DNA Repair Deficiency Associated with Obesity and the Meatbolic 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：
7387067
负责人：
R. Stephen Lloyd
金额：
$ 11.54万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7387067
关键词：
A Mouse Adult Affect Age Alcohols American Animals Backcrossings Base Excision Repairs Biological Cardiovascular Diseases Cell Line Cells Cleaved cell Condition DNA DNA Damage DNA Repair DNA Repair Disorder DNA biosynthesis DNA glycosylase DNA lesion Data Deoxyribose Depth Development Disease Dyslipidemias Enzymes Epidemic Event Excision Experimental Designs Exposure to Family Fatty Liver Female Frequencies Generations Genes Genetic Models Genetic Transcription Heterozygote Homeostasis Human Hypertension In Vitro Incidence Insulin Resistance Kinetics Knock-out Knockout Mice Laboratories Life Literature Liver diseases Localized Longevity Mammalian Cell Measures Metabolic syndrome Mitochondria Mitochondrial DNA Modeling Molecular Morbid Obesity Mus Mutagenesis Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nuclear Obesity Object Attachment Oxidative Stress Phenotype Play Population Production Protein Isoforms Publishing RNA Splicing Reactive Oxygen Species Relative (related person)Role Stress Stroke Symptoms Syndrome Testing Transgenes Variant Wild Type Mouse adduct base cell type cohort comparative design disease phenotype disorder prevention expression cloning human study in vivo knockout gene lipid metabolism male member mouse model repair enzyme repaired response sugar

项目摘要

The growing epidemic of human obesity is currently estimated to affect over 65 million adult Americans, with secondary consequences including but not limited to, decreased life span, non-alcohol-induced fatty liver disease, increased cardiovascular disease, increased incidence of stroke and type 2 diabetes. The majority of the total obese population (> 45 million Americans) has a combination of at least four of these disorders (obesity, insulin resistance, dyslipidemia, and hypertension), collectively known as the Metabolic Syndrome. The underlying causes of these diseases are not well established, but have been investigated using genetic models and/or exposure to conditions of exogenous stress. Although wild-type cells maintain overall energy homeostasis by minimizing cellular damage from exposure to reactive oxygen species (ROS), disease can be initiated by a variety of conditions that result in high levels of ROS. DMA is one of the major targets of ROS-induced damage, and the possible interrelationship between defective DNA repair and Metabolic Syndrome has not been explored in depth. However, we recently demonstrated that mice carrying a deletion of the DNA glycosylase NEIL1, develop symptoms consistent with Metabolic Syndrome: severe obesity, fatty liver, dyslipidemia, and insulin resistance. Disease is manifested primarily in male knockout mice and is observed in mice extensively backcrossed to C57BL/6 and heterozygotes. Our central hypothesis to understand the relationship between the loss of an enzyme that repairs oxidative-stressinduced DNA damage and the development of the Metabolic Syndrome is that in these animals, the threshold of DNA damage required to initiate events leading to Metabolic Syndrome is significantly reduced. Evidence supporting this model is that mitochondria! DNA contains significantly elevated levels of unrepaired damage and deletions. To discern the role that NEIL1 plays in cells, modulation of survival, mutagenesis and mitochondria! function will be evaluated. Additionally, due to its central role in maintaining mtDNA integrity, aims are designed to determine the identity and role of the mitochondrial- versus the nuclear-targeted forms of the enzyme. Since preliminary data show that some human polymorphic variants of NEIL1 are catalytically inactive, these variants will be characterized for their ability to initiate base excision repair and the ability to reverse the phenotype of the neiM -deficient mice.

据估计，人类肥胖症日益流行，影响了超过 6500 万美国成年人，其中次要后果包括但不限于寿命缩短、非酒精性脂肪肝疾病、增加心血管疾病、增加中风和 2 型糖尿病的发病率。大多数的肥胖人口（> 4500 万美国人）至少同时患有以下四种疾病（肥胖、胰岛素抵抗、血脂异常和高血压），统称为代谢综合征。这些疾病的根本原因尚未明确，但已使用遗传方法进行了研究模型和/或暴露于外源应激条件。尽管野生型细胞保持总体能量通过最大限度地减少暴露于活性氧 (ROS) 造成的细胞损伤来保持体内平衡，疾病可以由多种导致高水平 ROS 的条件引发。 DMA是主要目标之一 ROS 引起的损伤，以及缺陷 DNA 修复和代谢之间可能存在的相互关系综合症尚未得到深入探讨。然而，我们最近证明携带 DNA 糖基化酶 NEIL1 缺失，出现与代谢综合征一致的症状：严重肥胖、脂肪肝、血脂异常和胰岛素抵抗。疾病主要表现为雄性基因敲除小鼠中观察到，在与 C57BL/6 和杂合子广泛回交的小鼠中观察到。我们的中央假设来理解修复氧化应激诱导的酶的损失之间的关系 DNA 损伤和代谢综合征的发生是在这些动物中引发导致代谢综合征的事件所需的 DNA 损伤阈值显着降低。支持这个模型的证据就是线粒体！ DNA 的含量显着升高未修复的损坏和删除。为了了解 NEIL1 在细胞中发挥的作用，调节生存，诱变和线粒体！将评估功能。此外，由于其在维持 mtDNA 完整性，旨在确定线粒体的身份和作用酶的核靶向形式。由于初步数据表明一些人类多态性变异 NEIL1 的催化失活，这些变体将以其启动碱基的能力为特征切除修复和逆转 neiM 缺陷小鼠表型的能力。

项目成果

期刊论文数量（4）

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 elicits coordinated changes in lipid and mitochondrial metabolism in muscle.

DOI：
10.1371/journal.pone.0181687
发表时间：
2017
期刊：
PloS one
影响因子：
3.7
作者：
Vartanian V;Tumova J;Dobrzyn P;Dobrzyn A;Nakabeppu Y;Lloyd RS;Sampath H
通讯作者：
Sampath H

Targeted deletion of the genes encoding NTH1 and NEIL1 DNA N-glycosylases reveals the existence of novel carcinogenic oxidative damage to DNA.

DOI：
10.1016/j.dnarep.2009.03.001
发表时间：
2009-07-04
期刊：
DNA repair
影响因子：
3.8
作者：
Chan MK;Ocampo-Hafalla MT;Vartanian V;Jaruga P;Kirkali G;Koenig KL;Brown S;Lloyd RS;Dizdaroglu M;Teebor GW
通讯作者：
Teebor GW

Evidence for the involvement of DNA repair enzyme NEIL1 in nucleotide excision repair of (5'R)- and (5'S)-8,5'-cyclo-2'-deoxyadenosines.

DOI：
10.1021/bi902161f
发表时间：
2010-02-16
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Jaruga, Pawel;Xiao, Yan;Vartanian, Vladimir;Lloyd, R. Stephen;Dizdaroglu, Miral
通讯作者：
Dizdaroglu, Miral

The DNA Repair Protein OGG1 Protects Against Obesity by Altering Mitochondrial Energetics in White Adipose Tissue.

DOI：
10.1038/s41598-018-33151-1
发表时间：
2018-10-05
期刊：
Scientific reports
影响因子：
4.6
作者：
Komakula SSB;Tumova J;Kumaraswamy D;Burchat N;Vartanian V;Ye H;Dobrzyn A;Lloyd RS;Sampath H
通讯作者：
Sampath H