Activation of Nrf2 during embryonic development: mechanisms and consequences

胚胎发育过程中 Nrf2 的激活：机制和后果

基本信息

批准号：
9924600
负责人：
Alicia R Timme-Laragy
金额：
$ 33.73万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2022-03-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924600
关键词：
Address Adult Affect Age Animal Model Antioxidants Attenuated B-Cell Development Beta Cell Biological Process Biosensor Buffers Cell Culture Techniques Cells Chemical Exposure Chemical-Induced Change Chemicals Chimeric Proteins Data Detection Development Diabetes Mellitus Disease Dose Dyes Elderly Embryo Embryonic Development Endocrine Disruptors Engineering Environment Environmental Pollution Etiology Exposure to Fishes Gene Expression Generations Germ Lines Glutathione Goals Growth Homeostasis Human Image Immunohistochemistry In Vitro Individual Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knowledge Life Maps Measurement Mediating Metabolic Microscopy Modeling Morphology Mosaicism Non-Insulin-Dependent Diabetes Mellitus Nuclear Organ Organism Organogenesis Oxidants Oxidation-Reduction Oxidative Stress Pancreas Play Polychlorinated Biphenyls Predisposition Process Reactive Oxygen Species Recording of previous events Recovery Recurrence Research Role Signal Pathway Signal Transduction Speed Stress Structure Structure of beta Cell of islet Teflon Testing Therapeutic Intervention Time Tissues Toxic effect Toxicant exposure Toxicology Transgenic Organisms Ubiquitination Work Zebrafish amplification detection blastomere structure deviant endocrine pancreas development gene induction in vivo islet migration mono-(2-ethylhexyl)phthalate oxidative damage pancreas development phthalates premature programs public health relevance response spatiotemporal surfactant time use tool toxicant transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Early life stage exposures to environmental contaminants can result in aberrant pancreatic β-cell development, which may predispose an individual to diabetes. A common mode of toxicity shared by numerous, diverse environmental contaminants is the generation of reactive oxygen species (ROS) and oxidative stress. ROS and cellular redox potential play fundamental roles in normal embryonic development and cell signaling. Perturbation of these processes resulting from contaminant exposure can alter cell fate decisions, resulting in functional or structural alterations that only become apparent with subsequent stress or age. However, surprisingly little is known about how embryos respond to oxidative stress, or the impact of toxicant exposures on pancreas development. The long-term goal of this research is to understand how embryos respond to oxidative stress, and how toxicant exposures contribute to the developmental origins of diabetes. The zebrafish (Danio rerio) is a well-established, widely used, and powerful model organism for studying vertebrate embryonic development in vivo. To investigate how changes in the developmental redox microenvironment affect toxicant sensitivity and pancreatic β-cells at specific stages, we will us a fluorescent redox biosensor, redox imaging, and automated, time-lapse microscopy of transparent, transgenic zebrafish embryos exposed to environmental contaminants. This project will focus on environmentally relevant concentrations of persistent toxicants previously implicated in the etiology of diabetes (PCBs, phthalates, and the Teflon surfactant PFOS). We will examine the relationship between the most abundant antioxidant defense, glutathione (GSH), and the transcription factor Nrf2, that regulates the response to oxidative stress. Our specific aims are: 1) elucidate the relationship between GSH and contaminant activation of Nrf2 during embryonic development and create an embryo redox map; 2) determine how an oxidant exposure history affects Nrf2 activation and toxicant sensitivity, 3) ascertain the roles of oxidative stress, GSH, and Nrf2 activation in deviant pancreatic β-cell development, and identify critical sensitive windows of pancreas organogenesis. This research will lead to a mechanistic understanding of how early life chemical exposures and oxidative stress may damage the developing pancreas and predispose humans to diabetes and potentially other diseases. This work will also elucidate a poorly understood, but critical fundamental biological process- the role of the redox environment in embryonic development- and identify specific targets for mitigation and translational toxicology.

描述（由申请人提供）：生命早期暴露于环境污染物可能导致胰腺β细胞发育异常，这可能使个体易患糖尿病。许多不同的环境污染物共有的一种常见毒性模式是活性氧的产生。 ROS 和氧化应激在正常胚胎发育和细胞信号传导中发挥着重要作用，污染物暴露导致的这些过程的扰动可以改变细胞命运的决定。然而，令人惊讶的是，人们对胚胎如何应对氧化应激或有毒物质暴露对胰腺发育的影响知之甚少。了解胚胎如何应对氧化应激，以及有毒物质暴露如何导致糖尿病的发育起源。斑马鱼（Danio rerio）是研究脊椎动物的成熟、广泛使用和强大的模型生物。为了研究发育氧化还原微环境的变化如何影响特定阶段的毒物敏感性和胰腺 β 细胞，我们将使用荧光氧化还原生物传感器、氧化还原成像和透明转基因斑马鱼胚胎的自动延时显微镜。该项目将重点关注先前与糖尿病病因有关的持久性毒物（多氯联苯、邻苯二甲酸盐和聚四氟乙烯）的环境相关浓度。我们将研究最丰富的抗氧化防御谷胱甘肽 (GSH) 与调节氧化应激反应的转录因子 Nrf2 之间的关系。我们的具体目标是：1) 阐明 GSH 与污染物活化之间的关系。胚胎发育过程中 Nrf2 的变化并创建胚胎氧化还原图 2) 确定氧化剂暴露史如何影响 Nrf2 激活和毒物敏感性；3)确定氧化应激、GSH 和 Nrf2 激活在异常胰腺 β 细胞发育中的作用，并确定胰腺器官发生的关键敏感窗口。这项研究将有助于从机制上了解生命早期的化学暴露和氧化应激如何损害发育中的细胞。这项工作还将阐明一个人们知之甚少但至关重要的基本生物过程——胰腺的作用。胚胎发育中氧化还原环境的研究，并确定缓解和转化毒理学的具体目标。