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

项目总结/摘要 1 Kari Sant博士是圣地亚哥州立大学环境卫生终身助理教授。 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 2015-18年在马萨诸塞州大学3。作为一名发育毒理学家，桑特博士的公共健康目标 4是阐明环境，饮食和遗传因素，可能使儿童和青少年 5代谢功能障碍，并确定这些异常病理可以减轻或 6预防这个过渡到独立的环境健康研究（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）研究发展目标，包括 8.改进granectin并开发新的时空分析，以评估综合代谢 斑马鱼模型中的9个功能障碍，以及2）专业发展目标，包括磨练科学 10沟通，指导和项目管理技能，同时扩大我的专业网络，为未来 11篇合作研究Sant博士将由帕特里克阿拉德博士（主要导师，加州大学洛杉矶分校）、大卫沃尔兹博士 12（顾问，加州大学滨江），和博士Eunha Hoh（顾问，SDSU）在整个职业发展奖。 13.拟议的研究计划题为“阐明过氧化物酶体增殖物激活受体信号传导在胰腺器官发生中的作用”， 14和青少年代谢综合征”探讨了胚胎暴露于环境调节剂的影响， 15过氧化物酶体增殖物激活受体（PPAR）信号通路影响细胞的结构和功能， 图16在斑马鱼模型中的整个胚胎、幼虫和幼鱼发育中的胰腺。PPAR信号是一种 17种营养感应机制，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。过氧化物酶体增殖物激活受体信号的环境调节剂， 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 糖尿病、肥胖症、高血压和慢性肾病的风险增加。初步研究表明 21胚胎期接触全氟辛烷磺酸会缩小胰腺大小，并缩小胰岛面积， 22主要葡萄糖调节细胞团的身体。在这里，我们将研究这些形态的持久性 23进入少年时期，建立一个模型，毒物诱导的营养吸收中断，时空 24表征肥胖和代谢综合征的病理生理学指标。初步数据提示 在胰腺器官发生过程中对PPAR信号的调节改变了发育中胰腺的结构， 26，幼年斑马鱼在发育过程中接触全氟辛烷磺酸更有可能出现肝脂肪变性， 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， 28.发育过程中暴露于激活过氧化物酶体增殖体激活物的化合物直接影响早期营养、代谢和发育。 29器官发生，和2）确定这些暴露的持久病理和生化后果。

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.