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中文摘要
翻译
项目摘要/摘要 分子神经科学和细胞生物学中最基本的问题之一是适当的 信号传导膜的组装,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一个主要原因是 受体和其他信号或运输蛋白。 这项研究的目标是确定在运输过程中与视紫红质相互作用的蛋白质以及那些 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分子相互作用导致 形成健康的光感受器盘膜。这项工作将进一步加深对 受体及其他物质转运不当所致神经退行性疾病的机制 膜蛋白。这项研究的重点是了解蛋白质之间的相互作用。 当视紫红质在其羧基末端缺乏适当的结构时,它们是有缺陷的,就像在 几种最严重的常染色体显性遗传性视网膜色素变性。我们将用强大的 我和我的同事开发的鼠标敲门模型,以及提出的新模型 在这里。 在目标1中,我们将识别与视紫红质的羧基末端相互作用的蛋白质,以介导适当的 利用黄曲霉视网膜提取物进行亲和捕捉实验的转运和盘膜组装 具有缺陷羧基末端敲入动物的纯合子视紫红质突变体。在目标2中,我们将 首先在体外,然后在体内鉴定含有羧基末端的突变体视紫红质Ter349Glu 导致视紫红质介导的常染色体显性遗传的最严重形式之一的延长 视网膜色素变性。在目标3中,我们将开发一种新的工具,人视紫红质融合到可光激活 绿色荧光蛋白,紧随其后的是视紫红质羧基末端的重复(Rho-paGFP- 1D4)。此构造将以两种不同的方式使用:首先,我们将测试假设 通畅的视紫红质羧基末端足以在健康视杆中形成适当的外节段 敲门动物。第二,我们将研究特定的蛋白质-蛋白质相互作用在视紫红质中的作用 GFP光活化后的人口贩运,使我们能够追踪 视紫红质首次出现在细胞内。这为未来体内贩运研究奠定了基础。项目叙事 这项研究的重点是了解有缺陷的蛋白质之间的相互作用 当昏暗的光感受器视紫红质在其羧基上缺乏适当的结构时- 终末,就像在几种最严重的常染色体显性遗传形式中一样 视网膜色素变性。我们将研究视紫红质在视杆细胞正常形成和 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