Regulation of Antioxidant Genes and Oxidative Stress

抗氧化基因和氧化应激的调节

• 批准号: 8107277
• 负责人: YOSHIAKI TSUJI
• 金额: $ 27.61万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107277
• 关键词: Aging; Alzheimer' s Disease; Antioxidants; Arsenic; Beryllium; Binding; Binding Proteins; Bioavailable; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Communities; Complex; Defense Mechanisms; Disease; Drug Metabolic Detoxication; Elements; Enhancers; Epithelial Cells; Equilibrium; Eukaryotic Cell; Exhibits; Ferritin; Gene Expression Regulation; Gene Silencing; Genes; Genetic Transcription; H ferritin; Health; Histone Deacetylase Inhibitor; Histone Deacetylation; Histone H3; Histones; Homeostasis; Human; In Vitro; Intestines; Iron; Iron Metabolism Disorders; Iron Overload; Lead; Light; MAP kinase kinase kinase 7; MAP3K7 gene; Malignant Neoplasms; Metabolic; Methylation; Methyltransferase; Molecular; Molecular Target; Nerve Degeneration; Neurodegenerative Disorders; Oxidants; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Play; Predisposition; Prevention; Production; Protein Kinase; Proteins; Reactive Oxygen Species; Recruitment Activity; Regulation; Regulatory Element; Regulatory Pathway; Repression; Research; Research Proposals; Role; Signal Pathway; Site; Testing; Tissues; Toxic effect; Transcription Repressor/Corepressor; Transcriptional Activation; Transcriptional Regulation; Translational Regulation; activating transcription factor 1; biological adaptation to stress; chromatin modification; chromatin remodeling; gene repression; genetic regulatory protein; histone acetyltransferase; human disease; in vivo; in vivo Model; innovation; insight; iron metabolism; keratinocyte; novel; research study; response; sensor; transcription factor

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. PUBLIC HEALTH RELEVANCE: Oxidative stress is implicated in various disease states including cancer, neurodegeneration (such as Parkinson's and Alzheimer diseases), and aging. Cellular antioxidant genes play crucial roles in prevention and alleviation of these diseases; however, the regulatory mechanism of cellular antioxidant genes remains incompletely understood. This proposal will provide new insight into antioxidant gene regulation that is crucial for our understanding of the pathogenesis of oxidative stress related disease. In particular, disorder of iron metabolism causing iron overload is potentially toxic to the cells due to the catalytic role of iron in formation of reactive oxygen species (ROS). Thus, the tight regulation of intracellular antioxidant genes and iron levels is crucial to maintaining normal cellular function and prevention of excess ROS production and oxidative stress. This research proposal will elucidate the molecular mechanism through which oxidant- and iron-induced toxicity is alleviated in cells and tissues by investigating the regulation of major iron storage protein, ferritin. This proposal will also investigate the common regulatory mechanism of ferritin and other antioxidant genes that are involved in cellular defense mechanisms against 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的组成部分；然而，过量的铁是有害的，因为它会催化活性氧（ROS）的形成。涉及铁缺乏或过量的铁稳态紊乱与各种人类健康问题有关，例如神经退行性疾病、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，它通过解毒和以无毒但生物可利用的形式储存细胞内过量的铁，在铁代谢调节中发挥着至关重要的作用。铁蛋白合成在转录和翻译水平上受到调节。铁对铁蛋白的翻译调节机制已得到广泛研究和充分表征。相比之下，在细胞需要限制铁可用性的条件下，铁蛋白基因的独立于铁的转录调节仍不完全清楚。特别是，人们对氧化应激条件下通过染色质重塑机制进行铁蛋白转录调控知之甚少。铁蛋白和一系列抗氧化基因的转录由保守的增强子（称为 ARE（抗氧化反应元件））调节。我们假设，我们最近在人铁蛋白 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质。拟议的实验将重点关注这些新的 ARE 相互作用蛋白的表征及其在与 ARE 调节的铁蛋白和抗氧化基因相邻的染色质修饰中的作用。这项研究的科学影响将是广泛而重大的，因为它不仅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了新的见解，而且还定义了负责抗氧化基因的新调节蛋白。氧化应激条件下的细胞抗氧化反应和铁稳态，与各种涉及铁和ROS的人类疾病相关。 公共健康相关性：氧化应激与多种疾病状态有关，包括癌症、神经退行性疾病（如帕金森病和阿尔茨海默病）和衰老。细胞抗氧化基因在预防和缓解这些疾病中发挥着至关重要的作用；然而，细胞抗氧化基因的调节机制仍不完全清楚。该提案将为抗氧化基因调控提供新的见解，这对于我们理解氧化应激相关疾病的发病机制至关重要。特别是，由于铁在活性氧（ROS）形成中的催化作用，导致铁过载的铁代谢紊乱对细胞具有潜在的毒性。因此，细胞内抗氧化基因和铁水平的严格调节对于维持正常的细胞功能和防止过量的ROS产生和氧化应激至关重要。该研究计划将通过研究主要铁储存蛋白铁蛋白的调节，阐明减轻细胞和组织中氧化剂和铁诱导的毒性的分子机制。该提案还将研究铁蛋白和其他参与细胞氧化应激防御机制的抗氧化基因的共同调节机制。