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：
9326286
负责人：
Harini Sampath
金额：
$ 24.9万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
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：
2016-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9326286
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 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 Excision Repair Fasting Fatty Liver Fatty acid glycerol esters Functional disorder Gastrocnemius Muscle Genes Genetic Genomic DNA Goals Hepatic Hepatocyte High Fat Diet Homeostasis Human Impairment 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 Myocardial tissue Nuclear OGG1 gene Obesity Obesity associated disease Outcome Oxidative Stress Pathology Pathway interactions Pharmacology Physiological Prevalence Prevention Prevention strategy Preventive Process Public Health Reporting Respiration Role Skeletal Muscle Testing Therapeutic Tissues Transgenic Mice Transgenic Model United States Unsaturated Fats Up-Regulation combat fatty acid oxidation feeding genome integrity glucose uptake impaired glucose tolerance insulin sensitivity insulin signaling interest mouse model new therapeutic target novel novel therapeutics obesity in children overexpression oxidation oxidative DNA damage oxidative damage population health repaired response saturated fat tumorigenesis

项目摘要

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 highfat 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.

肥胖和相关并发症，如脂肪肝和糖尿病，对人口构成越来越大的威胁美国和世界各地的健康。更好地了解饮食因素和细胞导致肥胖发展的机制对于制定预防和治疗至关重要对抗这些代谢疾病的策略。氧化应激，例如由摄入高脂肪引起的氧化应激饮食被认为是导致肥胖的一个因素。氧化应激会导致损伤包括 DNA 在内的细胞成分，如果不加以修复，可能会导致突变和肿瘤发生。 DNA 氧化损伤通过碱基切除修复途径进行修复，该途径由 DNA 启动糖基化酶，例如 8-氧代鸟嘌呤 DNA 糖基化酶 (OGG1)。 OGG1识别和切除最多通常形成氧化DNA损伤，8-oxo-G。有趣的是，最近发现了缺乏 OGG1 的小鼠据报道易患肥胖症和脂肪肝，表明该 DNA 具有意想不到但至关重要的作用修复代谢疾病发展中的酶。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，并确定饮食因素有助于 DNA 损伤的发生或预防。初步数据表明OGG1 缺陷小鼠的肝脏脂质积累增加，同时肝脏中脂肪氧化的标志物减少肝。这些小鼠还表现出葡萄糖耐量受损和线粒体标记物的改变骨骼肌的形态。因此，该项目的前两个目标将解决 DNA 损伤改变肝脂质氧化和骨骼肌线粒体动力学。这些目标将借助由 DNA 缺陷引起的肥胖的新型细胞和转基因模型来完成修复缺陷并建立测量 DNA 损伤、脂肪氧化、线粒体形态的方法以及呼吸和胰岛素信号传导。这些目标的完成将进一步加深我们对氧化的理解压力引起的脂肪肝疾病发生和进展的损害以及胰岛素受损敏感性，最终会导致糖尿病的发展。凭借从这些中获得的知识研究中，第三个目标将扩大调查范围，以不同程度地描述膳食脂肪酸的作用去饱和诱导代谢活跃组织（包括肝脏、心脏、肌肉、和脂肪组织。此外，第三个目标将利用新开发的转基因小鼠模型过表达线粒体 OGG1 以确定膳食脂肪暴露和线粒体 DNA 的作用修复改变线粒体功能和细胞活力。这一关键目标将解决我们在了解饮食、DNA 损伤和代谢疾病之间的相互作用。获得的知识这一最终目标的完成也将指导未来的研究，重点是开发新的有针对性的通过调节 DNA 损伤识别和修复途径来对抗代谢功能障碍的疗法。