Paradoxical roles of Nrf2 activation in arsenic-induced beta-cell dysfunction

Nrf2 激活在砷诱导的 β 细胞功能障碍中的矛盾作用

• 批准号: 8274435
• 负责人: Jingbo Pi
• 金额: $ 43.67万
• 依托单位: THE HAMNER INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-12 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274435
• 关键词: 2-tert-butylhydroquinone; 3-nitrotyrosine; 4 hydroxynonenal; Acids; Adverse effects; Antioxidants; Apoptosis; Arsenates; Arsenic; Arsenicals; Arsenites; Backcrossings; Behavior; Beta Cell; Cacodylic Acid; California; Cell Survival; Cell physiology; Cells; Chronic; Collaborations; Complex; Computer Simulation; Contracts; DNA Damage; Development; Devices; Diabetes Mellitus; Dose; Drug Metabolic Detoxication; Effectiveness; Electrophoretic Mobility Shift Assay; Engineering; Environmental Risk Factor; Enzymes; Event; Exposure to; Failure; Feedback; Flow Cytometry; Functional disorder; Genes; Glucose; Glutathione Disulfide; Homeostasis; Human; Hydrogen Peroxide; Impairment; In Situ Nick-End Labeling; Incidence; Intervention; Knock-out; Letters; Lipids; Malondialdehyde; Measures; Mediating; Metabolic; Metabolic Diseases; Minor; Modeling; Mus; NF-E2-related factor 2; Nature; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Oxidants; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Pancreas; Pathogenesis; Peptide Signal Sequences; Physiological; Play; Prevention strategy; Preventive; Production; Proteins; Pyruvaldehyde; Reactive Oxygen Species; Regulation; Research Personnel; Role; Signal Transduction; Staining method; Stains; Stress; Sulforaphane; System; TNF gene; Testing; Therapeutic; Toxic effect; Universities; Viral; attenuation; biological adaptation to stress; blood glucose regulation; cell injury; cytokine; cytotoxic; cytotoxicity; design; dimethylarsinous acid; embryonic stem cell; exposed human population; genetic variant; glucose metabolism; glucose production; improved; insulin secretion; islet; man; monomethylarsonous acid; novel; novel therapeutics; overexpression; oxidative damage; prevent; response; stressor; transcription factor

DESCRIPTION (provided by applicant) There is growing evidence that chronic exposure of humans to inorganic arsenic, a potent environmental oxidative stressor, is associated with the incidence of Type 2 diabetes. In contrast to what has been a prevailing beneficial view of antioxidants in preventing pancreatic ?-cell dysfunction in diabetes, this project proposes that in response to arsenic exposure, transcription factor Nrf2-mediated adaptive induction of endogenous antioxidant enzymes plays paradoxical roles in ?-cell function. The investigators hypothesize that, on the one hand, Nrf2-mediated antioxidant response blunts glucose-triggered `ROS signaling' that plays an important role in glucose-stimulated insulin secretion (GSIS); on the other hand, the response protects ?-cells from oxidative damage and subsequent apoptosis/necrosis. The investigators propose three specific aims: (1) Test the hypothesis that induction of antioxidant enzymes in response to arsenic exposure and related oxidative stress impedes glucose-triggered `ROS signaling' and thus GSIS; (2) Test the hypothesis in silico that adaptive induction of antioxidant enzymes in response to chronic oxidative stress impedes `ROS signaling', and explore intervention approaches that can improve `ROS signaling'; (3) Test the hypothesis that Nrf2-mediated antioxidant response is critical for protecting ?-cells from oxidative damage and apoptosis/necrosis induced by arsenic and/or glucose toxicity. The integrated wet-lab and computational approaches will allow to: (1) understand how environmental arsenic exposure impairs ?-cell function; (2) characterize the quantitative nature of the effect of arsenic-induced oxidative stress on `ROS signaling' that is involved in GSIS; (3) distinguish the specific roles of Nrf2 and its target antioxidant enzymes in `ROS signaling' and ?-cell function; and (4) identify novel targets and approaches to modulate insulin secretion and protect ?-cells from oxidative damage. This project will investigate the pathogenic mechanisms of Type 2 Diabetes caused by environmental arsenic exposure. The results may enable new therapeutic managements and preventive strategies for arsenic or other environmental oxidative stress-associated diabetes.

描述（由申请人提供） 越来越多的证据表明，人类长期暴露于无机砷（一种有效的环境氧化应激源）与2型糖尿病的发生率有关。与糖尿病中抗氧化剂的主要有益观点相反，抗氧化剂的抗氧化剂在糖尿病中的功能障碍，该项目提出，响应砷暴露，转录因子NRF2介导的适应性介导的适应性诱导了内源性抗氧化酶的适应性诱导，从而扮演了抗氧化酶的疾病。研究人员假设，一方面，NRF2介导的抗氧化剂反应钝化了葡萄糖触发的“ ROS信号”，在葡萄糖刺激的胰岛素分泌（GSIS）中起着重要作用。另一方面，反应可以保护？ - 细胞免受氧化损伤和随后的细胞凋亡/坏死。研究人员提出了三个具体目的：（1）检验以下假设：抗氧化酶对砷暴露和相关氧化应激的响应诱导会阻碍葡萄糖触发的“ ROS信号传导”，从而阻碍GSIS； （2）检验硅中的假设，即响应慢性氧化应激会阻碍“ ROS信号传导”，并探索可以改善“ ROS信号传导”的干预方法； （3）检验以下假设：NRF2介导的抗氧化剂反应对于保护砷和/或葡萄糖毒性引起的氧化损伤和凋亡/坏死。集成的湿lab和计算方法将允许：（1）了解环境砷的暴露如何损害？-cell功能； （2）表征砷诱导的氧化应激对GSIS涉及的“ ROS信号”的作用的定量性质； （3）区分NRF2及其靶抗氧化酶在“ ROS信号”和？细胞函数中的特定作用； （4）确定新的靶标和方法来调节胰岛素分泌并保护？ - 细胞免受氧化损伤。该项目将研究由环境砷暴露引起的2型糖尿病的致病机制。该结果可能会为砷或其他环境氧化应激相关糖尿病提供新的治疗管理和预防策略。

项目成果

Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha.

• DOI: 10.1093/nar/gks409
• 发表时间: 2012-08
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
• 通讯作者: Bell DA

Cross-regulations among NRFs and KEAP1 and effects of their silencing on arsenic-induced antioxidant response and cytotoxicity in human keratinocytes.

NRF 和 KEAP1 之间的交叉调节及其沉默对砷诱导的人角质形成细胞抗氧化反应和细胞毒性的影响。

• DOI: 10.1289/ehp.1104580
• 发表时间: 2012-04
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Zhao R;Hou Y;Zhang Q;Woods CG;Xue P;Fu J;Yarborough K;Guan D;Andersen ME;Pi J
• 通讯作者: Pi J

Dose-dependent transitions in Nrf2-mediated adaptive response and related stress responses to hypochlorous acid in mouse macrophages.

• DOI: 10.1016/j.taap.2009.04.007
• 发表时间: 2009-07-01
• 期刊: Toxicology and applied pharmacology
• 影响因子: 3.8
• 作者: Woods CG;Fu J;Xue P;Hou Y;Pluta LJ;Yang L;Zhang Q;Thomas RS;Andersen ME;Pi J
• 通讯作者: Pi J

Regulatory role of KEAP1 and NRF2 in PPARγ expression and chemoresistance in human non-small-cell lung carcinoma cells.

• DOI: 10.1016/j.freeradbiomed.2012.05.041
• 发表时间: 2012-08-15
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Zhan, Lijuan;Zhang, Hao;Zhang, Qiang;Woods, Courtney G.;Chen, Yanyan;Xue, Peng;Dong, Jian;Tokar, Erik J.;Xu, Yuanyuan;Hou, Yongyong;Fu, Jingqi;Yarborough, Kathy;Wang, Aiping;Qu, Weidong;Waalkes, Michael P.;Andersen, Melvin E.;Pi, Jingbo
• 通讯作者: Pi, Jingbo

CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion.

• DOI: 10.1089/ars.2014.6017
• 发表时间: 2015-04
• 期刊: Antioxidants & redox signaling
• 影响因子: 6.6
• 作者: Hongzhi Zheng;Jingqi Fu;P. Xue;Rui Zhao;Jian Dong;Dianxin Liu;Masayuki Yamamoto;Qingchun Tong