Mechanisms of DNA damage induced emphysema
DNA损伤诱发肺气肿的机制
基本信息
- 批准号:10636855
- 负责人:
- 金额:$ 52.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-15 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:ATM deficientAccelerationAdoptionAdultAffectAgeAllelesAlveolarAnimal ModelAtaxia TelangiectasiaBiologyCause of DeathCell AgingCellsCharacteristicsChromosomesChronicCigarette smoke-induced emphysemaClinicalCollaborationsDNA DamageDNA Double Strand BreakDNA RepairDNA Repair DisorderDNA Repair GeneDNA Repair PathwayDNA SequenceDNA sequencingDataDefectDiagnosisDiseaseDouble Strand Break RepairEnzymesEpithelial CellsEpitheliumEtiologyExposure toFemaleFrequenciesFunctional disorderFundingGenesGeneticGenetic DeterminismGenetic Predisposition to DiseaseGerm-Line MutationGoalsHabitsHeterozygoteHumanIndividualInflammationInflammatory ResponseInheritedInjuryIonizing radiationKnowledgeLengthLungLung diseasesMusMutagenesisMutationNatural HistoryNonhomologous DNA End JoiningPathogenicityPatientsPatternPenetrancePeptide HydrolasesPhenotypePopulationPredispositionPremature aging syndromePrevalenceProtease InhibitorPublic PolicyPulmonary EmphysemaRisk FactorsSex DifferencesSmokerSmokingSyndromeTelomeraseTelomere MaintenanceTelomere Maintenance GeneTestingUnited StatesWomanWorkalpha 1-Antitrypsin Deficiencyalveolar destructionalveolar epitheliumataxia telangiectasia mutated proteinautosomecigarette smokecigarette smoke-induceddefined contributiondisabilityearly onsetexperimental studyexposure to cigarette smokegenotoxicitylung injurymalemenmortalitymutantmutation carriernovelpreventprospectivepublic health relevanceradiological imagingsenescencestemstem cell self renewalstem cellstelomerewhole genome
项目摘要
Abstract
This renewal application aims to understand the genetic determinants of emphysema susceptibility.
Emphysema-chronic obstructive disease (COPD) affect at least 10 million individuals in the United States and
are a major cause of mortality and disability around the world. Among smokers, only 10-15% COPD and
genetic factors are known to contribute to this susceptibility. In the prior funding period, we identified mutant
telomerase genes as a second Mendelian cause of familial and early-onset emphysema beyond alpha-1
antitrypsin deficiency. We documented a specific predilection in female smokers who comprised 90% of mutant
telomerase-associated emphysema. In animal models, we identified alveolar stem cell senescence as a driver
of alveolar destruction and inflammation. For this renewal application, we focus on understanding how genetic
defects in DNA damage, beyond telomere dysfunction, contribute to emphysema biology and susceptibility. We
have identified a new animal model in which females exposed to genotoxic damage develop lung disease but
not males. For the proposed experiments, we will prospectively examine male-female differences in cigarette
smoke susceptibility and define the contribution of defective DNA repair as a risk factor for human
emphysema. The focus on sex differences in our proposal is particularly timely since there is evidence that
elsewhere, and this phenomenon is expected to grow since cigarette smoke rates remain on the rise in
women. The proposed therefore have the potential to fill gaps in understanding emphysema biology and
susceptibility and to shed light on sex-specific differences of emphysema penetrance in a context of significant
摘要
项目成果
期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cancer and myeloid clonal evolution in the short telomere syndromes.
- DOI:10.1016/j.gde.2020.02.019
- 发表时间:2020-02
- 期刊:
- 影响因子:4
- 作者:Schratz KE;Armanios M
- 通讯作者:Armanios M
The Role of Telomeres in Human Disease.
- DOI:10.1146/annurev-genom-010422-091101
- 发表时间:2022-08-31
- 期刊:
- 影响因子:8.7
- 作者:
- 通讯作者:
Diagnostic utility of telomere length testing in a hospital-based setting.
- DOI:10.1073/pnas.1720427115
- 发表时间:2018-03-06
- 期刊:
- 影响因子:11.1
- 作者:Alder JK;Hanumanthu VS;Strong MA;DeZern AE;Stanley SE;Takemoto CM;Danilova L;Applegate CD;Bolton SG;Mohr DW;Brodsky RA;Casella JF;Greider CW;Jackson JB;Armanios M
- 通讯作者:Armanios M
Telomere-mediated lung disease.
端粒介导的肺部疾病。
- DOI:10.1152/physrev.00046.2021
- 发表时间:2022-10-01
- 期刊:
- 影响因子:33.6
- 作者:Alder, Jonathan K.;Armanios, Mary
- 通讯作者:Armanios, Mary
Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema.
- DOI:10.1126/scitranslmed.aaf7837
- 发表时间:2016-08-10
- 期刊:
- 影响因子:17.1
- 作者:Stanley SE;Gable DL;Wagner CL;Carlile TM;Hanumanthu VS;Podlevsky JD;Khalil SE;DeZern AE;Rojas-Duran MF;Applegate CD;Alder JK;Parry EM;Gilbert WV;Armanios M
- 通讯作者:Armanios M
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Mary Y Armanios其他文献
Mary Y Armanios的其他文献
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{{ truncateString('Mary Y Armanios', 18)}}的其他基金
The Role of Telomere Shortening in MDS-AML Pathogenesis (resubmission)
端粒缩短在 MDS-AML 发病机制中的作用(重新提交)
- 批准号:
8246709 - 财政年份:2012
- 资助金额:
$ 52.21万 - 项目类别:
The Role of Telomere Shortening in MDS-AML Pathogenesis (resubmission)
端粒缩短在 MDS-AML 发病机制中的作用(重新提交)
- 批准号:
8435373 - 财政年份:2012
- 资助金额:
$ 52.21万 - 项目类别:
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