Elucidating the role of PPAR signaling in pancreatic organogenesis and juvenile metabolic syndrome

阐明 PPAR 信号在胰腺器官发生和青少年代谢综合征中的作用

基本信息

批准号：
10229374
负责人：
Karilyn Elizabeth Sant
金额：
$ 16.74万
依托单位：
SAN DIEGO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-06 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229374
关键词：
Acids Address Adolescence Adolescent Adult Affect Agonist Area Attenuated Award Beta Cell Biochemical Biological Availability Birth Birth Weight Cells Chemicals Child Childhood Chronic Kidney Failure Communication Data Development Diabetes Mellitus Diagnosis Doctor of Philosophy Dyslipidemias Embryo Embryology Embryonic Development Endocrine Endocrine Disruptors Environment Environmental Health Environmental Risk Factor Enzymes Epidemic Event Exhibits Exocrine pancreas Exposure to Fatty Liver Functional disorder Future Genetic Gluconeogenesis Glycolysis Goals Growth Heart Diseases Homeostasis Human Hyperglycemia Hypertension Impairment Incidence Insulin Investigation Islets of Langerhans K-Series Research Career Programs Kinetics Lead Life Lipids Macronutrients Nutrition Massachusetts Measures Mentors Metabolic Metabolic dysfunction Metabolic syndrome Metabolism Michigan Modeling Molecular Morphology National Institute of Environmental Health Sciences Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Nutrient Obesity Organogenesis Pancreas Pancreatic Hormones Pancreatic enzyme Pathologic Pathology Peroxisome Proliferator-Activated Receptors Pharmacologic Substance Pharmacology Phenotype Play Population Postdoctoral Fellow Predisposition Prevention Process Production Protein Isoforms Proteins Public Health Receptor Activation Receptor Signaling Research Risk Role Science Scientist Sense Organs Signal Pathway Signal Transduction Structure Testing Tissues Toxicology Training United States Universities Weight Zebrafish attenuation blood glucose regulation carbohydrate metabolism career career networking detection of nutrient deviant diabetes risk dietary early childhood experience fetal glucose metabolism health goals healthspan improved islet lipid biosynthesis lipid metabolism metabolic phenotype nutrition obesity in children obesity risk pancreas development postnatal prenatal prevent professor receptor-mediated signaling research and development response restoration skills spatiotemporal tenure track toxicant trend type I and type II diabetes uptake

项目摘要

PROJECT SUMMARY/ ABSTRACT 1 Dr. Kari Sant is a tenure-track Assistant Professor of Environmental Health at San Diego State University. 2 Dr. Sant received her PhD in toxicology from the University of Michigan in 2014, and was a Postdoctoral Fellow 3 at the University of Massachusetts from 2015-18. As a developmental toxicologist, Dr. Sant’s public health goal 4 is to elucidate environmental, dietary, and genetic factors that may predispose children and adolescents to 5 metabolic dysfunction, and to identify mechanisms by which these aberrant pathologies can be mitigated or 6 prevented. This Transition to Independent Environmental Health Research (TIEHR) Career Award will provide 7 Dr. Sant the opportunity to increase training and experience to meet: 1) research development goals, including 8 improving grantsmanship and developing new spatiotemporal analyses to assess comprehensive metabolic 9 dysfunction in the zebrafish model, and 2) professional development goals, including honing science 10 communication, mentoring, and project management skills while expanding my professional network for future 11 collaborative research. Dr. Sant will be advised by Dr. Patrick Allard (primary mentor, UCLA), Dr. David Volz 12 (advisor, UC Riverside), and Dr. Eunha Hoh (advisor, SDSU) throughout this career development award. 13 The proposed research plan entitled “Elucidating the role of PPAR signaling in pancreatic organogenesis 14 and juvenile metabolic syndrome” explores how embryonic exposures to environmental modulators of the 15 peroxisome proliferator-activated receptor (PPAR) signaling pathway impact the structure and function of the 16 pancreas throughout embryonic, larval, and juvenile development in the zebrafish model. PPAR signaling is a 17 nutrient-sensing mechanism which regulates processes such as nutritient uptake and utilization, and more 18 specifically carbohydrate and lipid metabolism and storage. Environmental modulators of PPAR signaling, 19 including perfluorooctanesulfonic acid (PFOS) have been widely associated with metablic dysfunction, including 20 increased risk for diabetes, obesity, hypertension, and chronic kidney disease. Preliminary studies have shown 21 that embryonic PFOS exposures decrease pancreas size, and reduce the area of the Islet of Langerhaans, the 22 primary glucoregulatory cell cluster of the body. Here, we will examine the persistence of these morphologies 23 into the juvenile period, create a model for toxicant-induced disruption of nutrient uptake, and spatiotemporally 24 characterize pathophysiological measures of obesity and metabolic syndrome. Preliminary data suggests that 25 modulation of PPAR signaling during pancreatic organogenesis alters the structure of the developing pancreas, 26 and that juvenile zebrafish exposed to PFOS developmentally are more likely to exhibit hepatic steatosis and 27 increased adipogenesis. This project addresses NIEHS goals by: 1) providing a mechanism by which 28 developmental exposures to PPAR- activating compounds directly affects early nutrition, metabolism, and 29 organogenesis, and 2) identify the lasting pathologic and biochemical consequences of these exposures.

项目概要/摘要 1 Kari Sant 博士是圣地亚哥州立大学环境健康学终身教授助理教授。 2 Sant 博士于 2014 年获得密歇根大学毒理学博士学位，并担任博士后研究员 3 2015-18 年在马萨诸塞大学作为一名发育毒理学家，Sant 博士的公共卫生目标。 4 是阐明可能导致儿童和青少年易感的环境、饮食和遗传因素 5 代谢功能障碍，并确定可以减轻或缓解这些异常病理的机制 6 阻止了向独立环境健康研究 (TIEHR) 职业奖的过渡。 7 Sant 博士有机会增加培训和经验，以满足： 1) 研究发展目标，包括 8 改进资助方式并开发新的时空分析来评估综合代谢斑马鱼模型中的 9 个功能障碍，以及 2) 职业发展目标，包括珩磨科学 10 项沟通、指导和项目管理技能，同时扩展我未来的专业网络 11 Sant 博士将得到 Patrick Allard 博士（主要导师，加州大学洛杉矶分校）和 David Volz 博士的指导。 12（顾问，加州大学河滨分校）和 Eunha Hoh 博士（顾问，SDSU）在整个职业发展奖中。 13 拟议的研究计划题为“阐明 PPAR 信号在胰腺器官发生中的作用” 14 和青少年代谢综合征”探讨了胚胎如何暴露于环境调节剂 15 过氧化物酶体增殖物激活受体 (PPAR) 信号通路影响过氧化物酶体增殖物激活受体 (PPAR) 的结构和功能 16 斑马鱼模型中整个胚胎、幼体和幼体发育过程中的胰腺信号传导是一个过程。 17 营养感应机制，调节营养吸收和利用等过程 18 特别是碳水化合物和脂质代谢和储存的 PPAR 信号传导环境调节剂。包括全氟辛烷磺酸 (PFOS) 在内的 19 种物质与代谢功能障碍广泛相关，包括 20 初步研究表明，患糖尿病、肥胖、高血压和慢性肾病的风险增加。 21 胚胎时期的全氟辛烷磺酸暴露会减小胰腺的大小，并减少朗格汉斯岛的面积，即身体的 22 个初级葡萄糖调节细胞簇在这里，我们将检查这些形态的持久性。 23 进入青少年期，创建毒物引起的营养吸收破坏模型，并在时空上 24 表征肥胖和代谢综合征的病理生理学指标。 25 胰腺器官发生过程中 PPAR 信号传导的调节会改变发育中胰腺的结构， 26 并且发育过程中暴露于全氟辛烷磺酸的幼年斑马鱼更有可能表现出肝脂肪变性，并且 27 增加脂肪生成该项目通过以下方式实现 NIEHS 目标：1) 提供一种机制，通过该机制 28 发育时期接触 PPAR 激活化合物直接影响早期营养、代谢和发育 29 器官发生，2) 确定这些暴露的持久病理和生化后果。