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（由应用提供）：早期生命阶段暴露于环境污染物可能会导致异常的胰腺β细胞发育，这可能使人患有糖尿病。多种不同环境污染物共有的一种常见毒性模式是活性氧（ROS）和氧化应激的产生。 ROS和细胞氧化还原潜在在正常的胚胎发育和细胞信号传导中起着基本作用。污染物暴露引起的这些过程的扰动可以改变细胞脂肪的决策，从而导致功能或结构性改变，这些变化只会随后应力或年龄而变得明显。然而，关于胚胎如何应对氧化应激或毒性暴露对胰腺发育的影响，几乎没有任何了解。这项研究的长期目标是了解胚胎如何应对氧化应激，以及毒性暴露如何有助于发育。糖尿病的起源。斑马鱼（Danio Rerio）是一种良好的，广泛使用且功能强大的模型生物体，用于研究体内脊椎动物的胚胎发育。为了调查发育氧化还原微环境的变化如何在特定阶段影响毒性敏感性和胰腺β细胞，我们将为荧光氧化还原生物传感器，氧化还原成像和自动化的，透明的，转基因Zebrafish胚胎的延时显微镜，暴露于环境污染物上。该项目将重点关注以前在糖尿病病因（PCB，邻苯二甲酸酯和Teflon表面活性剂PFO）中实施的持久毒物的环境浓度。我们将研究最丰富的抗氧化剂防御，谷胱甘肽（GSH）和转录因子NRF2之间调节对氧化应激的反应之间的关系。我们的具体目的是：1）阐明胚胎发育过程中NRF2的GSH和污染物激活之间的关系并创建胚胎氧化还原图； 2）确定氧化物暴露历史如何影响NRF2激活和毒性敏感性，3）确定氧化应激，GSH和NRF2激活在变形胰腺β细胞发育中的作用，并确定胰腺机体发生的关键敏感窗口。这项研究将导致对早期生活暴露和氧化应激如何损害发育中的胰腺和诱发人类对糖尿病和潜在其他疾病的疾病的机械理解。这项工作还将阐明一个鲜为人知但至关重要的基本生物学过程 - 作用胚胎发育中的氧化还原环境 - 并确定缓解和转化毒理学的特定靶标。