Molecular mechanisms of translational control in mice with inherited retinal degeneration

遗传性视网膜变性小鼠翻译控制的分子机制

基本信息

批准号：
10360454
负责人：
Marina Gorbatyuk
金额：
$ 36.01万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10360454
关键词：
AKT inhibition Acute Address Affect Animal Model Attenuated Basic Science Binding Binding Proteins Blindness Cell Death Cells Cellular biology Chronic Chronic stress Clinical Complex Data Development Disease Down-Regulation EIF4EBP1 gene Endoplasmic Reticulum Eukaryotic Initiation Factor-4E Eukaryotic Initiation Factors FRAP1 gene Genes Genetic Translation Genetically Modified Animals Glucose Heat shock proteins Homologous Gene Human Individual Inherited Investigational Therapies Leber&apos s amaurosis Literature Mediating Mediator of activation protein Methods Molecular Molecular Target Mus Mutation Pathogenesis Pathologic Pathway interactions Pharmacology Phosphorylation Phosphotransferases Photoreceptors Protein Biosynthesis Protein Kinase Proteins Proto-Oncogene Proteins c-akt Publishing Recovery Repression Retina Retinal Degeneration Retinal Diseases Retinal Dystrophy Retinitis Pigmentosa Rhodopsin Role Signal Transduction Sphingolipids Stress System Testing Therapeutic Therapeutic Intervention Time Translational Regulation Translations Up-Regulation Viral Genes Work arm attenuation base biological adaptation to stress cytotoxic effective therapy endoplasmic reticulum stress experience gene replacement gene therapy human model improved inherited retinal degeneration lipid metabolism mRNA capping mouse model protein kinase R response response biomarker restoration retinal rods targeted treatment therapeutic development therapeutically effective translational impact viral gene delivery

项目摘要

Inherited retinal degeneration (IRD) diseases are a clinically and genetically diverse group of retinal dystrophies including Leber congenital amaurosis (LCA) and autosomal dominant retinitis pigmentosa (ADRP). Despite significant progress in the basic science and clinical aspects of many retinopathies, the cellular mechanisms responsible for inherited vision loss require further investigation, and effective therapies are still under development. Therefore, we focused on the elucidation of the IRD mechanism and the development of therapeutic strategies. In particular, we address the role of translational attenuation in retinal pathogenesis of mice-mimicking human ADRP and LCA and propose therapeutic approaches based on the restoration of protein synthesis in affected photoreceptors. The proposal is supported by strong scientific premises created by our published and preliminary data, as well as the works of others. They suggest that mice with IRD experience persistent activation of the unfolded protein response (UPR) and translational attenuation in the retinas. In addition, our preliminary data demonstrate that PERK (protein kinase R [PKR]-like endoplasmic reticulum kinase) UPR arm is responsible for the sustained translational suppression in stressed photoreceptors. To support this, we will investigate three PERK-induced targets that independently regulate the consensual work of translational machinery. First, we plan to evaluate the impact of translational attenuation on retinal degeneration provided by phosphorylated eIF2a, a major hallmark of translational block. Second, we plan to assess the role of TRB3 in retinal degeneration by modifying its expression, thereby testing the hypothesis that TRB3 increase during IRD progression is cytotoxic, while its down-regulation enhances protein synthesis and retards IRD progression. Finally, we plan to test the hypothesis that stabilization of the 5'cap mRNA recognition complex by deactivation of eukaryotic initiation factor 4E (4E-BP), a negative translational regulator slows the onset of IRD through augmentation of protein synthesis. Genetically modified mice expressing altered levels of UPR and mRNA translation-associated markers; mice-modeling human IRD; pharmacological approaches altering levels of UPR markers; and adeno-associated viral gene delivery will be used in the study to regulate protein synthesis and explore therapeutic approaches. To our knowledge, this is the first comprehensive study of translational regulation in healthy and diseased photoreceptors. If successful, this study will not only enhance our molecular understanding of how degenerating PRs die but also create a platform for therapeutic intervention to halt IRD progression in humans. PERK pathway-targeted therapies could be used as a mutation- independent treatment for retinas experiencing chronic ER stress or as a supplemental strategy to enhance pre-existing gene replacement approaches. They would be particularly attractive for mutations in large genes that cannot be treated using conventional AAV-mediated gene therapy.

遗传性视网膜变性（IRD）疾病是一组临床和遗传上多样化的视网膜疾病。营养不良包括莱伯先天性黑蒙（LCA）和常染色体显性视网膜色素变性（ADRP）。尽管许多视网膜病变的基础科学和临床方面取得了重大进展，但细胞导致遗传性视力丧失的机制需要进一步研究，有效的治疗方法仍在研究中正在开发中。因此，我们重点关注IRD机制的阐明和IRD的发展。治疗策略。特别是，我们探讨了翻译衰减在视网膜发病机制中的作用小鼠模仿人类 ADRP 和 LCA，并提出基于蛋白质恢复的治疗方法受影响的光感受器中的合成。该提案得到了我们创建的强有力的科学前提的支持已发表的数据和初步数据，以及其他人的作品。他们建议有 IRD 经历的小鼠视网膜中未折叠蛋白反应（UPR）的持续激活和翻译衰减。在此外，我们的初步数据表明 PERK（蛋白激酶 R [PKR] 样内质网激酶） UPR臂负责应激光感受器的持续翻译抑制。为了支持这一点，我们将研究三个 PERK 诱导的目标，这些目标独立调节翻译的共识工作机械。首先，我们计划评估平移衰减对视网膜变性的影响磷酸化 eIF2a，翻译阻断的主要标志。其次，我们计划评估 TRB3 在通过改变其表达来抑制视网膜变性，从而检验TRB3在IRD期间增加的假设 IRD 的进展具有细胞毒性，而其下调可增强蛋白质合成并延缓 IRD 进展。最后，我们计划测试通过失活稳定 5'cap mRNA 识别复合物的假设真核起始因子 4E (4E-BP) 是一种负翻译调节因子，可通过以下方式减缓 IRD 的发生：增强蛋白质合成。表达改变水平的 UPR 和 mRNA 的转基因小鼠翻译相关标记；小鼠模型人类 IRD；改变 UPR 水平的药理学方法标记；腺相关病毒基因传递将在研究中用于调节蛋白质合成和探索治疗方法。据我们所知，这是第一个关于翻译的综合研究健康和患病光感受器的调节。如果成功的话，这项研究不仅将增强我们的对退化 PR 如何死亡的分子理解，同时也为治疗干预创造了平台阻止人类 IRD 的进展。 PERK通路靶向疗法可用作突变- 对经历慢性 ER 应激的视网膜进行独立治疗或作为补充策略加强现有的基因替代方法。它们对突变特别有吸引力无法使用传统 AAV 介导的基因疗法治疗的大基因。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GADD34 Ablation Exacerbates Retinal Degeneration in P23H RHO Mice.

GADD34 消融会加剧 P23H RHO 小鼠的视网膜变性。

DOI：
发表时间：
2022-11-09
期刊：
影响因子：
5.6
作者：
Saltykova, Irina V;Zhylkibayev, Assylbek;Gorbatyuk, Oleg S;Gorbatyuk, Marina S
通讯作者：
Gorbatyuk, Marina S

Posttranslational modifications of proteins in diseased retina.

患病视网膜中蛋白质的翻译后修饰。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Starr, Christopher R;Gorbatyuk, Marina S
通讯作者：
Gorbatyuk, Marina S

Proteomic analysis of diabetic retinas.

糖尿病视网膜的蛋白质组学分析。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Starr, Christopher R;Zhylkibayev, Assylbek;Mobley, James A;Gorbatyuk, Marina S
通讯作者：
Gorbatyuk, Marina S

Retinal injury mouse model and pathophysiological assessment of the effect of arsenical vesicants.

视网膜损伤小鼠模型和砷起泡剂作用的病理生理学评估。

DOI：
10.1016/j.exer.2022.109354
发表时间：
2023-01
期刊：
Experimental eye research
影响因子：
3.4
作者：
Zhylkibayev, Assylbek;Srivastava, Ritesh;Anantharam, Poojya;Crotch, Claire;Athar, Mohammad;Gorbatyuk, Marina
通讯作者：
Gorbatyuk, Marina

Comparative Proteomic Study of Retinal Ganglion Cells Undergoing Various Types of Cellular Stressors.

经历各种类型细胞应激源的视网膜神经节细胞的比较蛋白质组学研究。