Developmental toxicants and congenital pancreas malformations

发育毒物和先天性胰腺畸形

基本信息

批准号：
10317634
负责人：
Alicia R Timme-Laragy
金额：
$ 19.11万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-10 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317634
关键词：
Acinar Cell Acridine Orange Age Animal Model Antibodies Antioxidants Apoptosis Apoptotic Autopsy Biosensor Bromodeoxyuridine CRISPR/Cas technology Cell Proliferation Cell physiology Cells Data Deformity Development Developmental Toxicant Disease Elderly Embryo Embryonic Development Endocrine Enzymes Event Exocrine pancreas Exposure to Failure Fishes Fluorescence Microscopy Generations Genetic Genetic Polymorphism Glutathione Glutathione Disulfide Goals Grant Growth Health Human Immunohistochemistry Impairment Incidence Individual Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knock-in Label Lead Life Lipids Measurement Measures Metabolic Metabolic Diseases Metabolic dysfunction Modeling Molecular Morphogenesis Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Oxidation-Reduction Oxidative Stress Pancreas Pancreatic enzyme Pancreatitis Patients Phenotype Physiologic pulse Play Population Process Publishing Reactive Oxygen Species Research Role Signal Pathway Signal Transduction Stress Structure Sulfonic Acids System Tail of pancreas Testing Therapeutic Intervention Time Toxic effect Toxicant exposure Transgenic Organisms Work Xenobiotics Zebrafish blastomere structure cell motility early life exposure fetal functional outcomes in vivo islet malformation migration pancreas development perfluorooctane small molecule tert-Butylhydroperoxide toxicant

项目摘要

Project Summary Early life stage exposures to xenobiotics can result in aberrant pancreatic development, which may predispose an individual to pancreatitis and metabolic dysfunction. A common mode of toxicity shared by numerous compounds is the generation of reactive oxygen species (ROS) and redox stress. ROS and cellular redox potential play fundamental roles in normal embryonic development and cell signaling. Perturbation of these processes resulting from xenobiotic 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 redox stress, or the impact of xenobiotic exposures on pancreas development. Congenital pancreas malformations in humans are estimated to occur in approximately ten percent of the population and are associated with obesity, pancreatitis, Type 1 and Type 2 diabetes mellitus. The causes of these malformations are not well understood, and cannot be fully explained by genetic polymorphisms, suggesting a strong exogenous component. We have found that early life exposures to PFAS compounds and pro-oxidants results in a short exocrine pancreas. This grant takes a systems-level approach in transgenic zebrafish (Danio rerio) embryos to investigate a potential mechanism of oxidative stress in this deformity, and seeks to establish the functional outcomes of the truncated exocrine pancreas phenotype. Zebrafish are a well- established, widely used, and powerful model organism for studying vertebrate embryonic development in vivo. This work will facilitate advancement of a mechanistic understanding of how early-life xenobiotic exposures and redox stress can damage the developing pancreas and predispose humans to metabolic diseases.

项目摘要早期生命阶段暴露于异生元可能会导致异常胰腺发育，这可能倾向于胰腺炎和代谢功能障碍。一种共同的毒性模式许多化合物是活性氧（ROS）和氧化还原应激的产生。 ROS和细胞氧化还原潜在的发挥作用在正常的胚胎发育和细胞信号传导中。扰动因异生物暴露而产生的这些过程可以改变细胞命运的决策，从而导致功能或结构性改变只会随后的压力或年龄而显而易见。但是，令人惊讶的是知道胚胎如何应对氧化还原胁迫或异种暴露对胰腺的影响发展。据估计，人类的先天性胰腺畸形估计发生在大约百分之十中种群，与肥胖，胰腺炎，1型和2型糖尿病有关。原因这些畸形尚未得到充分理解，不能用遗传多态性来完全解释提示强大的外源成分。我们发现，早期的生命暴露于PFAS化合物和促氧化剂导致外分泌胰腺短。该赠款采用转基因的系统级方法斑马鱼（Danio rerio）胚胎研究这种畸形中氧化应激的潜在机制，并且寻求建立截短的外分泌胰腺表型的功能结果。斑马鱼是一个很好的建立，广泛使用且强大的模型生物体用于研究体内脊椎动物胚胎发育。这项工作将有助于发展对早期生命植物生物暴露方式的机械理解氧化还原压力会损害发育中的胰腺和人类对代谢性疾病的偏爱。