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Genomic instability, susceptibility to oxidative stress and cellular senescence

基因组不稳定、对氧化应激和细胞衰老的易感性

基本信息

批准号：
9304443
负责人：
Marcus Stanley Cooke
金额：
$ 36.63万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2020-08-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304443
关键词：
Address Aging Aging-Related Process Automobile Driving Binding Binding Sites Biological Cardiovascular Diseases Cardiovascular system Cell Aging Cell Cycle Stage Cell model Cell physiology Cells Cellular Metabolic Process ChIP-seq Chemicals Coupled DNA DNA Damage DNA Repair Data Deoxyguanosine Development Disease Environment Event Exhibits Exons Exposure to Functional disorder Generations Genes Genome Genomic Instability Genomic Segment Goals Health Human Immunoprecipitation Intervention Introns Link Location Malignant Neoplasms Maps Measurement Methods Modeling Neurodegenerative Disorders Normal Cell Nuclear Nucleic Acid Regulatory Sequences Organism Oxidative Stress Oxidative Stress Induction Pathologic Pattern Play Predisposition Process Production Proteins Pyrimidine Dimers Research Role Site Stem cells Stress Students Techniques adult stem cell anthropogenesis base chromosomal location environmental stressor human disease insight knock-down next generation sequencing oxidation oxidative DNA damage repaired senescence spatiotemporal stressor

项目摘要

Project Summary / Abstract All living organisms are continually exposed to a variety of environmental stressors, be they anthropogenic or natural in origin. Many stressors share a common toxic mechanism that can have detrimental effects on the cell (e.g., generation of highly reactive chemical species). A proportion of these chemical species, evade the cell's defenses and damage cellular components including DNA, causing oxidation. Measurement of global genome levels of oxidatively damaged DNA, implicates environmental stressors in major human health issues (e.g., cancer, aging, cardiovascular, and neurodegenerative diseases). However, current associations between DNA damage and disease are based upon crude assessments of global genome damage, which provide limited mechanistic information on how damage leads to disease. Furthermore, DNA damage is not uniformly distributed across the genome; accumulation, or persistence, of damage in regions of the genome vital to the functioning of the cell will have downstream consequences. We propose, that the role of DNA damage in disease can only be understood by examination of damage in the context of its location. We currently lack information concerning how the cell maintains baseline levels of oxidatively damaged DNA, and its spatio-temporal distribution across the genome. This is fundamental to our understanding of how the cell responds to damage and targets regions for prioritized repair. The objective of this study is to identify regions of the genome with increased susceptibility to the formation, or slow repair, of oxidatively damaged DNA that play a functional role in senescence. This study will engage students in independent, meritorious research, strengthening the institutional research environment. Aim 1. To identify susceptible regions of the genome for oxidative stress-induced damage. A. Characterize the distribution of basal levels 8-oxodG, and its repair surveillance. Patterns of DNA damage and repair will be identified using DDIP-seq for 8-oxodG, and ChIP-seq for hOGG1 in an aging stem cell model. B. Develop a model to interrogate the factors influencing the distribution of DNA damage and repair and predict downstream effects. DNA damage and repair will be mapped to specific gene sequences, introns/exons, regulatory sequences, and chromosomal locations. Identifying regions of the genome that may have functional consequences in cellular dysfunction and ROS-induced senescence. C. Assess the role of nuclear organization on damage and repair. FISH will be utilized to form spatio-temporal topological maps of DNA damage and repair across the genomic regions identified in 1A and 1B. Aim 2. To determine the mechanisms linking increased susceptibility to oxidative stress to senescence. Examine the effect of increased endogenous ROS on the targeting of DNA damage and repair. We hypothesize that increased ROS alters the distribution of damage and repair driving the disease process. Using the above approaches, in our aging stem cell model with increased endogenous ROS production. We hypothesize that any new regions identified will represent candidates for having a role in triggering senescence.

项目摘要/摘要