Regulation of Antioxidant Genes and Oxidative Stress

描述（由申请人提供）：铁是一种必需元素，是参与多种细胞功能的重要细胞蛋白质的组成部分；然而，过量的铁是有害的，因为它催化活性氧（ROS）的形成。包括铁缺乏或超载在内的铁稳态紊乱与各种人类健康问题有关，如神经退行性疾病、癌症和衰老。因此，细胞内铁水平的微调对于维持正常的细胞功能和生理代谢平衡至关重要。铁蛋白是真核细胞中主要的铁储存蛋白，它通过解毒和以一种无毒但生物可利用的形式储存细胞内多余的铁，在铁代谢调节中起着至关重要的作用。铁蛋白的合成受转录和翻译两个水平的调控。铁对铁蛋白的翻译调控机制已经得到了广泛的研究和很好的表征。相比之下，在细胞需要限制铁可用性的情况下，铁蛋白基因的不依赖铁的转录调控仍然不完全清楚。特别是氧化应激条件下，铁蛋白通过染色质重塑的转录调控机制尚不清楚。铁蛋白和一系列抗氧化基因的转录是由一个保守的增强子调控的，这个增强子被称为are（抗氧化反应元件）。我们假设，我们最近在人类铁蛋白ARE上发现的染色质重塑和相关因子可以作为调节铁蛋白转录和铁稳态的关键蛋白。拟议的实验将集中在表征这些新的are相互作用蛋白及其在染色质修饰中的作用，邻近are调节的铁蛋白和抗氧化基因。这项研究的科学影响将是广泛而重要的，因为它不仅将通过转录因子和染色质重塑因子的协调调节为一组抗氧化基因的基本转录机制提供新的见解，而且还将定义与各种铁和ros相关的人类疾病相关的氧化应激条件下负责细胞抗氧化反应和铁稳态的新调控蛋白。

DESCRIPTION (provided by applicant): Iron is an essential element by serving as a constituent of vital cellular proteins involved in a variety of cellular functions; however, excess iron is detrimental because it catalyzes formation of reactive oxygen species (ROS). Disorder of iron homeostasis involving iron deficiency or overload is associated with various human health problems such as neurodegenerative disease, cancer and aging. Fine-tuning of intracellular iron levels is therefore essential for maintaining normal cellular function and physiological metabolic balance. Ferritin is the major iron-storage protein in eukaryotic cells and it plays a crucial role in regulation of iron metabolism by detoxifying and storing intracellular excess iron in a non-toxic but bioavailable form. Ferritin synthesis is regulated at both transcriptional and translational levels. Translational regulatory mechanism of ferritin by iron has been extensively studied and well characterized. In contrast, iron-independent transcriptional regulation of the ferritin gene under such conditions as cells need to limit iron availability remains incompletely understood. In particular, little is known about ferritin transcriptional regulation through chromatin remodeling mechanism under oxidative stress conditions. Transcription of ferritin and a battery of antioxidant genes are regulated by a conserved enhancer, termed the ARE (antioxidant responsive element). We hypothesize that chromatin remodeling and associated factors we have recently identified on the human ferritin ARE can serve as crucial proteins that regulate ferritin transcription and iron homeostasis. The proposed experiments will focus on characterization of these new ARE-interacting proteins and their roles in chromatin modifications adjacent to ARE-regulated ferritin and antioxidant genes. The scientific impact of this research will be broad and significant because it will not only provide new insight into the basic transcriptional mechanism of a group of antioxidant genes via coordinated regulation of transcription factors and chromatin-remodeling factors, but also define new regulatory proteins responsible for cellular antioxidant response and iron homeostasis under oxidative stress conditions that are associated with various iron- and ROS-involving human diseases.