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Role of oxidative DNA damage in the onset and progression of metabolic syndrome

DNA 氧化损伤在代谢综合征发生和进展中的作用

基本信息

批准号：
8764741
负责人：
Harini Sampath
金额：
$ 9万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764741
关键词：
8-Oxoguanine DNA Glycosylase 8-hydroxyguanosine Acute Address Adipose tissue Adult Affect Age Animal Model Animals Base Excision Repairs Body Weight Cell Culture Techniques Cell Survival Cell model Cells Childhood Consumption DNA DNA Damage DNA Repair DNA Repair Disorder DNA Repair Enzymes DNA glycosylase DNA lesion Data Defect Development Diabetes Mellitus Diet Dietary Factors Dietary Fats Dietary Fatty Acid Disease Fasting Fatty Liver Fatty acid glycerol esters Functional disorder Gastrocnemius Muscle Genes Genetic Genomic DNA Genomics Goals Hepatic Hepatocyte Homeostasis Human Individual Insulin Resistance Investigation Knowledge Lead Left Lesion Link Lipids Liver Liver diseases Macronutrients Nutrition Measures Mediating Metabolic Metabolic Diseases Metabolic syndrome Methods Mitochondria Mitochondrial DNA Modeling Molecular Morphology Mus Muscle Mutation Myoblasts Myocardium Nuclear OGG1 gene Obesity Obesity associated disease Outcome Oxidative Stress Pathology Pathway interactions Physiological Prevalence Prevention Prevention strategy Preventive Process Public Health Relative (related person)Reporting Respiration Role Skeletal Muscle Testing Therapeutic Tissues Transgenic Mice Transgenic Model United States Unsaturated Fats Up-Regulation combat fatty acid oxidation feeding glucose uptake impaired glucose tolerance insulin sensitivity insulin signaling interest mouse model new therapeutic target novel novel therapeutics overexpression oxidation oxidative DNA damage oxidative damage population health public health relevance repaired response role model saturated fat tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Obesity and related complications such as fatty liver disease and diabetes pose a growing threat to population health in the United States and around the world. A greater understanding of the dietary factors and cellular mechanisms that lead to the development of obesity is essential to devising preventive and therapeutic strategies to combat these metabolic diseases. Oxidative stress, such as that induced by consumption of high- fat diets, is thought to be a causal factor in the development of obesity. Oxidative stress induces damage to cellular components, including DNA, which, if left unrepaired, can lead to mutations and tumorigenesis. Oxidative DNA lesions are repaired by the base-excision repair pathway, which is initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). OGG1 recognizes and excises the most commonly formed oxidative DNA lesion, 8-oxo-G. Interestingly, mice deficient in OGG1 have been recently reported to be susceptible to obesity and fatty liver, indicating an unexpected but critical role for this DNA repair enzyme in the development of metabolic disease. The overall goal of this project is to delineate the mechanisms that link oxidative DNA damage to obesity and metabolic syndrome and to identify dietary factors contributing to the development or prevention of DNA damage. Preliminary data have indicated that OGG1 deficient mice have increased hepatic lipid accumulation, along with markers of decreased fat oxidation in the liver. These mice also display impaired glucose tolerance and alterations in markers of mitochondrial morphology in skeletal muscle. The first two aims of this project will therefore address the mechanistic role of DNA damage in altering hepatic lipid oxidation and skeletal muscle mitochondrial dynamics. These aims will be completed with the aid of novel cellular and transgenic models of obesity resulting from a defect in DNA repair deficiency and established methods to measure DNA damage, fat oxidation, mitochondrial morphology and respiration, and insulin signaling. The completion of these aims will further our understanding of oxidative stress-induced damage in the initiation and progression of fatty liver disease, as well as impaired insulin sensitivity, which can ultimately lead to the development of diabetes. With the knowledge gained from these studies, the third aim will broaden the investigation to delineate the role of dietary fatty acids of varying degrees of desaturation in the induction of DNA damage in metabolically active tissues, including liver, heart, muscle, and adipose tissue. Additionally, the third aim will utilize a newly developed transgenic mouse model overexpressing mitochondrial OGG1 to determine the role of dietary fat exposure and mitochondrial DNA repair in altering mitochondrial function and cell viability. This critical aim will address significant gaps in our understanding of the interplay between diet, DNA damage, and metabolic disease. The knowledge gained from the completion of this final aim will also guide future research focused on developing novel targeted therapeutics to combat metabolic dysfunction by modulating pathways of DNA damage recognition and repair.

描述（由申请人提供）：肥胖和相关并发症，如脂肪肝和糖尿病，对美国和世界各地的人口健康构成日益严重的威胁。更好地了解导致肥胖症发展的饮食因素和细胞机制对于制定预防和治疗策略以对抗这些代谢疾病至关重要。氧化应激，例如由高脂肪饮食引起的氧化应激，被认为是肥胖症发展的一个因果因素。氧化应激诱导细胞成分的损伤，包括DNA，如果不修复，可能导致突变和肿瘤发生。氧化性DNA损伤通过碱基切除修复途径修复，该途径由DNA糖基化酶如8-氧代鸟嘌呤DNA糖基化酶（OGG 1）启动。OGG 1识别并切除最常见的氧化DNA损伤8-oxo-G。有趣的是，最近有报道称OGG 1缺陷的小鼠易患肥胖和脂肪肝，这表明这种DNA修复酶在代谢疾病的发展中具有意想不到但关键的作用。该项目的总体目标是描绘将氧化DNA损伤与肥胖和代谢综合征联系起来的机制，并确定有助于DNA损伤发展或预防的饮食因素。初步数据表明，OGG 1缺陷小鼠肝脏脂质积累增加，沿着肝脏中脂肪氧化减少的标志物。这些小鼠还表现出葡萄糖耐量受损和骨骼肌中线粒体形态标志物的改变。因此，该项目的前两个目标将解决DNA损伤在改变肝脏脂质氧化和骨骼肌线粒体动力学中的机制作用。这些目标将在新型细胞和转基因肥胖模型的帮助下完成，这些模型是由DNA修复缺陷引起的，并建立了测量DNA损伤、脂肪氧化、线粒体形态和呼吸以及胰岛素信号传导的方法。这些目标的完成将进一步加深我们对脂肪肝发生和发展中氧化应激诱导的损伤以及胰岛素敏感性受损的理解，这些损伤最终可能导致糖尿病的发展。从这些研究中获得的知识，第三个目标将扩大调查，以描绘不同程度的去饱和的膳食脂肪酸在诱导代谢活性组织，包括肝脏，心脏，肌肉和脂肪组织中的DNA损伤的作用。此外，第三个目标将利用新开发的过表达线粒体OGG 1的转基因小鼠模型来确定膳食脂肪暴露和线粒体DNA修复在改变线粒体功能和细胞活力中的作用。这一关键目标将解决我们对饮食， DNA损伤和代谢疾病。从这一最终目标的完成中获得的知识也将指导未来的研究，重点是开发新的靶向疗法，通过调节DNA损伤识别和修复途径来对抗代谢功能障碍。