Quantitative Redox Biology

定量氧化还原生物学

• 批准号: 7764666
• 负责人: Garry R Buettner
• 金额: $ 38.76万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-05 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764666
• 关键词: 3-Dimensional; Accounting; Address; Animal Experiments; Animals; Antioxidants; Biochemical Process; Biochemistry; Biological; Biological Process; Biology; California; Categories; Cell Culture Techniques; Cell model; Cell physiology; Cells; Cellular biology; Chemical Models; Chemicals; Clinical Protocols; Communication; Communities; Complex; Coupled; Couples; Crowding; Data; Databases; Dependency; Development; Diffusion; Dimensions; Environment; Enzymes; Experimental Designs; Foundations; Free Radicals; Gene Expression; Gene Proteins; Genome; Goals; Hand; Health; Heart; Human; Human Genome; Human Genome Project; In Vitro; Kinetics; Lipids; Literature; Location; Manuscripts; Measurement; Measures; Medical; Membrane; Metabolism; Mitochondria; Modeling; Nature; Nitrogen; Nucleic Acids; Osmotic Pressure; Oxidants; Oxidation-Reduction; Oxygen; Pathology; Pathway interactions; Peroxides; Physiological; Plant Roots; Process; Property; Protein Databases; Proteins; Publications; Reaction; Reducing Agents; Regulator Genes; Research; Research Personnel; Route; Science; Signal Transduction; Solutions; System; Thermodynamics; Time; Tissues; Transport Process; United States National Institutes of Health; Universities; Variant; Work; biological research; cost; design; enzyme substrate; flexibility; graduate student; improved; in vivo; insight; mathematical algorithm; mathematical model; meetings; model development; professor; programs; protein function; research study; small molecule; success; symposium; tool

DESCRIPTION (provided by applicant): One of the major accomplishments in biology of the last century has been the sequencing of the human genome. This has brought about a revolution, allowing researchers to gain information on cellular proteins, function, and human health issues with entirely new tools. The principal reasons for the whirlwind of advances are the information-rich and broadly accessible genome- and protein-databases. However, in order to fully utilize these new scientific approaches, it remains imperative that the absolute quantitation range of the proteins, lipids, nucleic acids, and the many transient and quasi-stable species present in cells and tissues are determined. In addition, this information must be coupled to the dynamics of the reactions of all relevant species, especially the transient species of metabolism, e.g. reactive oxygen and nitrogen species. Therefore, we propose to address these critical issues in redox biology in this proposed research through four critical Specific Aims. In SA 1 and 2 we will experimentally determine these concentration ranges and needed kinetic and thermodynamic information and couple this with data in the literature. In SA 3 we will initiate the assembly of three categories of information in a publicly available set of databases. These will include: a) absolute concentrations (copy number) of all relevant species that define the redox environment of a cell/tissue -- this will include antioxidant enzymes and proteins, small molecule antioxidants or enzyme substrates, and ROS/RNS; b) the kinetic rate constants for the array of reactions for each species; and c) the thermodynamic parameters for all relevant redox couples. In the fourth SA we will develop initial deterministic or stochastic mathematical models that utilize these parameters to predict the biological state and biological functioning of cells and tissues. These models will be available as lumped-parameter (time-dependent only), 1-D or higher spatial dimension forms to reflect the complexity of the specific dynamic system at hand. Within the model, approximations of the confidence in the models predictability will be provided. These initial models, which will focus on species transport near the mitochondrion, will be publicly available for use in conjunction with the databases developed in SA 3. As experimental verification continues, both the databases and models can be expanded upon by the community to improve representation and prediction of how changes in the redox environment of cells and tissue change their basic biology. The information in these databases and the mathematical models will provide information that can guide the design of animal experiments, minimizing their use, and the development of clinical protocols to maximize success. UCR PORTION Dr. Victor G. Rodgers has moved to the University of California at Riverside. With modern systems of communication we have regular meetings to discuss our ongoing projects. With Skype we are able to conference very easily at no cost. He will on average devote 1.0 months/yr of his effort to the project. His efforts will be focused on Specific Aim 4, the development of modular mathematical algorithms to model the redoxome. He has extensive expertise in modeling kinetic and transport processes. He will also work with Professors Srinivason and Buettner to design the data bases so that there is a seamless interface with the mathematical modeling. He will also oversee a TBN graduate student at UCR that will be responsible for the day-to-day development of the modeling systems.Project Narrative: It is just now being realized that redox biochemistry is at the heart of the basic biology of the cell. In this work we propose to gather into publicly available databases thermodynamic, kinetic, and concentration information on the species at the heart of this redox biochemistry: antioxidants, reducing agents, antioxidant enzymes and proteins, as well as the transient and quasi-stable free radicals and related oxidants. We will construct and make available mathematical models to use this information to understand how the redox environment connects to cell biology and issues of human health; the models can guide experimental design to minimize the use of animals and maximize success in developing new treatments for human health problems.

描述（由申请人提供）：上世纪生物学的主要成就之一是人类基因组的测序。这引发了一场革命，使研究人员能够使用全新的工具获得有关细胞蛋白，功能和人类健康问题的信息。进步旋风的主要原因是信息丰富且广泛获取的基因组和蛋白质数据库。但是，为了充分利用这些新的科学方法，必须确定细胞和组织中存在的许多短暂和准稳定物种的蛋白质，脂质，核酸的绝对定量范围。此外，这些信息必须与所有相关物种的反应的动力学耦合，尤其是代谢的瞬时物种，例如活性氧和氮种。因此，我们建议通过四个关键特定目标在这项拟议的研究中解决氧化还原生物学中的这些关键问题。在SA 1和2中，我们将通过实验确定这些浓度范围，需要动力学和热力学信息，并将其与文献中的数据相结合。在SA 3中，我们将在公开可用的数据库中启动三类信息的组装。这些将包括：a）定义细胞/组织的氧化还原环境的所有相关物种的绝对浓度（拷贝数） - 这将包括抗氧化剂酶和蛋白质，小分子抗氧化剂或酶底物以及ROS/RNS； b）每个物种的一系列反应的动力学速率常数； c）所有相关氧化还原夫妇的热力学参数。在第四个SA中，我们将开发最初的确定性或随机数学模型，以利用这些参数来预测细胞和组织的生物学状态和生物学功能。这些模型将作为集总参数（仅限时间依赖），1-D或更高的空间维度形式提供，以反映当前特定动态系统的复杂性。在模型中，将提供对模型可预测性的置信度的近似值。这些最初的模型将集中在线粒体附近的物种运输上，将与SA 3中开发的数据库共同使用。随着实验验证的继续，社区都可以扩展数据库和模型，以改善对细胞环境和组织中的变化的代表性和预测，并预测其基本生物学。这些数据库和数学模型中的信息将提供可以指导动物实验设计，最小化其使用以及开发临床方案以最大程度地提高成功的信息。 UCR部分 维克多·罗杰斯（Victor G. Rodgers）博士已移居加利福尼亚大学里弗赛德大学。通过现代的沟通系统，我们定期开会讨论我们正在进行的项目。使用Skype，我们可以免费轻松地进行会议。他平均将努力1.0个月/年。他的努力将集中在特定的目标4上，即模块化数学算法来建模氧化还原剂。他在建模动力学和运输过程方面拥有广泛的专业知识。他还将与Srinivason和Buettner教授合作设计数据库，以便与数学建模具有无缝接口。他还将监督UCR的TBN研究生，这将负责建模系统的日常开发。项目叙述： 刚刚意识到，氧化还原生物化学是细胞基本生物学的核心。在这项工作中，我们建议将有关此氧化还原生物化学核心物种的热力学，动力学和浓度信息聚集：抗氧化剂，还原剂，抗氧化剂，抗氧化剂酶和蛋白质，以及瞬态和准稳定的稳定的自由放射线和相关的氧化剂。我们将构建并提供数学模型，以使用此信息来了解氧化还原环境如何与细胞生物学和人类健康问题联系起来；这些模型可以指导实验设计，以最大程度地减少动物的使用，并最大程度地在为人类健康问题开发新的治疗方法中成功。