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

项目摘要/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.