DNA Repair Deficiency Associated with Obesity and the Metabolic Syndrome

与肥胖和代谢综合征相关的 DNA 修复缺陷

基本信息

批准号：
8453441
负责人：
R. Stephen Lloyd
金额：
$ 31.68万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8453441
关键词：
A Mouse Adult Affect American Animals Backcrossings Base Excision Repairs Biological Biological Assay Body Composition Cardiovascular Diseases Cell Extracts Cell Line Cell Nucleus Cell Survival Cells Circadian Rhythms Complement DNA DNA Damage DNA Repair DNA Repair Disorder DNA biosynthesis DNA glycosylase DNA lesion Data Diet Disease Disease Progression Dyslipidemias Eating Embryo Enzymes Epidemic Etiology Evaluation Exhibits Experimental Designs Exposure to Fat-Restricted Diet Fatty Liver Fatty acid glycerol esters Female Fibroblasts Gene Expression Gene Mutation Generations Genes Genetic Transcription Genome Health Hepatic Home environment Homeostasis Human Hyperinsulinism Hypertension Insulin Resistance Investigation Knock-out Knockout Mice Lead Lesion Lipids Liver diseases Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Measures Metabolic Metabolic syndrome Mitochondria Mitochondrial DNA Molecular Monitor Morbid Obesity Movement Mus Mutagenesis Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nuclear Nucleic Acids OGG1 gene Obesity Organism Outcome Oxidative Stress Phenotype Physiological Production Protein Isoforms Proteins Purines Reactive Oxygen Species Relative (related person)Role Running Shuttle Vectors Site Stress Symptoms System Techniques Testing Transcript Transgenic Mice Variant Vitamin K 3 Weight base carcinogenesis cellular targeting comparative human disease killings lipid metabolism liquid chromatography mass spectrometry male middle age mitochondrial dysfunction mouse model oxidant stress prevent purine repaired response

项目摘要

DESCRIPTION (provided by applicant): Exposure to oxidative stress conditions and the generation of excessive reactive oxygen species (ROS) are generally hypothesized to be a common causative factor in the etiology of several human diseases including, but not limited to, fatty liver disease, dyslipidemia, insulin-resistant type 2 diabetes, cardiovascular disease/hypertension, and obesity (collectively known as Metabolic Syndrome). Although it is well established that lipids, proteins and nucleic acids are critical cellular targets for endogenously and exogenously produced ROS, until recently, deficiencies in repair of ROS-induced DNA base damage had not been considered to be key in the aforementioned diseases, while being considered central to carcinogenesis. However, two knockout mouse models (neil1 and ogg1) have been created in which the initiation of base excision repair of oxidatively-damaged DNA is defective, and in both models, mice develop subsets of symptoms consistent with Metabolic Syndrome. Disease manifestations in the neil1 knockout mice may include obesity, fatty liver disease, dyslipidemia and hyperinsulinemia, with male knockouts much more severely affected than females. In addition, analyses of nuclear DNAs isolated from these mice reveal the accumulation of high levels of ROS-damaged bases and mitochondrial DNAs (mtDNA) show both increased steady-state base damage and large deletions relative to control littermates. Since it known that excessive oxidative stress can induce symptoms of Metabolic Syndrome in repair-proficient organisms, it is hypothesized that the loss of NEIL1 or OGG1 lowers the threshold at which oxidatively stress-induced disease is manifested. In the absence of repair, the progressive accumulation of compromised mtDNA genomes leads to deficiencies in energy production, as well as alterations in free fatty acid and lipid metabolism. In order to test this hypothesis, multiple physiological parameters will be evaluated for changes in neil1-/-, ogg1-/- and neil1-/-ogg1-/- mice and their wild-type littermates during pro-oxidant challenges versus control conditions. These data will be correlated with rates of pathological changes and mitochondrial and nuclear DNA damage accumulation as measured by GC/MS and quantitative PCR. These analyses will be complemented by examining the role of NEIL1 in the modulation of survival, mutagenesis, and mitochondrial function in response to oxidative or nitric oxide stress conditions. Further, since repair of mtDNA is hypothesized to be critical in maintaining metabolic homeostasis, experimental designs are proposed to establish intracellular distribution of various NEIL1 isoforms and determine the biological consequences of expressing nuclear or mitochondrially-targeted forms of these enzymes in neil1-/- cells.

描述（由申请人提供）：通常假设暴露于氧化应激条件和产生过量的活性氧（ROS）是多种人类疾病的常见致病因素，包括但不限于脂肪肝、血脂异常、胰岛素抵抗 2 型糖尿病、心血管疾病/高血压和肥胖（统称为代谢综合征）。尽管众所周知，脂质、蛋白质和核酸是内源性和外源性产生的 ROS 的关键细胞靶标，但直到最近，ROS 诱导的 DNA 碱基损伤修复缺陷尚未被认为是上述疾病的关键，同时被认为是致癌的核心。然而，已经创建了两种基因敲除小鼠模型（neil1 和 ogg1），其中氧化损伤 DNA 的碱基切除修复启动有缺陷，并且在这两种模型中，小鼠都会出现与代谢综合征一致的症状子集。 neil1基因敲除小鼠的疾病表现可能包括肥胖、脂肪肝、血脂异常和高胰岛素血症，其中雄性基因敲除小鼠受到的影响比雌性严重得多。此外，对从这些小鼠中分离出的核 DNA 的分析表明，与对照同窝小鼠相比，ROS 损伤碱基的高水平积累和线粒体 DNA (mtDNA) 均显示出稳态碱基损伤增加和大量缺失。由于已知过度的氧化应激可在修复能力强的生物体中诱发代谢综合征的症状，因此推测 NEIL1 或 OGG1 的缺失会降低氧化应激诱发的疾病出现的阈值。在缺乏修复的情况下，受损线粒体DNA基因组的逐渐积累会导致能量产生不足，以及游离脂肪酸和脂质代谢的改变。为了检验这一假设，将评估在促氧化剂挑战期间与对照条件下 neil1-/-、ogg1-/- 和 neil1-/-ogg1-/- 小鼠及其野生型同窝小鼠的多个生理参数的变化。这些数据将与通过 GC/MS 和定量 PCR 测量的病理变化率以及线粒体和核 DNA 损伤积累相关。这些分析将通过检查 NEIL1 在响应氧化或一氧化氮应激条件而调节生存、诱变和线粒体功能中的作用来补充。此外，由于假设线粒体DNA的修复对于维持代谢稳态至关重要，因此提出了实验设计来建立各种NEIL1亚型的细胞内分布，并确定在neil1-/-细胞中表达这些酶的核或线粒体靶向形式的生物学后果。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

8-Oxoguanine DNA glycosylase (OGG1) deficiency increases susceptibility to obesity and metabolic dysfunction.

DOI：
10.1371/journal.pone.0051697
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Sampath H;Vartanian V;Rollins MR;Sakumi K;Nakabeppu Y;Lloyd RS
通讯作者：
Lloyd RS

Deficiency of the oxidative damage-specific DNA glycosylase NEIL1 leads to reduced germinal center B cell expansion.

DOI：
10.1016/j.dnarep.2009.08.007
发表时间：
2009-11-02
期刊：
DNA repair
影响因子：
3.8
作者：
Mori H;Ouchida R;Hijikata A;Kitamura H;Ohara O;Li Y;Gao X;Yasui A;Lloyd RS;Wang JY
通讯作者：
Wang JY