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）：铁是与各种细胞功能有关的重要细胞蛋白组成的组成部分。但是，过量铁是有害的，因为它催化了活性氧（ROS）的形成。涉及铁缺乏或超负荷的铁稳态障碍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蛋白，它通过以无毒但可生物可利用的形式排毒和储存细胞内过量铁在调节铁代谢中起着至关重要的作用。铁蛋白合成在转录和翻译水平均受调节。铁蛋白的翻译调节机制已通过经过广泛的研究和充分的特征。相反，在细胞需要限制铁的可用性的条件下，铁蛋白基因的铁不依赖性转录调节仍然不完全理解。特别是，对于在氧化应激条件下通过染色质重塑机制进行铁蛋白转录调节知之甚少。铁蛋白的转录和一系列抗氧化剂基因受保守增强子的调节，称为are（抗氧化剂响应元件）。我们假设我们最近在人铁蛋白上发现的染色质重塑和相关因素可以用作调节铁蛋白转录和铁稳态的关键蛋白质。提出的实验将集中于这些新的相互作用蛋白的表征及其在与受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要的，因为它不仅将通过对转录因子和染色质 - 复发因素的协调调节来对一组抗氧化基因的基本转录机制，而且还定义了负责在氧化剂和氧化液中相关的细胞抗氧化反应和铁稳态条件下的新调节蛋白。 公共卫生相关性：氧化应激与各种疾病状态有关，包括癌症，神经退行性（例如帕金森氏症和阿尔茨海默氏病）和衰老。细胞抗氧化剂基因在预防和减轻这些疾病中起着至关重要的作用。然而，细胞抗氧化基因的调节机制仍未完全理解。该建议将为我们对氧化应激相关疾病的发病机理至关重要的抗氧化基因调节提供新的见解。特别是，由于铁在活性氧（ROS）形成中的催化作用，导致铁超负荷的铁代谢障碍可能对细胞有毒。因此，细胞内抗氧化剂基因和铁水平的严格调节对于维持正常的细胞功能以及预防过量ROS产生和氧化应激至关重要。该研究建议将通过研究主要铁储存蛋白铁蛋白的调节来阐明氧化剂和铁诱导的毒性在细胞和组织中减轻的分子机制。该建议还将研究参与针对氧化应激的细胞防御机制的铁蛋白和其他抗氧化基因的常见调节机制。