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Synergistic toxicity of reactive oxygen species

活性氧的协同毒性

基本信息

批准号：
10552702
负责人：
Andrei Kuzminov
金额：
$ 30万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552702
关键词：
Affect Bacteria Binding Biocide Cancerous Cells Chemosensitization Chromosome Structures Chromosomes Complex Confusion Cyanides Cytoplasm DNA DNA Double Strand Break DNA Maintenance DNA Repair Disorder DNA lesion DNA replication fork Dependence Development Diffusion Drug Design Enzymes Escherichia coli Future Genetic Goals Hunger Hydrogen Peroxide Hydroxyl Radical Immune Immune system In Vitro Invaded Iron Knowledge Measures Medical Membrane Metabolic Microbe Modeling Nature Nitric Oxide Phagosomes Physiological Poisoning Reaction Reactive Oxygen Species Research Respiration Role Shock Single-Stranded DNA Starvation Testing Toxic effect Toxin Work bioweapon catalase cell killing cell type cellular targeting cytotoxicity design in vivo iron metabolism meter microbial novel therapeutics oxidation plasmid DNA predictive modeling programs recruit repaired response stability testing synergism

项目摘要

Hydrogen peroxide is a bio-specific toxin, inert with common organic or inorganic molecules, but in sufficient concentrations killing any type of cells almost on contact, using cellular iron to produce highly-reactive oxidizing species (Fenton's reaction). Chromosomal DNA is the main cellular target of HP poisoning, although the nature of lethal chromosomal damage is still unknown. Even more confusingly, HP turns out to be a surprising choice for a bio- weapon, as the killing concentrations are 1,000-fold higher than the physiological ones, while accumulation of HP in a particular cellular compartment is problematic, because its small size and uncharged nature facilitates diffusion through membranes. Yet, our immune cells somehow use these much lower HP concentrations to efficiently kill invading microbes, by unclear mechanisms. Remarkably, HP toxicity is synergized by other simple molecules, like nitric oxide (NO) or cyanide (CN). We hypothesize that our immune cells use otherwise insufficient HP concentrations to kill bacteria by accumulating potentiator molecules (for example, NO) in the compartments where high [HP] does not accumulate. However, the metabolic mechanisms behind potentiated HP toxicity, thought to elevate the intracellular free iron, are inconsistent with the newest results, while the mechanisms of irreparable chromosomal damage remain mostly unclear. Our recent studies of HP+CN co-toxicity uncovered new aspects of the phenomenon, like iron recruitment from intracellular depots directly to DNA, or catastrophic chromosome fragmentation, which is responsible for the cell killing. We propose to study HP+NO co-toxicity with three specific aims: 1) the nature of this synergistic toxicity and the targets of NO action; 2) the DNA mechanisms behind the catastrophic chromosomal fragmentation; 3) hunger shock as a metabolic potentiator of HP toxicity. The major difference of our approach from the previous work is the emphasis on DNA and chromosome damage, on the significantly expanded genetic scope and on testing specific ways to enhance Fenton. Our long-term goals in this project are to understand the mechanisms behind the catastrophic chromosome fragmentation on the one hand, and those responsible for potentiation of HP toxicity on the other.

过氧化氢是一种生物特有的毒素，与常见的有机或无机分子具有惰性，但在足够的浓度下，使用细胞铁几乎可以杀死接触到的任何类型的细胞产生高活性的氧化物种(芬顿反应)。染色体DNA是 HP中毒的主要细胞靶点，尽管致命的染色体损伤的本质是仍然未知。更令人困惑的是，惠普被证明是一个令人惊讶的选择武器，因为杀戮浓度是生理浓度的1000倍，虽然幽门螺杆菌在特定细胞隔间的积累是有问题的，因为它的小尺寸和不带电荷的性质有利于通过膜扩散。然而，我们的免疫力细胞不知何故利用这些低得多的幽门螺杆菌浓度来有效地杀死入侵的微生物，不清楚的机制。值得注意的是，幽门螺杆菌的毒性与其他简单分子协同作用，如一氧化氮(NO)或氰化物(CN)。我们假设我们的免疫细胞使用不同的 HP浓度不足以通过积累增强剂分子来杀灭细菌(用于例如，否)在不累积高[HP]的隔室中。然而，增强幽门螺杆菌毒性背后的代谢机制，被认为是提高细胞内游离铁，与最新的结果不一致，而机理是不可修复的染色体受损的情况大多仍不清楚。我们最近对HP+CN共毒性的研究发现了这一现象的新方面，比如从细胞内仓库中重新招募铁直接导致DNA，或灾难性的染色体断裂，这是细胞的责任杀戮。我们建议研究HP+NO的联合毒性，具体有三个目标：1)这种毒性的性质协同毒性与NO作用靶点；2)DNA作用机制灾难性的染色体碎裂；3)饥饿休克是幽门螺杆菌的代谢增强剂毒性。我们的方法与以前工作的主要不同之处在于强调 DNA和染色体损伤，关于显著扩大的遗传范围和测试增强芬顿的具体方法。我们在这个项目中的长期目标是了解一方面，灾难性的染色体断裂背后的机制，以及那些负责增强幽门螺杆菌的毒性。