The Impacts of NR5A2 Pharmacologic Agonism on Pancreas Development and Disease

项目摘要/摘要

Project Summary / Abstract Pancreas disease is a major cause of morbidity and mortality in the United States. Pancreatitis is a common gastrointestinal cause of hospital admission, and pancreatic cancer remains one of the most lethal cancers today. Pancreas disease has been linked to obesity, but mechanisms for this remain poorly understood. The broad objective of this work is to characterize genes that have been implicated by genome-wide association studies for pancreatic cancer in order to elucidate pathogenic mechanisms and identify new treatment strategies critically needed for pancreas disease. The Nuclear Receptor 5A2 (NR5A2) is one such gene associated with both pancreatic cancer and obesity, but its pathogenic mechanisms and translational potential are not known. We have harnessed the zebrafish model system to interrogate new pathways using the context of pancreas development and disease. In work supported by a K08 using loss-of-function genetic and pharmacologic approaches in the zebrafish, we have previously shown that NR5A2 is required for the normal differentiation of progenitor endodermal cells into mature acinar cells of the exocrine pancreas. We have also found that nuclear expression of NR5A2 is diminished in the context of a high-fat diet, chronic pancreatitis and pancreatic cancer. Thus, an emerging model is that NR5A2 is necessary not only to establish but also to maintain acinar cell fate, and loss of NR5A2 may promote cancer formation by destabilizing acinar cell identity. Building on these observations, here we will perform pre-clinical studies in zebrafish to investigate the hypothesis that NR5A2 pharmacologic agonism may have beneficial effects in pancreas disease, specifically in enhancing acinar cell recovery following pancreatitis and slowing progression to pancreatic cancer. In Aim 1, we will investigate the impacts of RJW100, a recently developed pharmacologic agonist of NR5A2, in the zebrafish contexts of acinar cell recovery following pancreatitis and in pancreatic cancer formation. In Aim 2, we will explore the impacts of obesity on NR5A2 activity in the exocrine pancreas, and determine whether the agonist RJW100 can mitigate the increased risk of pancreatic cancer conferred by obesity. These proposed studies will offer key novel insights into the function of NR5A2 in the pancreas, and will provide the first in vivo examination of NR5A2 pharmacologic agonism as a therapeutic and preventative strategy in pancreas disease.