Targeting the Etiology of Diabetic Retinopathy

针对糖尿病视网膜病变的病因

基本信息

批准号：
10224208
负责人：
Michael D. Dennis
金额：
$ 36.68万
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：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224208
关键词：
Ablation Address Blindness Blood Vessels Carbohydrates Clinical Defect Detection Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Diet Disease EIF4EBP1 gene Elements Environment Epitopes Etiology Event Experimental Models Fatty acid glycerol esters Functional disorder Gene Expression Genetic Genetic Translation Glucose Growth Factor Hexosamines Homeostasis Hormones Inflammation Innovative Therapy Insulin-Dependent Diabetes Mellitus Intervention Laboratories Lead Link Mediating Messenger RNA Metabolic Metabolic stress Modeling Molecular Molecular Target Muller&apos s cell Mus Neuroglia Neurons Nutrient Outcome Pathogenesis Pathology Pathway interactions Peptide Initiation Factors Pharmacology Photoreceptors Play Prediabetes syndrome Production Proteins Research Retina Retinal Defect Retinal Diseases RiboTag Ribosomes Role Source Streptozocin Streptozocin Diabetes Testing Therapeutic Tissues Translational Activation Translations Vascular Endothelial Growth Factors Visual biological adaptation to stress cytokine design diabetic diabetic patient genetic manipulation genetic regulatory protein glial activation glycosylation improved mouse model novel novel therapeutics prevent protein expression recruit response retinal adaptation retinal neuron vascular factor vision development visual dysfunction

项目摘要

Project Summary Diabetic retinopathy (DR) is clinically defined as a disease of the retinal microvasculature, and most research on its pathogenesis to date has focused on the vasculature itself. Recent advances in multifocal ERG demonstrate that neuro-retinal defects precede and even predict the development of DR. Thus, it is important to investigate the molecular events that contribute to early loss of retinal adaptation to the metabolic environment in diabetes.!Translation of mRNA is a major regulatory step in gene expression that is important for controlling the expression of vascular endothelial growth factor (VEGF), as well as other critical growth factors and cytokines in response to metabolic stress. Our central hypothesis is that a diabetes-induced shift in the selection of mRNAs for translation within Müller glia results in loss of retinal homeostasis and the eventual development of DR. Müller cells, the principal glial cell of the retina, are well recognized for the role they play in the production of homeostatic and trophic factors that support both the vasculature and neuronal layers of the retina. In diabetic patients, glial activation occurs prior to clinical manifestation of DR and likely serves as an adaptive response to mitigate tissue damage. However, prolonged changes in Müller glial protein expression become causative in the development of retinal complications. Specifically, Müller glia are the principal source of increased retinal VEGF expression in diabetes, as conditional Muller cell specific disruption of VEGF prevents elevated growth factor expression and reduces retinal vascular pathology. Our laboratory has shown that diabetes-induced activation of the translational repressor 4E-BP1 promotes retinal VEGF expression and the development of visual dysfunction in a model of type 1 diabetes. The objective here is to address a fundamental gap in our understanding of the molecular events that produce early changes in Müller cell specific protein expression. Using a newly developed RiboTag mouse model, wherein expression of an epitope-tagged ribosomal subunit is directed to Müller glia, the proposed studies will provide an unprecedented assessment of translationally active mRNAs in Müller glia within the intact retina. The proposed studies are designed to characterize defects in the selection of specific mRNAs for translation in two experimental models of diabetes: streptozotocin administration and high fat/high carbohydrate diet. In addition to identifying regulatory mechanisms for specific mRNAs that contribute to glial dysfunction, the proposed studies will also assess the development of retinal defects and visual deficits in the two experimental models following Müller-specific genetic manipulation of the stress response protein REDD1 or protein O- GlcNAcylation (i.e. two novel mechanisms for mediating specific changes in mRNA translation). The rationale is that once the molecular defects in translational control mechanisms in retinal Müller cells are known, the function/assembly of translation initiation factors can be manipulated pharmacologically, resulting in new therapeutics that address dysregulated expression of multiple growth factors and cytokines including VEGF. !

项目概要糖尿病视网膜病变（DR）在临床上被定义为一种视网膜微血管疾病，大多数研究迄今为止，关于其发病机制的研究主要集中在脉管系统本身。证明神经视网膜缺陷先于甚至预测 DR 的发展，因此，这一点很重要。研究导致视网膜早期丧失代谢适应能力的分子事件糖尿病的环境。！mRNA 的翻译是基因表达的一个主要调控步骤，非常重要用于控制血管内皮生长因子 (VEGF) 以及其他关键生长因子的表达我们的中心假设是糖尿病引起的转变。选择在 Müller 胶质细胞内进行翻译的 mRNA 会导致视网膜稳态丧失， DR 细胞（视网膜的主要神经胶质细胞）的最终发育因其作用而得到广泛认可。它们在支持脉管系统和神经系统的稳态和营养因子的产生中发挥作用在糖尿病患者的视网膜层中，神经胶质细胞的激活可能发生在 DR 的临床表现之前。作为减轻组织损伤的适应性反应，然而，穆勒胶质细胞的长期变化。具体而言，穆勒神经胶质细胞的蛋白质表达成为视网膜并发症发生的原因。糖尿病视网膜 VEGF 表达增加的主要来源，作为条件性 Muller 细胞特异性 VEGF 的破坏可防止生长因子表达升高并减少视网膜血管病变。实验室表明，糖尿病诱导的翻译阻遏物 4E-BP1 激活可促进视网膜 1 型糖尿病模型中 VEGF 的表达和视觉功能障碍的发展。这是为了解决我们对产生早期分子事件的理解中的一个根本差距使用新开发的 RiboTag 小鼠模型，Müller 细胞特异性蛋白质表达发生变化。表位标记的核糖体亚基的表达针对穆勒神经胶质细胞，拟议的研究将提供对完整视网膜内 Müller 胶质细胞中翻译活性 mRNA 的前所未有的评估。拟议的研究旨在表征在两种情况下选择特定 mRNA 进行翻译时的缺陷糖尿病实验模型：链脲佐菌素给药和高脂肪/高碳水化合物饮食。为了确定导致神经胶质细胞功能障碍的特定 mRNA 的调节机制，提出的研究还将评估两个实验模型中视网膜缺陷和视力缺陷的发展情况对应激反应蛋白 REDD1 或蛋白 O- 进行 Müller 特异性基因操作后 GlcNAcylation（即介导 mRNA 翻译特定变化的两种新机制）。是一旦知道视网膜穆勒细胞翻译控制机制的分子缺陷，翻译起始因子的功能/组装可以通过药理学进行操纵，从而产生新的解决多种生长因子和细胞因子（包括 VEGF）表达失调的治疗方法。！