreceptor Disk Formation and Retinal Degenerations
Photoreceptor Disk Formation and Retinal Degenerations
海外基金