Redox regulation of cellular information processing

细胞信息处理的氧化还原调节

• 批准号: 7848626
• 负责人: Melissa Lambeth Kemp
• 金额: $ 226.48万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848626
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Atherosclerosis; Biological Assay; Cell Line; Cells; Complex; Computer Simulation; Cues; Development; Environment; Goals; Hydrogen Peroxide; Immune; Immunology; Inflammation; Inflammatory; Investigation; Laboratories; Lead; Literature; Malignant Neoplasms; Medical Research; Metabolism; Methods; Modification; Normal Cell; Oxidation-Reduction; Pathology; Pharmaceutical Preparations; Phosphorylation; Proteins; Reactive Oxygen Species; Receptor Signaling; Regulation; Reporting; Research; Research Personnel; Rheumatoid Arthritis; Role; Series; Signal Transduction; Sulfhydryl Compounds; Systems Biology; Therapeutic; Time; abstracting; antioxidant therapy; attenuation; cell growth regulation; computational network modeling; design; experience; extracellular; information processing; innovation; predictive modeling; programs; public health relevance; receptor; research study; response; success

DESCRIPTION (Provided by the applicant) Abstract: Elevated concentrations of extracellular reactive oxygen species (ROS) are hallmarks of inflammation, and decades of medical research have focused on suppression of these molecules to treat pathologies as diverse as rheumatoid arthritis, cancer, and atherosclerosis with mixed results. More recently, researchers have discovered that these same molecules are produced during the course of normal signal transduction. In order to effectively treat inflammation, we must understand these distinct roles for reactive oxygen species. I propose an innovative research program that will elucidate the role of hydrogen peroxide, a key ROS, in normal cell signaling through computational models and laboratory experiments. This research will lead to a new, quantitative understanding of ROS and facilitate the development of effective antioxidant treatments for inflammation. This project will use three complementary approaches to evaluate the complex regulatory role of hydrogen peroxide on receptor-induced signaling. First, we will develop computational network models describing redox regulation of proteins in time-dependent manner. Secondly, we are designing new methods to detect oxidative changes on multiple proteins simultaneously. These assays will allow investigation of the relationships between phosphorylation of signal transduction molecules and reversible thiol modifications. Finally, we have created a series of cell lines in which key components of the redox network have been perturbed that demonstrate augmentation and attenuation of receptor signaling. These lines will be used to systematically investigate the efficiency of three receptor networks - a pro-inflammatory cue (TNF-a), anti-inflammatory cue (TGF-¿) and antigenic response (TCR) - under different oxidative environments. The results of these studies will provide the first computational modeling platform capable of interpreting incongruous literature reports of oxidative effects on cellular information processing. This project leverages my unique experience at the interface of immunology, systems biology, and metabolism to address a fundamental mechanism of cellular regulation critical for a large class of therapeutic drugs. Public Health Relevance: Elevated concentrations of extracellular reactive oxygen species are a hallmark of inflammation. Antioxidant therapies aim to suppress these molecules for treatment of pathologies as diverse as rheumatoid arthritis, cancer, and atherosclerosis with limited success. This project investigates the changes in signaling that are caused by reactive oxygen species in immune cells with the goal of generating predictive models useful for new antioxidant therapies.

描述（由申请人提供） 摘要：细胞外活性氧（ROS）浓度升高是炎症的标志，几十年的医学研究都集中在抑制这些分子来治疗各种病理，如类风湿性关节炎，癌症和动脉粥样硬化，结果好坏参半。最近，研究人员发现，这些相同的分子在正常的信号转导过程中产生。为了有效地治疗炎症，我们必须了解活性氧的这些不同作用。我提出了一个创新的研究计划，将阐明过氧化氢的作用，一个关键的活性氧，在正常的细胞信号通过计算模型和实验室实验。这项研究将导致对ROS的新的定量理解，并促进有效的抗氧化治疗炎症的发展。该项目将使用三种互补的方法来评估过氧化氢对受体诱导的信号传导的复杂调节作用。首先，我们将开发计算网络模型描述氧化还原调节蛋白质的时间依赖性的方式。其次，我们正在设计新的方法来同时检测多种蛋白质的氧化变化。这些试验将允许信号转导分子的磷酸化和可逆的巯基修饰之间的关系的调查。最后，我们已经创建了一系列细胞系，其中氧化还原网络的关键组件已被扰动，表现出受体信号的增强和衰减。这些细胞系将被用于系统地研究三种受体网络的效率-促炎因子（TNF-α），抗炎因子（TGF-β）和抗原反应（TCR）-在不同的氧化环境下。这些研究的结果将提供第一个计算建模平台，能够解释氧化对细胞信息处理的影响的不一致的文献报告。该项目利用我在免疫学，系统生物学和代谢界面的独特经验，以解决对一大类治疗药物至关重要的细胞调节的基本机制。 公共卫生相关性：细胞外活性氧浓度升高是炎症的标志。抗氧化剂疗法旨在抑制这些分子以治疗如类风湿性关节炎、癌症和动脉粥样硬化等多种病理，但成功有限。该项目研究了由免疫细胞中的活性氧引起的信号变化，目的是生成可用于新的抗氧化疗法的预测模型。