Reaction and Diffusion of Nitric Oxide in Biological Systems

一氧化氮在生物系统中的反应和扩散

• 批准号: 8017417
• 负责人: WILLIAM M DEEN
• 金额: $ 14.67万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8017417
• 关键词: Address; Antioxidants; Biological; Biological Markers; Cell Culture Techniques; Cell Line; Cells; Chemicals; Chronic; Colon; Computer Simulation; Computer Systems Development; Consumption; Development; Diffusion; Experimental Models; Exposure to; Gases; Genome; Immune system; In Vitro; Inflammation; Kinetics; Lipids; Malignant Neoplasms; Measurement; Measures; Mediator of activation protein; Methods; Microfluidics; Modeling; Mutation; Nitric Oxide; Nitrogen Dioxide; Nitrogen Oxides; Pathway interactions; Peroxonitrite; Physiological; Production; Reaction; Reactive Nitrogen Species; Solutions; System; Technology; Testing; Tissue Model; Tissues; Toxic effect; base; biological systems; carcinogenesis; chemical reaction; improved; in vitro testing; interest; melanoma; multicatalytic endopeptidase complex; nitrogen compounds; nitrogen trioxide; novel strategies; oxidation

Project 1. Sustained, high rates of production of nitric oxide (NO) by cells of the immune system, as occurs during chronic inflammation, has been strongly implicated in the development of various forms of cancer. Quantifying pathophysiological levels of NO is crucial for understanding the relationship between endogenous NO synthesis and carcinogenesis. Equally important is knowing the concentrations of reactive intermediates derived from NO, such as nitrogen dioxide (NO2), nitrous anhydride (N2O3), and peroxynitrite (ONOO-), because these species are likely mediators of damage to cells arising from NO. It is not feasible to directly measure the concentrations of any of these compounds under most conditions of interest, yet such information is needed to correlate levels of toxicity and rates of mutation in cell cultures with actual levels of exposure, and to extrapolate those findings to situations in the body. There is a need also for "delivery systems" to control the exposure of cells or biological solutions to specific reactive nitrogen compounds, so that mechanistic hypotheses can be tested in vitro. It is proposed to address these needs using a combination of delivery system development, tissue modeling, and kinetic analysis. Reactors employing gas- permeable tubing will be used to provide a new method for NO2 delivery at physiological levels and to improve methods for controlled exposure to N2O3. Microfluidics technology will be exploited to develop a novel approach for delivery of ONOO-. Computational models will be developed to predict NO concentrations in specific tissues, including inflamed colon and melanoma. Rates of NO synthesis, NO consumption, and O2 consumption will be measured in cell lines that are representative of these tissues, providing key inputs for the models. A kinetic analysis of NO oxidation pathways and of reactions involving antioxidants and cellular lipids will be used to predict concentrations of NO2, N2O3, and related radicals in defined solutions and in cells. These predictions will be tested by measuring rates of production of selected biomarkers in vitro.

项目1。一氧化氮：免疫系统细胞持续、高速率地产生一氧化氮(NO