Genomic instability, susceptibility to oxidative stress and cellular senescence Grant

abstract

  • Project Summary / AbstractAll living organisms are continually exposed to a variety of environmental stressors, be they anthropogenic ornatural 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'sdefenses and damage cellular components including DNA, causing oxidation. Measurement of global genomelevels of oxidatively damaged DNA, implicates environmental stressors in major human health issues (e.g.,cancer, aging, cardiovascular, and neurodegenerative diseases). However, current associations between DNAdamage and disease are based upon crude assessments of global genome damage, which provide limitedmechanistic information on how damage leads to disease. Furthermore, DNA damage is not uniformly distributedacross the genome; accumulation, or persistence, of damage in regions of the genome vital to the functioning ofthe cell will have downstream consequences. We propose, that the role of DNA damage in disease can only beunderstood by examination of damage in the context of its location. We currently lack information concerninghow the cell maintains baseline levels of oxidatively damaged DNA, and its spatio-temporal distribution acrossthe genome. This is fundamental to our understanding of how the cell responds to damage and targets regionsfor prioritized repair. The objective of this study is to identify regions of the genome with increased susceptibilityto the formation, or slow repair, of oxidatively damaged DNA that play a functional role in senescence. This studywill 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 damageand 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 predictdownstream 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 functionalconsequences 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-temporaltopological 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 hypothesizethat increased ROS alters the distribution of damage and repair driving the disease process. Using the aboveapproaches, in our aging stem cell model with increased endogenous ROS production. We hypothesize that anynew regions identified will represent candidates for having a role in triggering senescence.

date/time interval

  • May 1, 2017 - April 30, 2020

sponsor award ID

  • 1R15ES027196-01A1

local award ID

  • AWD000000006956

contributor

keywords

  • 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