Pathogenic Role of DNA-Damage Response Pathway in the Diabetic Retina

DNA 损伤反应途径在糖尿病视网膜中的致病作用

基本信息

批准号：
9176558
负责人：
PARTHA S SARKAR
金额：
$ 34.88万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176558
关键词：
Acetylation Affect Animal Model Animals Antioxidants Apoptosis Apoptotic Awareness Biochemical Pathway Biogenesis Blood Vessels Brain Cell Death Cell physiology Cells Chronic Clinical Trials Complications of Diabetes Mellitus Consensus DNA Damage Data Development Diabetes Mellitus Diabetic Retinopathy Disease Down-Regulation Energy Metabolism Exclusion Genetic Transcription Goals Homeostasis Human Hyperglycemia Individual Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Investigation Knowledge Link Machado-Joseph Disease Mediating Metabolic Metabolic Pathway Mitochondria Modification Molecular Nerve Degeneration Neurons Nuclear Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathway interactions Patients Phosphotransferases Photoreceptors Play Production Regulation Research Retina Retinal Retinal Diseases Role Signal Pathway Signal Transduction Site Stimulus Testing Transcription Coactivator Work ataxia telangiectasia mutated protein base cytokine diabetic ds-DNA genome integrity insight mitochondrial dysfunction novel oxidative DNA damage repaired research study response sensor tissue culture

Acetylation Affect Animal Model Animals Antioxidants Apoptosis Apoptotic Awareness Biochemical Pathway Biogenesis Blood Vessels Brain Cell Death Cell physiology Cells Chronic Clinical Trials Complications of Diabetes Mellitus Consensus DNA Damage Data Development Diabetes Mellitus Diabetic Retinopathy Disease Down-Regulation Energy Metabolism Exclusion Genetic Transcription Goals Homeostasis Human Hyperglycemia Individual Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Investigation Knowledge Link Machado-Joseph Disease Mediating Metabolic Metabolic Pathway Mitochondria Modification Molecular Nerve Degeneration Neurons Nuclear Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathway interactions Patients Phosphotransferases Photoreceptors Play Production Regulation Research Retina Retinal Retinal Diseases Role Signal Pathway Signal Transduction Site Stimulus Testing Transcription Coactivator Work ataxia telangiectasia mutated protein base cytokine diabetic ds-DNA genome integrity insight mitochondrial dysfunction novel oxidative DNA damage repaired research study response sensor tissue culture

展开

项目摘要

Diabetic retinopathy has been associated with oxidative stress, mitochondrial dysfunction, and chronic activation of inflammatory and degenerative pathways. Substantial evidence implicates the retinal mitochondrial ‒ oxidative stress axis as a major unifying pathogenic factor for virtually all diabetes-induced cellular changes implicated in the development of retinal complications. Therapies directed against these individual pathways have provided disappointing results in human clinical trials. Likewise, clinical trials utilizing antioxidants have produced equally ambiguous results. Taken together, these trials suggest a significant knowledge gap regarding underlying mechanism(s) linking oxidative stress to activation of pro-inflammatory and pro-degenerative pathways in diabetic retinas. Based on our previous work in Spinocerebellar ataxia type 3 patients, together with new data provided in this revised application using relevant retinal cells, we propose the novel hypothesis that ROS-mediated DNA damage in diabetes chronically activates the DNA damage response (DDR) ATM (ataxia-telangiectasia mutated) pathway. There is a strong link between increased DNA damage accumulation and development of diabetic complications including retinopathy. Also, there is a growing consensus that ATM not only acts as a DNA damage sensor to coordinate repair of damaged sites to maintain genome integrity but also plays a critical role in modulating the activities of cellular metabolic sensors to interfere with mitochondrial function, cellular energy homeostasis, inflammation, and apoptosis. How the DDR-ATM pathway interconnects various signaling components to disrupt cellular energy metabolism and enhance pro-degenerative signaling is the subject of intense investigation but remains unexplored in the retina. Our recent studies have shown that chronic activation of the DDR pathway interferes with mitochondrial function by suppressing PGC-1α activity, a key transcription co-activator that regulates mitochondrial biogenesis, oxidative phosphorylation, and cellular energy homeostasis. Our new preliminary data demonstrating increased DNA damage and ATM activation in diabetic retina supports our hypothesis. The experiments proposed in this application will test the central hypothesis that diabetes-induced oxidative stress causes double stranded DNA damage resulting in ATM activation, leading to downregulation of PGC1α that impacts multiple pathogenic pathways observed in diabetic retinas. We hypothesize that ATM activation induces a significant amplification of diabetes-induced oxidative stress via mitochondrial disruption by multiple mechanisms (aim 1), vascular and neuronal degeneration (aim 2), and chronic inflammation (aim 3). These aims have the potential to establish a unifying molecular mechanism that links enhanced DNA damage to chronic oxidative, degenerative, and inflammatory abnormalities observed in diabetes. The greatest impact of our work is to provide a regulatory mechanism offering a novel explanation for how hyperglycemia impacts mitochondrial dysfunction to amplify oxidative, inflammatory and degenerative changes in the retina. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

糖尿病性视网膜病与氧化应激，线粒体功能障碍和慢性有关炎症和退化途径的激活。大量证据实施其余部分线粒体 - 氧化应激轴是几乎所有糖尿病诱导的主要统一致病因素在视网膜并发症发展中实施的细胞变化。针对这些的疗法各个途径在人类临床试验中提供了令人失望的结果。同样，临床试验使用抗氧化剂产生了同样模棱两可的结果。综上所述，这些试验表明很重要关于将氧化应激与促炎的激活联系起来的潜在机制的知识差距糖尿病视网膜中的促途径。根据我们以前在脊椎动物共济失调类型的工作 3例患者，以及使用相关残留细胞中此修订应用程序提供的新数据，我们提出 ROS介导的糖尿病中DNA损伤的新型假设长期激活DNA损伤响应（DDR）ATM（共济失调 - 旋转突变）途径。 DNA增加之间有很强的联系包括视网膜病在内的糖尿病并发症的损害积累和发展。另外，还有一个日益增长的共识，即ATM不仅充当DNA损伤传感器，以协调损坏位点的维修保持基因组完整性，但在调节细胞代谢传感器的活性中也起着至关重要的作用干扰线粒体功能，细胞能量稳态，感染和凋亡。如何 DDR-ATM途径互连各种信号成分，以破坏细胞能量代谢和增强促降信号传导是激烈研究的主题，但在视网膜中仍然是出乎意料的。我们最近的研究表明，DDR途径干扰线粒体的慢性激活通过抑制PGC-1α活性（一种调节线粒体的关键转录共激活器）的功能生物发生，氧化磷酸化和细胞能量稳态。我们的新初步数据证明糖尿病视网膜中DNA损伤和ATM激活增加的增加支持了我们的假设。这本应用中提出的实验将检验糖尿病诱导的氧化的中心假设。应力导致双链DNA损伤导致ATM激活，导致PGC1α下调这会影响糖尿病性视网膜中观察到的多种致病途径。我们假设ATM激活通过多个线粒体破坏诱导糖尿病诱导的氧化应激的显着扩增机理（AIM 1），血管和神经元变性（AIM 2）和慢性炎症（AIM 3）。这些目的有可能建立统一的分子机制，该机制将增强的DNA损伤与糖尿病中观察到的慢性氧化物，退化性和炎症异常。最大的影响我们的工作是提供一种调节机制，为高血糖的影响提供新颖的解释线粒体功能障碍可扩增视网膜的氧化，炎症和退化性变化。 PHS 398/2590（修订版06/09）页面延续格式页面