Integrative, age-related changes in genome and epigenome in human lung in relation to smoking

与吸烟相关的人肺基因组和表观基因组的综合、年龄相关变化

基本信息

批准号：
9895468
负责人：
SIMON D SPIVACK
金额：
$ 65.23万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895468
关键词：
Affect Age Aging Airway Disease Aneuploidy Cell Aging Cell Nucleus Cell division Cells Chromosome abnormality Chronic Obstructive Airway Disease Complex Copy Number Polymorphism Cytosine DNA DNA Damage DNA Methylation DNA Repair DNA Sequence Alteration DNA Structure DNA biosynthesis Data Depurination Detection Development Disease Early Diagnosis Environmental Risk Factor Epigenetic Process Future Gene Expression Genetic Genetic Code Genetic Transcription Genome Genomic Instability Genomics Human Individual Lead Link Lung Lung diseases Malignant Neoplasms Maps Methods Methylation Molecular Mutation Noise Normal tissue morphology Organ Pattern Prevention Pulmonary Fibrosis Retrotransposition Risk Risk Factors Sampling Smoker Smoking Source Stress Structure Testing Therapeutic Time Tobacco smoke Variant age related base bronchial epithelium cigarette smoking crosslink environmental tobacco smoke exposure epigenome epigenomics functional loss human tissue methylation pattern methylome methylomics non-smoker normal aging repaired response single cell analysis single-cell RNA sequencing tobacco exposure transcriptome transcriptomics

项目摘要

ABSTRACT Aging is the main risk factor for many age-related lung diseases, including COPD and pulmonary fibrosis. It has been speculated that this aging-disease relationship is due to the complex interaction of multiple genetic, epigenetic and transcriptomic alterations that occur in normal human lung over time. In turn, these age-related changes are impacted by environmental factors, such as cigarette smoking. Unfortunately, little is known about age-related molecular alterations in human lung. To some extent this is due to the lack of methods to analyze human tissues for changes occurring stochastically, i.e., affecting individual cells or groups of cells in different ways. The best example is genome instability, one of the hallmarks of aging. Genome instability can be defined as changes in the genetic code, varying from large chromosomal aberrations, to smaller deletions, insertions and copy number variation, and base substitution mutations. The underlying causes of genome instability are errors during cell division, DNA replication or DNA repair of DNA damage. Such changes are irreversible and are in striking contrast to DNA damage, which can be repaired. DNA damage involves physical alterations in DNA structure, e.g., breaks, depurination, depyrimidination, crosslinks, modified bases. Unfortunately, mutations in normal tissues are different from cell to cell and very difficult to study, except using single cell approaches as we will do in the proposed project. However, DNA damage induced in the lung during aging also evokes a DNA damage response, which can lead to multiple epigenetic alterations that are consistent from cell to cell and can be detected in bulk DNA. In addition, a stochastic pattern of age-related changes is likely to occur during aging, the detection of which requires a single cell approach. Here we propose to comprehensively analyze human lung bronchial epithelium for both stochastic and adaptive changes in the genome, epigenome and transcriptome. This project will integrate these comprehensive spectra of genomic and epigenomic change of normal human bronchial epithelium in relation to age and tobacco smoke exposure. This will provide reference data for future comparisons of lung disease states, enhance our understanding of age-and smoking-related mechanisms of lung disease, and thereby facilitate the development of early detection, prevention and therapeutic strategies.

抽象的衰老是许多与年龄有关的肺部疾病（包括COPD和肺纤维化）的主要危险因素。它据推测，这种衰老的关系是由于多种遗传的复杂相互作用，随着时间的推移，正常人肺中发生的表观遗传和转录组改变。反过来，这些与年龄有关变化受到环境因素的影响，例如吸烟。不幸的是，对人肺与年龄相关的分子改变。在某种程度上，这是由于缺乏分析方法人体组织随机发生变化，即影响不同的单个细胞或不同的细胞组方式。最好的例子是基因组不稳定性，这是衰老的标志之一。基因组不稳定性可以定义随着遗传密码的变化，从大染色体畸变到较小的缺失，插入和拷贝数变化以及基本替代突变。基因组不稳定性的根本原因是细胞分裂期间的误差，DNA复制或DNA损伤的DNA修复。这样的变化是不可逆转的，与DNA损伤形成鲜明对比的是可以修复的。 DNA损伤涉及身体改变 DNA结构，例如断裂，驱逐，去二次映，交联，修饰碱基。很遗憾，正常组织中的突变因细胞到细胞而不同，而且很难研究，除了使用单细胞就像在拟议项目中所做的那样。但是，衰老期间肺部诱导的DNA损伤还唤起了DNA损伤反应，这可能导致多种表观遗传改变，这些改变是一致的从细胞到细胞，可以在散装DNA中检测到。另外，与年龄相关的随机模式是可能在衰老过程中发生，其检测需要单个细胞进近。在这里我们建议全面分析人类肺支气管上皮，以进行随机变化和适应性变化基因组，表观基因组和转录组。该项目将整合这些全面的基因组光谱与年龄和烟草烟雾相关的正常人支气管上皮细胞的表观基因组变化。这将提供参考数据，以进行肺部疾病状态的未来比较，增强我们对肺部疾病的年龄与吸烟相关的机制，从而有助于早期发展检测，预防和治疗策略。