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ROS driven mitochondrial-telomere dysfunction during environmental stress

环境应激期间ROS驱动线粒体端粒功能障碍

基本信息

批准号：
8926521
负责人：
Patricia L Opresko
金额：
$ 20.79万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-07 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8926521
关键词：
1-Methyl-4-phenylpyridinium Animal Model Biogenesis Biological Assay Cell Survival Cells Chemicals Chemistry Complex DNA Damage Development Disease Embryo Environmental Exposure Environmental Risk Factor Exhibits Exposure to Foundations Functional disorder Generations Housing Human Intervention Life Light Maintenance Mammalian Cell Measures Mediating Mitochondria Mitochondrial DNA Modeling Molecular Monitor Nerve Degeneration Neurons Nuclear Organ Parkinson Disease Parkinsonian Disorders Pathogenesis Pathology Peptides Pesticides Phase Phenotype Physiological Process Production Proteins Reactive Oxygen Species Role Rotenone Singlet Oxygen Site Stress Structure Symptoms System TERF1 gene Technology Telomere Shortening Telomere-Binding Proteins Testing Tetanus Helper Peptide Toxic Environmental Substances Toxic effect Transgenic Animals Transgenic Mice Transgenic Organisms Visible Radiation Whole Organism Zebrafish age related cell type dopaminergic neuron environmental stressor event cycle functional decline healthy aging human disease innovation insight mitochondrial dysfunction neuron loss novel oxidative damage public health relevance response sensor telomere tool toxicant

项目摘要

DESCRIPTION (provided by applicant): Maintenance of mitochondrial and telomere function are critical for healthy aging, and significant cross-talk occurs between these distinct compartments. Many environmental factors cause mitochondrial dysfunction and subsequent reactive oxygen species (ROS) generation that particularly damage the telomeres. This project will directly test the hypothesis that oxidative damage at telomeres cause mitochondrial dysfunction, and conversely that oxidative damage to mitochondrial DNA cause telomere dysfunction, and that this reciprocal damage contributes to several environmentally-induced human disease, including neurodegeneration in Parkinson's disease (PD). We will monitor ROS flux in distinct cellular compartments using a highly innovative system consisting of fluorescent protein tagging and visible light to rapidly induce ROS, and fluorogen-activating peptides (FAPs) with unique chemical sensors to detect ROS. These FAPs will also be used with different chemical moieties to generate different types of ROS. We will use an environmental pesticide associated with PD as a mitochondrial toxicant to examine ROS flux and subsequent telomere damage. The R21 phase will develop and validate this approach first in human cells and will generate transgenic animals for applying this system to zebrafish. Aim 1 will use the KillerRed ROS-generating system to examine how ROS generation in mitochondria impacts telomere function, and reciprocally how ROS generation at telomeres alters mitochondrial function. Aim 2 will develop the FAP system for sensing and producing ROS within the mitochondria or telomeres, and will use this technology to examine ROS flux from the mitochondria to the telomeres. We will create transgenic zebrafish driver lines for localized FAP-mediated ROS sensing and generation in the mitochondria or telomeres. The R33 phase will apply the targeted ROS sensing/producing system toward investigating the underlying mechanisms of dysfunctional mitochondria and telomere cross-talk in human neuronal cells (Aim 3), in transgenic zebrafish embryos (Aim 4) and in a specific zebrafish model of PD (Aim 5). These innovative studies will measure the temporal and spatial generation of ROS in living cells and provide mechanistic insight into how dysfunctional telomeres or mitochondria influence each other in the process of environmentally-induced human diseases, including PD. This project builds tools and capacity for examining ROS-mediated flux and mitochondrial cross-talk in response to environmental stressors. Completion of this project will lay the foundation for developing new interventions to better mitigate the negative effects of environmental exposures on telomere and mitochondria function, serving to ameliorate or delay aging-related diseases and pathologies.