Mechanisms of DNA damage induced emphysema
DNA损伤诱发肺气肿的机制
基本信息
- 批准号:10187637
- 负责人:
- 金额:$ 67.88万
- 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 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:ATM deficientAdoptionAdultAffectAgeAllelesAlveolarAnimal ModelAtaxia TelangiectasiaBiologyCause of DeathCell AgingCellsCharacteristicsChromosomesChronicCigarette smoke-induced emphysemaClinicalDNA DamageDNA Double Strand BreakDNA RepairDNA Repair GeneDNA Repair PathwayDNA SequenceDNA sequencingDataDefectDiagnosisDiagnostic radiologic examinationDiseaseDouble Strand Break RepairEnzymesEpithelialEpithelial CellsEtiologyExposure toFemaleFrequenciesFunctional disorderFundingGenesGeneticGenetic DeterminismGenetic Predisposition to DiseaseGerm-Line MutationGoalsHabitsHumanIndividualInflammationInflammatoryInheritedInjuryIonizing radiationKnowledgeLengthLightLungLung diseasesMusMutagenesisMutationNatural HistoryNonhomologous DNA End JoiningPathogenicityPatientsPatternPenetrancePeptide HydrolasesPhenotypePopulationPredispositionPremature aging syndromePrevalenceProtease InhibitorPublic PolicyPulmonary EmphysemaRisk FactorsSex DifferencesSmokerSmokingSyndromeTelomeraseTelomere Maintenance GeneTestingTimeUnited StatesWomanWorkalpha 1-Antitrypsinalpha 1-Antitrypsin Deficiencyalveolar destructionalveolar epitheliumataxia telangiectasia mutated proteinbasecigarette smokecigarette smoke-induceddefined contributiondisabilityds-DNAearly onsetexperimental studyexposure to cigarette smokegenotoxicitylung injurymalemenmortalitymutantmutation carriernovelpreventprospectivepublic health relevancesenescencestemstem 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 public/health/relevance.
抽象的
该更新应用旨在了解肺气肿易感性的遗传决定因素。
肺气肿慢性阻塞性疾病 (COPD) 影响美国至少 1000 万人,
是世界各地死亡和残疾的主要原因。在吸烟者中,只有 10-15% 患有慢性阻塞性肺病 (COPD)
已知遗传因素会导致这种易感性。在之前的资助期间,我们发现了突变体
端粒酶基因是 alpha-1 以外的家族性和早发性肺气肿的第二个孟德尔原因
抗胰蛋白酶缺乏症。我们记录了女性吸烟者的特殊偏好,其中 90% 为突变型吸烟者
端粒酶相关性肺气肿。在动物模型中,我们发现肺泡干细胞衰老是一个驱动因素
肺泡破坏和炎症。对于这个更新应用程序,我们重点了解遗传如何
除了端粒功能障碍之外,DNA 损伤缺陷也会导致肺气肿生物学和易感性。我们
确定了一种新的动物模型,其中暴露于基因毒性损伤的雌性会患上肺部疾病,但
不是男性。对于拟议的实验,我们将前瞻性地研究男性和女性在吸烟方面的差异
烟雾敏感性并将缺陷 DNA 修复的贡献定义为人类危险因素
气肿。我们的提案中对性别差异的关注特别及时,因为有证据表明
在其他地方,这种现象预计会加剧,因为吸烟率仍在上升
女性。因此,该提议有可能填补理解肺气肿生物学和
易感性,并在重要的公共/健康/相关性背景下阐明肺气肿外显率的性别特异性差异。
项目成果
期刊论文数量(0)
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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:
$ 67.88万 - 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:
$ 67.88万 - 项目类别:
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