Mechanisms of DNA damage induced emphysema

DNA损伤诱发肺气肿的机制

基本信息

批准号：
10431937
负责人：
Mary Y Armanios
金额：
$ 62.71万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431937
关键词：
ATM deficient 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 DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA Repair Pathway DNA Sequence DNA sequencing Data Defect Diagnosis Disease Double Strand Break Repair Enzymes Epithelial Epithelial Cells Etiology Exposure to Female Frequencies Functional disorder Funding Genes Genetic Genetic Determinism Genetic Predisposition to Disease Germ-Line Mutation Goals Habits Human Individual Inflammation Inflammatory Inherited Injury Ionizing radiation Knowledge Length Light 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 Gene Testing Time United States Woman Work alpha 1-Antitrypsin alpha 1-Antitrypsin Deficiency alveolar destruction alveolar epithelium ataxia telangiectasia mutated protein base cigarette smoke cigarette smoke-induced defined contribution disability ds-DNA 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

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 - 基质阻塞性疾病（COPD）在美国至少有1000万个人和是世界各地死亡和残疾的主要原因。在吸烟者中，只有10-15％的COPD和已知遗传因素有助于这种敏感性。在以前的资金期间，我们确定了突变体端粒酶基因是孟德尔的第二个因素和早期肺气肿以外的肺气肿抗胰蛋白酶缺乏症。我们记录了占突变体90％的女性吸烟者的特定偏好端粒酶相关的肺气肿。在动物模型中，我们确定牙槽干细胞衰老是驱动器肺泡破坏和炎症。对于此续签应用，我们专注于了解遗传 DNA损伤的缺陷，超出端粒功能障碍，有助于肺气肿生物学和敏感性。我们已经确定了一种新的动物模型，在该模型中，女性暴露于遗传毒性损伤会发展出肺部疾病，但不是男性。对于拟议的实验，我们将前瞻性检查香烟的男女差异烟雾敏感性并定义有缺陷的DNA修复作为人类的危险因素的贡献气肿。在我们的提案中关注性别差异的关注特别及时，因为有证据表明在其他地方，由于香烟烟雾的速度在上升，预计这种现象将会增长女性。因此，提出的有可能填补理解肺气肿生物学和敏感性并阐明在重要的背景下，肺气肿渗透的性别差异