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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：
Mary Y Armanios
金额：
$ 52.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
https://reporter.nih.gov/project-details/10636855
关键词：
ATM deficient Acceleration Adoption Adult Affect Age Alleles Alveolar Animal Model Ataxia Telangiectasia Biology Cause of Death Cell Aging Cells Characteristics Chromosomes Chronic Cigarette smoke-induced emphysema Clinical Collaborations DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder DNA Repair Gene DNA Repair Pathway DNA Sequence DNA sequencing Data Defect Diagnosis Disease Double Strand Break Repair Enzymes Epithelial Cells Epithelium Etiology Exposure to Female Frequencies Functional disorder Funding Genes Genetic Genetic Determinism Genetic Predisposition to Disease Germ-Line Mutation Goals Habits Heterozygote Human Individual Inflammation Inflammatory Response Inherited Injury Ionizing radiation Knowledge Length Lung Lung diseases Mus Mutagenesis Mutation Natural History Nonhomologous DNA End Joining Pathogenicity Patients Pattern Penetrance Peptide Hydrolases Phenotype Population Predisposition Premature aging syndrome Prevalence Protease Inhibitor Public Policy Pulmonary Emphysema Risk Factors Sex Differences Smoker Smoking Syndrome Telomerase Telomere Maintenance Telomere Maintenance Gene Testing United States Woman Work alpha 1-Antitrypsin Deficiency alveolar destruction alveolar epithelium ataxia telangiectasia mutated protein autosome cigarette smoke cigarette smoke-induced defined contribution disability early onset experimental study exposure to cigarette smoke genotoxicity lung injury male men mortality mutant mutation carrier novel prevent prospective public health relevance radiological imaging senescence stem stem cell self renewal stem cells telomere whole 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：
Current opinion in genetics & development
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：
Annual review of genomics and human genetics
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：
Proceedings of the National Academy of Sciences of the United States of America
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：
PHYSIOLOGICAL REVIEWS
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：
Science translational medicine
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