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

• 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
• 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

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.

项目摘要/摘要 1 Kari Sant博士是圣地亚哥州立大学环境卫生助理教授。 2 Sant博士于2014年获得密歇根大学的毒理学博士学位，是博士后研究员 3 2015 - 18年度在马萨诸塞大学。作为发展毒理学家，桑特博士的公共卫生目标 4是为了阐明可能使儿童和青少年易于使用的环境，饮食和遗传因素 5个代谢功能障碍，并确定可以缓解这些异常病理的机制或 6防止。该过渡到独立环境健康研究（TIEHR）职业奖将提供 7桑特博士有机会增加培训和经验以满足：1）研究开发目标，包括 8改善赠款和开发新的时空分析以评估全面的代谢 9斑马鱼模型中的功能障碍和2）专业发展目标，包括磨练科学 10沟通，心理和项目管理技能，同时扩大我的专业网络以供未来 11合作研究。帕特里克·阿拉德（​​Patrick Allard）博士（加州大学洛杉矶分校的主要导师），大卫·沃尔兹（David David） 12（UC Riverside顾问）和Eunha Hoh博士（SDSU顾问）在整个职业发展奖中。 13拟议的研究计划，名为“阐明了PPAR信号在胰腺器官发生中的作用 14和少年代谢综合症”探讨了胚胎如何暴露于环境调节剂 15过氧化物体增生剂激活受体（PPAR）信号通路影响的结构和功能 斑马鱼模型中的整个胚胎，幼虫和少年发育中的16个胰腺。 PPAR信号是一个 17个营养感应机制，可调节养分吸收和利用等过程，以及更多 18特别是碳氢和脂质代谢和储存。 PPAR信号的环境调节器， 19包括全氟辛磺酸（PFO）已广泛与Metablic功能障碍相关，包括 20增加了糖尿病，肥胖，高血压和慢性肾脏疾病的风险。初步研究表明 21胚胎PFOS暴露会减少胰腺大小，并减少Langerhaans胰岛的面积 22人体的原发性葡萄糖调节细胞簇。在这里，我们将研究这些形态的持久性 23到少年时期，为毒物引起的营养摄取破坏和时空创建一个模型 24表征肥胖和代谢综合征的病理生理测量。初步数据表明 25胰腺器官发生过程中PPAR信号传导的调节改变了发育中的胰腺的结构， 26，并且在发育中暴露于PFO的斑马鱼更有可能表现出肝脂肪变性和 27增加了脂肪形成。该项目通过以下方式解决NIEHS目标：1）提供一种机制 28发育暴露于激活化合物直接影响早期营养，代谢和 29器官发生，2）确定这些暴露的持久病理和生化后果。