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

• 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
• 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

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，例如脂肪肝病和糖尿病对人群构成日益严重的威胁 美国和世界各地的健康。对饮食因素和细胞的更多了解 导致肥胖发展的机制对于设计预防和治疗至关重要 打击这些代谢疾病的策略。氧化应激，例如由高脂消耗引起的氧化应激 饮食被认为是肥胖发展的因素。氧化应激引起的损害 细胞成分（包括DNA），如果未修复，则可能导致突变和肿瘤发生。 氧化性DNA病变通过基础拆卸修复途径修复，该途径由DNA引发 糖基酶，例如8-氧气素DNA糖基酶（OGG1）。 OGG1识别和切除最多 通常形成的氧化DNA病变，8-oxo-g。有趣的是，最近缺乏OGG1的小鼠 据报道容易受到肥胖和脂肪肝的影响，表明该DNA的意外但至关重要 修复代谢性疾病发展中的酶。该项目的总体目标是描述 将氧化性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 有助于开发或预防DNA损伤。初步数据表明OGG1 不足的小鼠增加了肝脂质的积累，以及脂肪氧化减少的标记 肝。这些小鼠还显示出葡萄糖耐量受损和线粒体标记的改变 骨骼肌的形态。因此，该项目的前两个目标将解决 DNA损伤改变了肝脂质氧化和骨骼肌线粒体动力学。这些目标会 借助于DNA缺陷而借助新的细胞和转基因模型来完成 修复缺陷和测量DNA损伤，脂肪氧化，线粒体形态的既定方法 和呼吸和胰岛素信号传导。这些目标的完成将进一步我们对氧化的理解 压力诱导的脂肪肝病的起始和进展以及胰岛素受损的损害 敏感性，最终可能导致糖尿病的发展。从这些知识中获得的知识 研究，第三个目标将扩大研究，以描绘不同程度的饮食脂肪酸的作用 在代谢活性组织中诱导DNA损伤的诱导（包括肝，心脏，肌肉）中的饱和度 和脂肪组织。此外，第三个目标将利用新开发的转基因鼠标模型 过表达线粒体OGG1，以确定饮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。这个关键目标将解决我们的重大差距 了解饮食，DNA损伤和代谢疾病之间的相互作用。知识获得了 从完成这个最终目标开始还将指导未来的研究专注于开发针对性的新颖针对性 通过调节DNA损伤识别和修复的途径来应对代谢功能障碍的治疗剂。