DNA Repair Deficiency Associated with Obesity and the Meatbolic Syndrome
DNA Repair Deficiency Associated with Obesity and the Meatbolic Syndrome
批准号:
7387067
负责人:
R. Stephen Lloyd
金额:
$11.54万
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-04-01 至 2009-03-31
关键词:
A MouseAdultAffectAgeAlcoholsAmericanAnimalsBackcrossingsBase Excision RepairsBiologicalCardiovascular DiseasesCell LineCellsCleaved cellConditionDNADNA DamageDNA RepairDNA Repair DisorderDNA biosynthesisDNA glycosylaseDNA lesionDataDeoxyriboseDepthDevelopmentDiseaseDyslipidemiasEnzymesEpidemicEventExcisionExperimental DesignsExposure toFamilyFatty LiverFemaleFrequenciesGenerationsGenesGenetic ModelsGenetic TranscriptionHeterozygoteHomeostasisHumanHypertensionIn VitroIncidenceInsulin ResistanceKineticsKnock-outKnockout MiceLaboratoriesLifeLiteratureLiver diseasesLocalizedLongevityMammalian CellMeasuresMetabolic syndromeMitochondriaMitochondrial DNAModelingMolecularMorbid ObesityMusMutagenesisNitric OxideNon-Insulin-Dependent Diabetes MellitusNonesterified Fatty AcidsNuclearObesityObject AttachmentOxidative StressPhenotypePlayPopulationProductionProtein IsoformsPublishingRNA SplicingReactive Oxygen SpeciesRelative (related person)RoleStressStrokeSymptomsSyndromeTestingTransgenesVariantWild Type Mouseadductbasecell typecohortcomparativedesigndisease phenotypedisorder preventionexpression cloninghuman studyin vivoknockout genelipid metabolismmalemembermouse modelrepair enzymerepairedresponsesugar
中文摘要
目前,据估计,人类肥胖症的日益流行影响了超过6500万的美国成年人,
继发性后果,包括但不限于寿命缩短、非酒精性脂肪肝
疾病、心血管疾病增加、中风和2型糖尿病发病率增加。大多数
总肥胖人口(> 4500万美国人)中有至少四种以上疾病的组合
(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还没有很好地确定,但已经使用遗传学方法进行了研究。
模型和/或暴露于外源性应激条件。虽然野生型细胞保持整体能量
通过使暴露于活性氧(ROS)的细胞损伤最小化,疾病可以
由导致高水平ROS的各种条件引发。DMA是一个主要的目标,
ROS诱导的损伤,以及缺陷DNA修复和代谢之间可能的相互关系
综合征尚未深入探讨。然而,我们最近证明,携带一种
DNA糖基化酶NEIL 1缺失,出现与代谢综合征一致的症状:重度
肥胖、脂肪肝、血脂异常和胰岛素抵抗。疾病主要表现在男性基因敲除
在与C57 BL/6和杂合子广泛回交的小鼠中观察到。我们的中央
这一假说旨在了解修复氧化应激诱导的酶的损失与
DNA损伤和代谢综合征的发展是,在这些动物中,
启动导致代谢综合征的事件所需的DNA损伤阈值显著降低。
支持这一模型的证据是线粒体!DNA中含有大量的
未修复的损坏和删除。为了辨别NEIL 1在细胞中的作用,存活的调节,
突变和线粒体功能将被评估。此外,由于其在维护
线粒体DNA完整性,目的是确定线粒体的身份和作用-与
酶的核靶向形式。由于初步数据显示,一些人类多态性变体
的NEIL 1是催化失活的,这些变体将表征其引发碱基转移的能力。
切除修复和逆转neiM缺陷小鼠表型的能力。
英文摘要
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.
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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
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
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
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
Role of Base Excision Repair in Limiting Hepatocellular Carcinomas
-
批准号:10292967
-
项目类别:
-
资助金额:$35.71万
-
财政年份:2020
-
负责人:R. Stephen Lloyd
-
依托单位:
Role of Base Excision Repair in Limiting Hepatocellular Carcinomas -Administrative Supplement
-
批准号:10378947
-
项目类别:
-
资助金额:$22.25万
-
财政年份:2020
-
负责人:R. Stephen Lloyd
-
依托单位:
Role of Base Excision Repair in Limiting Hepatocellular Carcinomas
-
批准号:10513822
-
项目类别:
-
资助金额:$35.71万
-
财政年份:2020
-
负责人:R. Stephen Lloyd
-
依托单位:
Inhibitors of DNA polymerase kappa
-
批准号:8259424
-
项目类别:
-
资助金额:$3.85万
-
财政年份:2011
-
负责人:R. Stephen Lloyd
-
依托单位:
Inhibitors of DNA polymerase kappa
-
批准号:8138315
-
项目类别:
-
资助金额:$3.85万
-
财政年份:2011
-
负责人:R. Stephen Lloyd
-
依托单位:
DNA Repair Deficiency Associated with Obesity and the Metabolic Syndrome
-
批准号:7728334
-
项目类别:
-
资助金额:$36.57万
-
财政年份:2009
-
负责人:R. Stephen Lloyd
-
依托单位:
DNA Repair Deficiency Associated with Obesity and the Metabolic Syndrome
-
批准号:8098171
-
项目类别:
-
资助金额:$32.83万
-
财政年份:2009
-
负责人:R. Stephen Lloyd
-
依托单位:
T4 Endonuclease V Structure-Function Analysis
-
批准号:7911342
-
项目类别:
-
资助金额:$33.1万
-
财政年份:2009
-
负责人:R. Stephen Lloyd
-
依托单位:
DNA Repair Deficiency Associated with Obesity and the Metabolic Syndrome
-
批准号:8453441
-
项目类别:
-
资助金额:$31.68万
-
财政年份:2009
-
负责人:R. Stephen Lloyd
-
依托单位:
DNA Repair Deficiency Associated with Obesity and the Metabolic Syndrome
-
批准号:8249438
-
项目类别:
-
资助金额:$32.83万
-
财政年份:2009
-
负责人:R. Stephen Lloyd
-
依托单位:
Cellular Responses to DNA-Protein Crosslinks
-
批准号:6898814
-
项目类别:
-
资助金额:$27.86万
-
财政年份:2004
-
负责人:R. Stephen Lloyd
-
依托单位:
Cellular responses to DNA-protein crosslinks
-
批准号:8106880
-
项目类别:
-
资助金额:$27.75万
-
财政年份:2004
-
负责人:R. Stephen Lloyd
-
依托单位:
Cellular Responses to DNA-Protein Crosslinks
-
批准号:7064790
-
项目类别:
-
资助金额:$27.2万
-
财政年份:2004
-
负责人:R. Stephen Lloyd
-
依托单位:
Cellular responses to DNA-protein crosslinks
-
批准号:8633416
-
项目类别:
-
资助金额:$26.92万
-
财政年份:2004
-
负责人:R. Stephen Lloyd
-
依托单位:
Cellular Responses to DNA-Protein Crosslinks
-
批准号:7731070
-
项目类别:
-
资助金额:$27.75万
-
财政年份:2004
-
负责人:R. Stephen Lloyd
-
依托单位:
Cellular Responses to DNA-Protein Crosslinks
-
批准号:7876843
-
项目类别:
-
资助金额:$27.75万
-
财政年份:2004
-
负责人:R. Stephen Lloyd
-
依托单位:
Cellular Responses to DNA-protein Crosslinks
-
批准号:8775570
-
项目类别:
-
资助金额:$6.17万
-
财政年份:2004
-
负责人:R. Stephen Lloyd
-
依托单位:
Cellular responses to DNA-protein crosslinks
-
批准号:8444576
-
项目类别:
-
资助金额:$26.08万
-
财政年份:2004
-
负责人:R. Stephen Lloyd
-
依托单位:
Cellular responses to DNA-protein crosslinks
-
批准号:9320093
-
项目类别:
-
资助金额:$4.61万
-
财政年份:2004
-
负责人:R. Stephen Lloyd
-
依托单位:
Cellular responses to DNA-protein crosslinks
-
批准号:9026272
-
项目类别:
-
资助金额:$6.17万
-
财政年份:2004
-
负责人:R. Stephen Lloyd
-
依托单位:
海外基金