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NADPH oxidase, mitochondrial dysfunction and diabetic retinopathy

NADPH 氧化酶、线粒体功能障碍和糖尿病视网膜病变

基本信息

批准号：
10116380
负责人：
RENU A. KOWLURU
金额：
$ 37.35万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116380
关键词：
Address Anabolism Animal Model Apoptosis Apoptotic Binding Biological Blindness Blood capillaries Cells Ceramides Complex Complications of Diabetes Mellitus Cytosine DNA DNA Methylation DNA Modification Methylases DNA Modification Process DNA Sequence Data Development Diabetes Mellitus Diabetic Retinopathy Disease Dyslipidemias Electron Transport Endothelial Cells Enzymes Epigenetic Process Exposure to Funding G-Protein Signaling Pathway GTP Binding GTPase-Activating Proteins Gene Expression Genes Genetic Transcription Goals Guanine Guanine Nucleotide Dissociation Inhibitors Guanine Nucleotide Exchange Factors Holoenzymes Human Hydroxyl Radical Hydroxylation Hyperglycemia Hyperlipidemia Laboratories Lipids Mediating Membrane Messenger RNA Methodology Methylation Mitochondria Modification Molecular Monomeric GTP-Binding Proteins NADPH Oxidase NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Pathogenesis Patients Pattern Pharmacology Post-Translational Protein Processing Prediabetes syndrome Process Production Protein Isoprenylation Publishing Reactive Oxygen Species Regulation Reporting Research Retina Retinal Diseases Rodent Rodent Model Role Signal Transduction Structure Testing Tetanus Helper Peptide Therapeutic Transcript Transcriptional Activation Transcriptional Regulation Translating Type 2 diabetic Vision Work base diabetic gene induction gene repression in vitro Model in vivo inhibitor/antagonist innovation member methyl group mitochondrial dysfunction multidisciplinary new therapeutic target novel predictive modeling prenylation prevent promoter rac1 GTP-Binding Protein small molecule inhibitor thermozymocidin translational impact translocase young adult

项目摘要

Diabetic retinopathy remains a major cause of blindness, and despite cutting edge research in the field, the molecular mechanism of its pathogenesis remains unclear. Our recent research has shown that during early stages of this progressing disease, activation of cytosolic NADPH oxidase 2 (Nox2) generates reactive oxygen species (ROS), and sustained increase in cytosolic ROS damages mitochondrial structure and its DNA, dysregulating the electron transport chain and initiating a vicious cycle of ROS. Furthermore, we have shown that dyslipidemia accelerates Nox2-mediated mitochondrial damage and the development of diabetic retinopathy in a type 2 diabetic animal model. An integral part of the cytosolic core of Nox2 holoenzyme is the small G-protein, Rac1, and diabetes increases Rac1 activity and gene transcripts in retinal microvasculature. Rac1 functional activation is mediated by its binding with the guanine exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Many epigenetic modifications are also favored by diabetic milieu, and these covalent modifications regulate gene expression without altering the DNA sequence. Thus, the central hypothesis of the current application is that covalent modifications of Rac1 modulate its functional and transcriptional activation, and activated Rac1, via Nox2-mediated ROS production, damages the mitochondria, resulting in accelerated apoptosis and the development of diabetic retinopathy. Aim 1 will investigate the molecular mechanism(s) by which hyperglycemia promotes activation of Rac1. Our model predicts that defective prenylation of Rac1 results in its sustained activation and mislocalization, and dynamic DNA methylation- hydroxymethylation of Rac1 promoter facilitates its transcriptional activation. Aim 2 will delineate the mechanism(s) by which gluco/lipotoxicity accelerates the development of diabetic retinopathy, and will investigate the effect of dyslipidemia on functional and transcriptional activation of Rac1. Questions asked under Aim 3 will address the therapeutic potential of regulation of Rac1 activation on inhibition of diabetic retinopathy, and will test novel small molecule inhibitors of GEF and of ceramide biosynthesis. The plan will employ fully optimized molecular biological and pharmacological approaches to assess the effect of diabetes on functional and transcriptional regulation of Rac1 activation in isolated retinal endothelial cells in culture, and in retinal microvessels from (pre-, type 1 and type 2) diabetic rodent models and from human donors with established diabetic retinopathy. Our overall goal is to identify novel regulatory mechanisms involved in the pathogenesis of diabetic retinopathy, specifically at the level of functional and transcriptional regulation of Rac1. The proposal is based on a testable central hypothesis, and these innovative studies carry a significant translational impact as they are expected to identify novel therapeutic targets to inhibit the development and progression of diabetic retinopathy.

糖尿病视网膜病变仍然是失明的主要原因，尽管在该领域进行了前沿研究，但