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）：上个世纪生物学的主要成就之一是人类基因组测序。这带来了一场革命，使研究人员能够利用全新的工具获取有关细胞蛋白质、功能和人类健康问题的信息。快速进步的主要原因是信息丰富且可广泛访问的基因组和蛋白质数据库。然而，为了充分利用这些新的科学方法，仍然必须确定细胞和组织中存在的蛋白质、脂质、核酸以及许多瞬时和准稳定物质的绝对定量范围。此外，该信息必须与所有相关物种的反应动力学相结合，特别是代谢的瞬时物种，例如。活性氧和氮物种。因此，我们建议在这项拟议的研究中通过四个关键的具体目标来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以及所需的动力学和热力学信息，并将其与文献中的数据结合起来。在 SA 3 中，我们将在一组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）——这将包括抗氧化酶和蛋白质、小分子抗氧化剂或酶底物以及 ROS/RNS； b) 每种物质的一系列反应的动力学速率常数； c) 所有相关氧化还原对的热力学参数。在第四个 SA 中，我们将开发初始确定性或随机数学模型，利用这些参数来预测细胞和组织的生物状态和生物功能。这些模型将以集总参数（仅与时间相关）、一维或更高空间维度的形式提供，以反映当前特定动态系统的复杂性。在模型内，将提供模型可预测性的置信度的近似值。这些初始模型将重点关注线粒体附近的物种运输，将与 SA 3 中开发的数据库一起公开使用。随着实验验证的继续，社区可以扩展数据库和模型，以提高代表性并预测细胞和组织氧化还原环境的变化如何改变其基本生物学。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、最大限度地减少其使用以及临床方案开发以最大限度地取得成功的信息。 加州大学河滨分校部分 Victor G. Rodgers 博士已调至加州大学河滨分校。借助现代通信系统，我们定期召开会议来讨论我们正在进行的项目。借助 Skype，我们可以轻松、免费地召开会议。他平均每年会为该项目投入 1.0 个月的时间。他的工作重点是 Specific Aim 4，即开发用于模拟氧化还原体的模块化数学算法。他在动力学和传输过程建模方面拥有丰富的专业知识。他还将与 Srinivason 和 Buettner 教授合作设计数据库，以便与数学建模实现无缝接口。他还将监督 UCR 的一名 TBN 研究生，该研究生将负责建模系统的日常开发。项目叙述： 人们现在才认识到氧化还原生物化学是细胞基础生物学的核心。在这项工作中，我们建议将氧化还原生物化学核心物种的热力学、动力学和浓度信息收集到公开数据库中：抗氧化剂、还原剂、抗氧化酶和蛋白质，以及瞬态和准稳定自由基及相关氧化剂。我们将构建并提供可用的数学模型，以使用这些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，最大限度地减少动物的使用，并最大限度地成功开发人类健康问题的新疗法。