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.

项目摘要糖尿病性视网膜病（DR）是视力丧失的主要原因，但关于分子的尚不清楚导致这种普遍并发症的事件。糖尿病促进应力反应蛋白的表达在视网膜中受到发育和DNA损伤1（REDD1）的调节，这与视觉缺陷有关在临床前模型和糖尿病患者中。 REDD1蛋白表达在啮齿动物的视网膜中增加 1型和2型糖尿病的模型以及REDD1缺失可防止糖尿病引起的视网膜的发展视力中的病理和功能定义。靶向REDD1 mRNA的siRNA的玻璃体内给药还表现出有望改善糖尿病黄斑水肿患者的视觉功能。在一起发现提供了强有力的支持，REDD1在视觉中的功能定义中起着重要作用由糖尿病引起。这里的目的是解决两个关键的未解决的基础研究问题扮演Redd1在Dr中的作用。拟议的研究将研究为什么视网膜REDD1蛋白表达为何糖尿病增加。我们还将探索REDD1下游的分子事件，以确定它的方式有助于视觉障碍。理由是对导致分子事件的理解 REDD1蛋白含量增加，以及负责其对视觉影响有害影响的蛋白质，可能确定改进的治疗策略的分子靶标，这些策略早期提供干预措施和博士的非增量阶段。中心假设是糖尿病抑制REDD1蛋白视网膜中的降解以促进氧化应激，感染和随后的视网膜病理。目标1意志研究REDD1蛋白中可能被糖尿病激活的分子开关，导致降低 REDD1降解。拟议的研究将使用体内卡片来定义生化事件调节糖尿病小鼠视网膜中的REDD1降解。 AIM 2将以我们实验室的最新证据为基础支持REDD1充当核因子红系2相关因子2（NRF2）的主要州长抗氧化剂反应。我们预测，糖尿病通过促进视网膜中的适当抗氧化剂反应 NRF2通过糖原合酶激酶3（GSK3）的REDD1依赖性激活的NRF2核排除。目标3意志研究REDD1在视网膜注射中的作用，因为最近显示REDD1促进非典型激活通过与κB（IκB）的隔离抑制剂直接相互作用和隔离抑制剂，核因子KAPPA B（NF-κB）很好确定氧化应激和感染是在开发和发展中的关键因素引起视觉障碍的并发症。拟议的研究旨在识别和表征特定的分子事件有助于产生视网膜氧化物应激和类型的炎症 1和2型糖尿病通过解决与尖端治疗靶点有关的关键知识差距。为此，我们将探讨一个完全新颖的概念，即REDD1的非酶后翻译后修改蛋白质是DR中NRF2和NF-κB激活不当的共同机制。