Role of the Unfolded Protein Response in Photoreceptor Degeneration

未折叠蛋白反应在光感受器变性中的作用

基本信息

批准号：
10090604
负责人：
Douglas Gould
金额：
$ 54.97万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090604
关键词：
American Animal Model Apoptosis Apoptotic Attenuated Binding Cell Differentiation process Cells Cessation of life Chronic Client Development Disease Endoplasmic Reticulum Endoribonucleases Enzymes Event Exhibits Functional disorder Generations Genetic Genetic Transcription Goals Health Homeostasis Human Hyperactivity Inflammasome Inflammation Integral Membrane Protein Intervention Knock-in Lead Maintenance Measures Messenger RNA Modeling Molecular Molecular Chaperones Mus Mutation Neurons Output Pathogenicity Pathway interactions Pharmaceutical Preparations Pharmacology Phosphotransferases Photoreceptors Phototransduction Physiological Preclinical Testing Prevention Proteins RNA Splicing Reaction Research Project Grants Retina Retinal Degeneration Retinal Photoreceptors Retinitis Pigmentosa Rhodopsin Ribonucleases Risk Role Shapes Signal Pathway Signal Transduction Sterility Suicide TXNIP gene Testing Therapeutic Vertebrate Photoreceptors Vision XBP1 gene cell suicide endoplasmic reticulum stress experience in vivo insight kinase inhibitor mouse model nanomolar novel strategies novel therapeutics photoreceptor degeneration premature preservation prevent programs response secretory protein skills small molecule transcription factor

项目摘要

PROJECT SUMMARY Client proteins of the secretory pathway fold to their native shapes in the endoplasmic reticulum (ER) through reactions catalyzed by chaperones and other ER protein-modifying enzymes. Under high secretory demand, these activities are overwhelmed, causing unfolded proteins to accumulate. If uncorrected, such “ER stress” increases the risk of cell degeneration and death. Photoreceptors, specialized neurons in the retina responsible for phototransduction, have one of the highest secretory burdens of any human cell, making them particularly susceptible to ER stress. Recent evidence has implicated pathogenic ER stress as a potential cause of retinitis pigmentosa (RP), a blinding disease marked by the progressive loss of photoreceptors, especially in cases due to mutations in rhodopsin that prevents its proper folding. Accumulation of unfolded proteins in the ER triggers signaling pathways called the unfolded protein response (UPR). Under remediable levels of ER stress, the adaptive UPR (A-UPR) activates transcriptional and translational changes that restore homeostasis. However, under irremediably high ER stress, these adaptive measures fail and the signaling pathways instead trigger programmed cell death—referred to as the terminal UPR (T-UPR). We discovered that the ER transmembrane protein IRE1, a bifunctional kinase/endoribonuclease (RNase), converts an A-UPR to a T-UPR. During rectifiable ER stress, IRE1 transiently trans-autophosphorylates, causing its RNase to trigger the A-UPR through frame-shift splicing of the mRNA encoding XBP1 transcription factor. But under high/chronic ER stress, IRE1's kinase becomes hyperphosphorylated, causing RNase hyperactivation that leads to massive degradation of ER-localized mRNA and T-UPR events including: (1) loss of differentiated cell identity, (2) local sterile inflammation, and (3) programmed cell death through pyroptosis and apoptosis. We hypothesize that an IRE1-induced switch from an A-UPR to a T-UPR contributes to ER stress-induced photoreceptor loss. Our overall goal for this R01 is threefold: (1) define the role of IRE1 signaling on normal photoreceptor health; (2) elucidate key underlying molecular mechanisms through which IRE1 converts an A- UPR to a T-UPR in photoreceptors; and (3) target IRE1 in photoreceptors using our recently developed kinase inhibitors for long-term prevention of retinal degeneration. Our research project, to be driven by three labs with complementary and synergistic skills as well as experienced collaborators, promises to provide powerful mechanistic insights into the role of the UPR in photoreceptor health and degeneration, and to establish whether the UPR can be successfully drugged to prevent photoreceptor loss in RP.

项目概要分泌途径的客户蛋白在内质网 (ER) 中通过以下方式折叠成其天然形状：在高分泌需求下，分子伴侣和其他 ER 蛋白修饰酶催化的反应。如果不加以纠正，这些活动就会不堪重负，导致未折叠的蛋白质积聚，形成“内质网应激”。增加细胞退化和死亡的风险，感光细胞是视网膜中的特殊神经元。负责光转导，是人类细胞中分泌负担最高的细胞之一，使它们特别容易受到 ER 应激的影响，最近的证据表明致病性 ER 应激是一种潜在的因素。色素性视网膜炎 (RP) 的病因，这是一种以光感受器逐渐丧失为特征的致盲性疾病，尤其是在视紫红质突变导致其无法正确折叠的情况下。内质网中未折叠蛋白的积累会触发称为未折叠蛋白反应的信号通路 (UPR) 在可修复的 ER 应激水平下，适应性 UPR (A-UPR) 激活转录和然而，在不可挽回的高内质网压力下，这些适应性改变。措施失败，信号通路反而触发程序性细胞死亡——称为终端我们发现内质网跨膜蛋白 IRE1，一种双功能蛋白。激酶/核糖核酸内切酶 (RNase) 在可纠正的 ER 应激期间将 A-UPR 转化为 T-UPR。瞬时反式自磷酸化，导致其 RNase 通过移码剪接触发 A-UPR 编码 XBP1 转录因子的 mRNA 但在高/慢性 ER 应激下，IRE1 的激酶变成。过度磷酸化，导致 RNase 过度激活，导致 ER 局部化的大量降解 mRNA 和 T-UPR 事件包括：(1) 分化细胞身份丧失，(2) 局部无菌炎症，以及 (3) 通过细胞焦亡和细胞凋亡进行程序性细胞死亡。我们发现 IRE1α 诱导的从 A-UPR 到 T-UPR 的转变有助于 ER 应激诱导我们对此 R01 的总体目标有三个：(1) 定义 IRE1 信号传导对正常的作用。光感受器健康；(2) 阐明 IRE1 转化 A- 的关键潜在分子机制光感受器中的 UPR 到 T-UPR；以及 (3) 使用我们最近开发的光感受器中的 IRE1 目标我们的研究项目由三个因素驱动，用于长期预防视网膜变性。具有互补和协同技能的实验室以及经验丰富的合作者，承诺提供对 UPR 在光感受器健康和退化中的作用的强大机制见解，并确定是否可以成功对 UPR 进行药物治疗以防止 RP 中光感受器损失。