Redox-sensitive activation of REDD1 in diabetic retinopathy

糖尿病视网膜病变中 REDD1 的氧化还原敏感激活

基本信息

批准号：
10275722
负责人：
Michael D. Dennis
金额：
$ 47.28万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10275722
关键词：
Acute-Phase Proteins Address Antioxidants Autophagocytosis Basic Science Biochemical Blindness Cell Surface Receptors Complex Complication DNA Binding DNA Damage Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Early Intervention Environment Event Exclusion Gene Chips Glycogen Synthase Kinase 3 Impairment Inflammation Inflammatory Inflammatory Response Innovative Therapy Insulin-Dependent Diabetes Mellitus Intervention Knockout Mice Knowledge Laboratories Lead Mediating Messenger RNA Molecular Molecular Chaperones Molecular Target Mutation NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Nuclear Oxidation-Reduction Oxidative Stress Pathogenesis Pathology Patients Pharmacology Phosphotransferases Play Post-Translational Protein Processing Pre-Clinical Model Production Proteins Repression Retina Retinal Defect Rodent Model Role S-nitro-N-acetylpenicillamine Sampling Signal Pathway Small Interfering RNA Stimulus TXNIP gene Therapeutic Transcriptional Activation Transducin Vascular Permeabilities Vision Visual Visual impairment biological adaptation to stress chemokine combat cytokine design diabetic diabetic patient disulfide bond gene product improved in vivo inhibitor/antagonist insight macular edema novel nuclear factor-erythroid 2 oxidation pre-clinical prevent protein degradation protein expression response role model targeted treatment therapeutic target transcription factor ubiquitin ligase visual dysfunction

项目摘要

Project Summary Diabetic retinopathy (DR) is a leading cause of vision loss, yet much remains unknown regarding the molecular events that cause this pervasive complication. Diabetes promotes expression of the stress response protein regulated in development and DNA damage 1 (REDD1) in the retina, which has been implicated in visual deficits in both preclinical models and diabetic patients. REDD1 protein expression is increased in the retina of rodent models of type 1 and type 2 diabetes, and REDD1 deletion prevents the development of diabetes-induced retinal pathology and functional deficits in vision. Intravitreal administration of a siRNA targeting the REDD1 mRNA has also demonstrated promise for improving visual function in patients with diabetic macular edema. Together these findings provide strong support that REDD1 plays an important role in the functional deficits in vision that are caused by diabetes. The objective here is to address two critical unresolved basic research questions related to the role of REDD1 in DR. The proposed studies will investigate why retinal REDD1 protein expression is increased by diabetes. We will also explore the molecular events downstream of REDD1 to determine how it contributes to visual impairment. The rationale is that an understanding of the molecular events that lead to increased REDD1 protein content, as well as those that are responsible for its deleterious effects on vision, may identify molecular targets for improved therapeutic strategies that provide interventions early in the preclinical and non-proliferative stages of DR. The central hypothesis is that diabetes suppresses REDD1 protein degradation in the retina to promote oxidative stress, inflammation, and subsequent retinal pathology. Aim 1 will investigate a molecular switch in the REDD1 protein that is potentially activated by diabetes, leading to reduced REDD1 degradation. The proposed studies will use in vivo SNAP-tagging to define the biochemical events that regulate REDD1 degradation in the retina of diabetic mice. Aim 2 will build on recent evidence from our laboratory supporting that REDD1 acts as a dominant governor of the nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant response. We predict that diabetes prevents a proper antioxidant response in the retina by promoting Nrf2 nuclear exclusion via REDD1-dependent activation of glycogen synthase kinase 3 (GSK3). Aim 3 will investigate a role for REDD1 in retinal inflammation, as REDD1 was recently shown to promote atypical activation of nuclear factor kappa B (NF-κB) by directly interacting with and sequestering inhibitor of κB (IκB). It is well established that oxidative stress and inflammation are crucial factors in the development and progression of the complications that cause visual impairment. The proposed studies are designed to identify and characterize specific molecular events that contribute to the development of retinal oxidative stress and inflammation in type 1 and type 2 diabetes by addressing key knowledge gaps related to a cutting-edge therapeutic target. To do so, we will explore the entirely novel concept that non-enzymatic post-translational modification of the REDD1 protein is a shared mechanism for improper activation of Nrf2 and NF-κB in DR.

项目概要糖尿病视网膜病变 (DR) 是视力丧失的主要原因，但关于其分子机制仍有许多未知之处。导致这种普遍并发症的事件会促进应激反应蛋白的表达。在视网膜的发育和 DNA 损伤 1 (REDD1) 中受到调节，该损伤与视力缺陷有关在临床前模型和糖尿病患者的视网膜中，REDD1 蛋白表达均增加。 1 型和 2 型糖尿病模型，REDD1 缺失可预防糖尿病引起的视网膜发育玻璃体内注射靶向 REDD1 mRNA 的 siRNA 可改善视力的病理学和功能缺陷。还证明了改善糖尿病黄斑水肿患者视觉功能的前景。研究结果有力地证明了 REDD1 在视觉功能缺陷中发挥着重要作用，这里的目的是解决两个相关的未解决的关键基础研究问题。 REDD1 在 DR 中的作用拟议的研究将调查视网膜 REDD1 蛋白表达的原因我们还将探索 REDD1 下游的分子事件，以确定它是如何增加的。造成视力障碍的基本原理是对导致视力障碍的分子事件的理解。 REDD1 蛋白含量的增加以及那些对视力产生有害影响的蛋白可能确定改进治疗策略的分子靶标，在临床前早期提供干预措施 DR 的非增殖期和非增殖期的中心假设是糖尿病抑制 REDD1 蛋白。视网膜退化，促进氧化应激、炎症和随后的视网膜病理学。研究 REDD1 蛋白中的一个分子开关，该开关可能被糖尿病激活，从而减少拟议的研究将使用体内 SNAP 标记来定义 REDD1 降解。目标 2 将基于我们实验室的最新证据来调节糖尿病小鼠视网膜中的 REDD1 降解。支持 REDD1 作为核因子 erythroid-2 相关因子 2 (Nrf2) 的主导调控者我们预测，通过促进视网膜中适当的抗氧化反应来预防糖尿病。 Nrf2 通过 REDD1 依赖性糖原合成酶激酶 3 (GSK3) 的激活进行核排除。研究 REDD1 在视网膜炎症中的作用，因为 REDD1 最近被证明可以促进非典型激活通过直接与 κB (IκB) 抑制剂相互作用并隔离核因子 κ B (NF-κB) 的作用效果很好。确定氧化应激和炎症是疾病发生和进展的关键因素拟议的研究旨在识别和表征导致视力障碍的并发症。有助于视网膜氧化应激和炎症发展的特定分子事件 1 型和 2 型糖尿病通过解决与前沿治疗目标相关的关键知识差距。我们将探索一个全新的概念，即 REDD1 的非酶促翻译后修饰蛋白是 DR 中 Nrf2 和 NF-κB 不当激活的共同机制。