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Molecular Mechanisms of Severe Diabetic Retinopathy

严重糖尿病视网膜病变的分子机制

基本信息

批准号：
10357740
负责人：
Sarah X Zhang
金额：
$ 39.93万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357740
关键词：
Abbreviations Ablation Address Animal Model Apoptosis Area Background Diabetic Retinopathy Blindness Blood Vessels Blood capillaries Blood-Retinal Barrier Caspase Cell Aging Cell Culture Techniques Cell Death Cells Cessation of life Clinical Clinical Data Cre lox recombination system Data Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Disease Progression Endothelial Cells Endothelium Enzymes Equilibrium Event Extravasation Eye Family member Fibrosis Genes Genetic Genetic study Glucose Goals Growth Hematopoietic Heritability Human Human Genetics Hydrogen Peroxide Impairment In Vitro Individual Inflammasome Inflammation Injury Insulin-Dependent Diabetes Mellitus Knock-in Knock-in Mouse Knockout Mice Knowledge Lead Lipid Peroxidation Measures Mediating Membrane Mitochondria Molecular Molecular Target Mus NADPH Oxidase Neurons Outcome Oxidation-Reduction Oxygen Pathogenesis Pathologic Pathology Pathway interactions Persons Pharmacology Pharmacotherapy Prevention Prevention approach Preventive Primary Cell Cultures Production Protein Isoforms Proteins Publishing Reactive Oxygen Species Research Retina Retinal Diseases Retinal Neovascularization Role Signal Pathway Signal Transduction Stimulus Streptozocin Testing Therapeutic Therapeutic Effect Time Tissues Transgenic Organisms Type 2 diabetic Up-Regulation Vascular Diseases Vascular Permeabilities Visual impairment Work activating transcription factor 4 aging population base brain endothelial cell cell injury conditional knockout diabetic disorder prevention endoplasmic reticulum stress experimental study genome wide association study genome-wide linkage human disease in vivo inhibitor insight macular edema mouse model novel novel strategies overexpression pre-clinical prevent proliferative diabetic retinopathy retina blood vessel structure retinal damage risk variant senescence therapeutic target trait unpublished works vascular abnormality

项目摘要

Abstract: Major causes of vision loss in people with diabetes include diabetic macular edema and severe diabetic retinopathy (including severe non-proliferative diabetic retinopathy and proliferative diabetic retinopathy), both of which are associated with extensive injury of retinal endothelial cells; however, the molecular mechanisms underlying the progressive damage to endothelial cells in diabetes are poorly understood. Further, despite preventable measures, severe diabetic retinopathy still occurs in a large number of diabetic individuals eventually leading to blindness. Thus, identifying novel molecular targets to prevent the progression of diabetic retinopathy is an unmet need. In this project, we propose to test the role of NADPH oxidase 4 (Nox4) in retinal endothelial cells as a novel molecular target for the prevention and treatment of severe diabetic retinopathy. In recent studies, we have shown that Nox4 is a major isoform of NADPH oxidases in retinal endothelial cells and Nox4 expression is upregulated in retinal blood vessels in animal models of diabetic retinopathy. Genetic ablation of Nox4 gene in endothelial cells reduces retinal vascular permeability in diabetic mice and alleviates aberrant new vessel growth in oxygen-induced retinopathy. In contrast, overexpression of Nox4 in endothelial cells is sufficient to induce retinal vascular leakage and degeneration. Furthermore, a recent genome-wide association study (GWAS) identified Nox4 as a potential risk gene for severe diabetic retinopathy. Collectively, these experimental and clinical findings suggest an important role of Nox4 in diabetes-mediated endothelial cell injury and retinal vasculopathy. However, the mechanisms by which Nox4 induces endothelial injury and its relevance to human disease remain an understudied area. In this project, we will first characterize Nox4 expression in human retinas with different stages of diabetic retinopathy. Using an inducible endothelial cell specific conditional knockout mouse line, we will delete Nox4 at various time points after diabetes onset to establish the role of endothelial Nox4 in the development and progression of diabetic retinopathy. We will investigate the mechanisms of Nox4- mediated endothelial death and senescence and elucidate novel signaling pathways activated by Nox4 upregulation in endothelial cells. Finally, we will test novel pharmacological inhibitor that specifically targets Nox4 for its preventive and therapeutic effects on diabetic retinopathy. We anticipate that the successful completion of the proposed studies will not only provide mechanistic insight of diabetic retinopathy but also develop new treatment that targets a risk gene identified by human genetic study for prevention of severe diabetic retinopathy.

抽象的：糖尿病患者视力丧失的主要原因包括糖尿病性黄斑水肿和严重糖尿病视网膜病变（包括严重的非增殖性糖尿病视网膜病变和增殖性糖尿病视网膜病变），两者与视网膜内皮细胞的广泛损伤有关；然而，分子机制糖尿病中内皮细胞进行性损伤的背后机制尚不清楚。此外，尽管尽管采取了可预防的措施，但最终仍有大量糖尿病患者出现严重的糖尿病视网膜病变导致失明。因此，确定新的分子靶点来预防糖尿病视网膜病变的进展是一种未满足的需求。在这个项目中，我们建议测试 NADPH 氧化酶 4 (Nox4) 在视网膜内皮细胞中的作用细胞作为预防和治疗严重糖尿病视网膜病变的新分子靶点。在最近的研究中，我们已经证明Nox4是视网膜内皮细胞中NADPH氧化酶的主要亚型以及Nox4的表达在糖尿病视网膜病变动物模型中视网膜血管中表达上调。 Nox4基因的基因消融内皮细胞中的降低糖尿病小鼠视网膜血管通透性并减轻异常新血管氧诱发的视网膜病变的生长。相反，内皮细胞中Nox4的过度表达足以引起视网膜血管渗漏和变性。此外，最近的一项全基因组关联研究（GWAS）确定 Nox4 是严重糖尿病视网膜病变的潜在风险基因。总的来说，这些实验性和临床结果表明 Nox4 在糖尿病介导的内皮细胞损伤和视网膜损伤中发挥重要作用血管病变。然而，Nox4 诱导内皮损伤的机制及其与人类的相关性疾病仍然是一个未被充分研究的领域。在这个项目中，我们将首先表征人类视网膜中的 Nox4 表达糖尿病视网膜病变的不同阶段。使用诱导型内皮细胞特异性条件敲除小鼠系，我们将在糖尿病发病后的各个时间点删除 Nox4，以确定内皮细胞的作用 Nox4 在糖尿病视网膜病变的发生和进展中的作用。我们将研究Nox4-的机制介导内皮死亡和衰老并阐明 Nox4 激活的新信号通路内皮细胞的上调。最后，我们将测试专门针对Nox4的新型药物抑制剂因其对糖尿病视网膜病变的预防和治疗作用。我们预计顺利完成拟议的研究不仅将提供糖尿病视网膜病变的机制见解，而且还将开发新的针对人类基因研究确定的风险基因的治疗，用于预防严重的糖尿病视网膜病变。