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. !

项目摘要糖尿病性视网膜病（DR）在临床上被定义为视网膜微举行的疾病，大多数研究迄今为止，其发病机理集中在脉管系统上。多灶性ERG的最新进展证明神经视网膜缺陷在先前，甚至预测DR的发展。那很重要研究有助于早期丧失代谢的分子事件糖尿病的环境。！mRNA的翻译是基因表达的主要调节步骤，很重要控制血管内皮生长因子（VEGF）的表达以及其他临界生长因素和细胞因子响应代谢应激。我们的中心假设是糖尿病诱导的移位在选择müller胶质中翻译的mRNA中，导致永久体内平衡和 DR的最终发展。 Müller细胞是视网膜的主要神经胶质细胞，对此作用众所周知他们发挥了支持脉管系统和神经元的稳态和营养因素的生产视网膜层。在糖尿病患者中，神经胶质激活发生在DR临床表现之前作为减轻组织损伤的适应性反应。但是，müller神经胶质的长期变化蛋白质表达在视网膜并发症的发展中变得谨慎。具体来说，穆勒神经胶质是糖尿病中视网膜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残留的血管病理。我们的实验室表明，糖尿病诱导的转化复制品4E-BP1的激活促进了残留 VEGF表达和1型糖尿病模型中视觉功能障碍的发展。目标这是解决我们对早期产生的分子事件的理解中的根本差距 Müller细胞特异性蛋白表达的变化。使用新开发的Ribotag鼠标模型，其中表达式标记的核糖体亚基的表达针对MüllerGlia，拟议的研究将提供完整视网膜中Müller神经胶质中翻译活性mRNA的空前评估。这拟议的研究旨在表征选择特定mRNA的缺陷，以翻译两次糖尿病的实验模型：链蛋白酶施用和高脂肪/高碳水化合物饮食。此外为了确定导致神经胶质功能障碍的特定mRNA的调节机制，该提议研究还将评估两个实验模型中残留缺陷和视觉缺陷的发展遵循Müller特异性的遗传操纵，对应激反应蛋白REDD1或蛋白O- Glcnacylation（即介导mRNA翻译中特定变化的两种新型机制）。理由是，一旦已知残留müller细胞中翻译控制机制中的分子缺陷，翻译起始因子的功能/组装可以通过药物处理，从而导致新的解决了包括VEGF在内的多种生长因子和细胞因子的表达失调的治疗方法。呢