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：
10467508
负责人：
Alicia R Timme-Laragy
金额：
$ 48.86万
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 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467508
关键词：
Adolescent Age Age of Onset Anabolism Antioxidants B-Cell Development Beta Cell Biological Assay Biological Markers Biology Cell Culture Techniques Cell Death Cell Maturation Cell physiology Cells Characteristics Chemical Exposure Chemicals Clinical Complex Confocal Microscopy Cysteine Data Defect Development Diabetes Mellitus Disease Dose Elderly Embryo Embryonic Development Environment Environmental Exposure Exposure to Film Fructosamine Functional disorder Funding Future Glutathione Goals Guidelines Health Health Policy Human Hybrids Immunofluorescence Immunologic Impairment Individual Insulin Intervention Laboratories Lead Life Link Mediating Metabolic Metabolic Diseases Metabolic dysfunction Modeling Non-Insulin-Dependent Diabetes Mellitus Organogenesis Oxidation-Reduction Oxidative Stress Pancreas Pathologic Play Poly-fluoroalkyl substances Post-Translational Protein Processing Prediabetes syndrome Predisposition Production Proinsulin Proteomics Public Health Publications Publishing Reactive Oxygen Species Reporting Role Science Signal Pathway Signal Transduction Stress Structure of beta Cell of islet Techniques Testing Time Tissues Toxic effect Toxicant exposure Transcriptional Activation Transgenic Organisms Translating Uncertainty Variant Work Youth Zebrafish aqueous base blastomere structure chemical genetics developmental toxicology disorder risk disulfide bond endocrine pancreas development epidemiology study ethnic minority genetic approach in vivo islet malformation mutant novel oxidation persistent organic pollutants prevent receptor binding resilience response single-cell RNA sequencing stressor toxicant transcription factor

项目摘要

Abstract Early life stage exposures to toxicants can result in islet malformations, which may predispose individuals to diabetes. The glutathione redox microenvironment plays fundamental roles in embryonic development and cell signaling, perturbation of which can result in functional or structural alterations that only become apparent with subsequent stress or age. Surprisingly little is known about how embryos respond to oxidative stress, or the impact of toxicant exposures on pancreatic β-cell development. This project takes a multi-level approach using state-of-the-art techniques to elucidate the complex pathophysiological mechanisms by which exposures to Per-and-polyfluoroalkyl substances (PFAS) that cause oxidative stress derail islet development, and the consequences for β-cell function. We test the central hypothesis that deviations from the GSH redox microenvironment and aberrant activation of the transcription factor Nrf2- at the wrong place and the wrong time- impair β-cell development and function. There are three overarching goals of this project: 1) to deepen our understanding of the role of Nrf2 activation in embryonic β-cells and islet development; 2) ascertain the impact of PFAS on insulin biosynthesis; and 3) identify β-cell fragility and bioindicators of later-life metabolic impacts that can be translated to human health. We will use transgenic zebrafish, confocal microscopy and immunofluorescence, redox proteomics and insulin misfolding assays, and cultured β-cells to investigate exposures to two common PFAS (PFOS, PFHxS), and a legacy aqueous film-forming foam (AFFF). This work will have a sustained and powerful impact on the fields of developmental toxicology, redox biology, and the developmental origins of health and disease and provides critical advances towards developing science-based PFAS guidelines, targets for clinical interventions, and public health policies.

抽象的生命早期阶段接触有毒物质可能导致胰岛畸形，这可能使个体容易出现谷胱甘肽氧化还原微环境在胚胎发育和细胞中发挥着重要作用。信号传导，其扰动可能导致功能或结构改变，只有在以下情况下才会变得明显令人惊讶的是，人们对胚胎如何应对氧化应激或氧化应激知之甚少。该项目采用多层次方法来研究有毒物质暴露对胰腺 β 细胞发育的影响。最先进的技术来阐明暴露于环境中的复杂病理生理机制导致氧化应激破坏胰岛发育的全氟烷基物质 (PFAS) 我们测试了 GSH 氧化还原偏差的中心假设。微环境和转录因子 Nrf2- 在错误的位置和错误的异常激活该项目有三个总体目标：1）深化。我们对 Nrf2 激活在胚胎 β 细胞和胰岛发育中的作用的理解；2) 确定 PFAS 对胰岛素生物合成的影响；3) 确定 β 细胞脆弱性和晚年代谢的生物指标我们将使用转基因斑马鱼、共聚焦显微镜和免疫荧光、氧化还原蛋白质组学和胰岛素错误折叠测定以及培养的 β 细胞进行研究这项工作暴露于两种常见的 PFAS（PFOS、PFHxS）和传统的水成膜泡沫 (AFFF)。将对发育毒理学、氧化还原生物学等领域产生持续而强大的影响健康和疾病的发展起源，并为发展基于科学的 PFAS 指南、临床干预目标和公共卫生政策。