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Mitochondrial ROS microdomains and neuronal ischemia

线粒体 ROS 微区和神经元缺血

基本信息

批准号：
9277588
负责人：
Andrew Phillip Wojtovich
金额：
$ 33.58万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277588
关键词：
Acute Address Alpha Cell Animal Model Antioxidants Back Behavioral Assay Biochemistry Bioenergetics Biological Biological Models Biology Biosensor CRISPR/Cas technology Caenorhabditis elegans Calcium Cell Death Cell Line Cells Chimeric Proteins Complex Diffuse Disease Exhibits Generations Genes Genetic Genetic Epistasis Genetic Models Genome Goals Homeostasis Human Huntington Disease Hydrogen Peroxide Individual Injury Ischemia Lead Light Lighting Location Mammals Membrane Metabolic Metabolism Methodology Mitochondria Modeling Modification Mus Nature Neurodegenerative Disorders Neurons Nuclear Optics Outcome Output Oxidation-Reduction Oxidative Stress Parkinson Disease Pathology Pathway interactions Phenotype Physiological Physiology Positioning Attribute Predisposition Process Production Proteins Reactive Oxygen Species Resistance Respiratory Chain Role Second Messenger Systems Signal Pathway Signal Transduction Site Stress Stroke Succinate Dehydrogenase Superoxides Techniques Technology Testing Transgenic Organisms Translating Translations Variant biological adaptation to stress experimental study genome editing innovative technologies light effects macromolecule new technology novel novel strategies novel therapeutic intervention optogenetics oxidative damage public health relevance respiratory response spatiotemporal tool

项目摘要

DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) contribute to a diverse range of neurodegenerative diseases and the pathology of acute injuries such as stroke in mammals. However, not all ROS are equal, and the disease output depends strongly on the timing and location of ROS production. Furthermore, ROS in limited quantities have been shown to trigger adaptive signaling pathways and may contribute to mitohormesis. These facts lead to our central hypothesis that the biological impact of ROS, like other second messengers, depends on their timing, quantity and site of generation. However, due to their reactive nature, there is currently no means to control the site or timing of ROS production. This proposal addresses this gap by combining novel photo- inducible genetically-encoded ROS generating proteins with the power of C. elegans genetics to determine the evolutionarily-conserved role of ROS signaling in the context of neuronal ischemic sensitivity and stress resistance. In brief, new optogenetic tools for making ROS will be expressed as protein fusions using CRISPR/Cas9 technology with nuclear genes that encode mitochondrial respiratory chain subunits. The proposal focuses on the complex II subunit SDHC and utilizes expertise in biosensors, the model organism C. elegans, and optics to study ROS signaling with an unprecedented degree of precision. Parallel approaches utilizing cortical neurons in culture will address the evolutionarily conserved role of mitochondrial ROS in regulating neuronal sensitivity to ischemia. This approach could potentially yield new therapeutic strategies for diseases in which redox homeostasis has been disrupted. Overall, this novel approach will advance our understanding of mitochondrial redox signaling, allowing us to ask questions that have previously been unanswerable using conventional methodologies.