Redox regulation of cellular information processing

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，数十年来的医学研究一直专注于抑制这些分子来治疗类风湿性关节炎、癌症和动脉粥样硬化等各种病理疾病，结果喜忧参半。最近，研究人员发现，在正常的信号转导过程中，也会产生同样的分子。为了有效地治疗炎症，我们必须了解这些不同的活性氧物种的作用。我提出了一个创新的研究计划，通过计算模型和实验室实验来阐明过氧化氢在正常细胞信号转导中的作用。这项研究将导致对ROS的新的、定量的理解，并有助于开发有效的抗炎抗氧化剂治疗方法。这个项目将使用三种互补的方法来评估过氧化氢在受体诱导的信号转导中的复杂调控作用。首先，我们将开发计算网络模型，以时间依赖的方式描述蛋白质的氧化还原调节。其次，我们正在设计新的方法来同时检测多个蛋白质的氧化变化。这些检测将有助于研究信号转导分子的磷酸化和可逆的硫醇修饰之间的关系。最后，我们创建了一系列细胞系，在这些细胞系中，氧化还原网络的关键成分受到干扰，表明受体信号的增强和减弱。这些线条将被用来系统地研究三种受体网络--促炎信号(TNF-α)、抗炎信号(TGF-β)和抗原反应(TCR)--在不同氧化环境下的效率。这些研究的结果将提供第一个能够解释氧化对细胞信息处理影响的不一致文献报告的计算建模平台。这个项目利用我在免疫学、系统生物学和新陈代谢方面的独特经验，解决对一大类治疗药物至关重要的细胞调节的基本机制。 与公共卫生相关：细胞外活性氧浓度升高是炎症的一个标志。抗氧化剂疗法旨在抑制这些分子，用于治疗各种病理疾病，如类风湿性关节炎、癌症和动脉粥样硬化，但收效甚微。该项目研究免疫细胞中活性氧引起的信号变化，目的是生成对新的抗氧化剂治疗有用的预测模型。

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.