Endoplasmic Reticulum Stress in Retinal Degeneration

视网膜变性中的内质网应激

基本信息

批准号：
8468003
负责人：
JONATHAN LIN
金额：
$ 35.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8468003
关键词：
Acute Age Amino Acids Animal Model Animals Apoptosis Award Biochemical Blindness Cell Death Cell Survival Chronic Data Defect Disease Endoplasmic Reticulum Family Gene Mutation Genes Genetic Genetic Processes Goals Histidine In Vitro Inherited Knowledge Lead Link Microscopy Missense Mutation Molecular Molecular Genetics Morphology Mus Mutation Organelles Pathogenesis Pathway interactions Photoreceptors Play Positioning Attribute Process Proline Proteins Quality of life Research Resolution Retina Retinal Degeneration Retinitis Pigmentosa Rhodopsin Role Seminal Signal Pathway Signal Transduction Solubility Structure Testing Therapeutic Transgenic Animals Transgenic Mice United States Vision base chemical genetics endoplasmic reticulum stress glycosylation improved in vivo insight mutant new therapeutic target photoreceptor degeneration prevent protein folding protein misfolding research study response therapy development tool transcription factor ATF6

项目摘要

ABSTRACT The most common cause of inherited blindness is retinitis pigmentosa (RP), a family of diseases with various forms of inheritance caused by mutations in more than 45 genes. Over 100 distinct mutations have been identified in the rhodopsin gene that lead to RP. Many of these mutations cause rhodopsin protein misfolding and retention within the endoplasmic reticulum (ER). The cellular and molecular processes that link rhodopsin misfolding and ER retention to photoreceptor cell death are not well understood. During our previous research period, we investigated the role of the unfolded protein response (UPR) in retinal degeneration. The UPR comprises a set of cellular signaling pathways that detects misfolded proteins in the ER and promotes cell survival by reducing misfolded protein levels. However, if protein misfolding persists, the UPR switches to promote apoptosis. Here, we provide data that mutant rhodopsin linked to RP activates the UPR in vitro and in animal models of RP and that selective manipulation of UPR signaling can prevent cell death in vitro. Based on these findings, we hypothesize that ER stress and UPR signaling play important causal roles in determining photoreceptor cell survival in response to rhodopsin protein misfolding. To test this hypothesis, we will 1) investigate how UPR signaling regulates rhodopsin protein folding; 2) test if we can enhance photoreceptor cell survival in vivo by artificial control of UPR; and 3) determine how mutant rhodopsin expression changes ER structure and morphology in photoreceptors. These studies will provide important molecular, cellular, and genetic insights into the pathogenesis of retinitis pigmentosa arising from mutant rhodopsin expression. These studies may also provide new therapeutic targets to prevent blindness.

抽象的遗传失明的最常见原因是色素性视网膜炎（RP），一个家庭由超过45个基因突变引起的各种遗传形式的疾病。在导致RP的视紫红质基因中已经鉴定出了100多种不同的突变。这些突变中的许多突变引起视紫红质蛋白的错误折叠和保留率内质网（ER）。连接视紫红质的细胞和分子过程对感光细胞死亡的错误折叠和ER保留率尚不清楚。期间我们以前的研究期，我们研究了展开的蛋白质反应的作用（UPR）视网膜变性。 UPR包括一组细胞信号通路这检测到ER中错误折叠的蛋白质并通过降低来促进细胞存活错误折叠的蛋白质水平。但是，如果蛋白质错误折叠持续存在，则UPR切换到促进凋亡。在这里，我们提供的数据突变的视紫红质与RP链接的数据激活 UPR在体外和RP的动物模型中以及对UPR的选择性操纵信号传导可以预防细胞死亡。基于这些发现，我们假设 ER应力和UPR信号在确定感光器中起重要因果作用响应视紫红质蛋白折叠的细胞存活。为了检验这一假设，我们将 1）研究UPR信号如何调节视紫红质蛋白折叠； 2）测试我们是否可以通过人工控制UPR增强体内的感光细胞存活； 3）确定突变的视紫红质表达如何改变ER的结构和形态感受器。这些研究将提供重要的分子，细胞和遗传对突变视紫红质引起的视网膜炎的发病机理的见解表达。这些研究还可能提供新的治疗靶标以防止失明。