The Impacts of NR5A2 Pharmacologic Agonism on Pancreas Development and Disease

项目概要/摘要 胰腺疾病是美国发病率和死亡率的主要原因。胰腺炎是一种常见的 消化道原因入院，胰腺癌仍然是最致命的癌症之一 今天胰腺疾病与肥胖有关，但其机制仍知之甚少。的 这项工作的一个广泛的目标是表征与全基因组关联有关的基因 胰腺癌的研究，以阐明致病机制并确定新的治疗方法 胰腺疾病急需的策略。核受体5A 2（NR 5A 2）就是这样一个基因 与胰腺癌和肥胖相关，但其致病机制和转化潜力 不知道。我们已经利用斑马鱼模型系统来询问新的途径， 胰腺的发育和疾病。在K 08支持的工作中， 在斑马鱼的药理学方法，我们以前已经表明，NR 5A 2是所需的正常 内胚层祖细胞分化为胰腺外分泌的成熟腺泡细胞。我们还 发现NR 5A 2的核表达在高脂饮食、慢性胰腺炎和 胰腺癌因此，一个新兴的模型是，NR 5A 2不仅是建立，而且是必要的， 维持腺泡细胞的命运，并且NR 5A 2的缺失可能通过破坏腺泡细胞身份而促进癌症形成。 基于这些观察结果，我们将在斑马鱼中进行临床前研究，以调查 假设NR 5A 2药理学激动作用可能对胰腺疾病，特别是 增强胰腺炎后腺泡细胞的恢复并减缓胰腺癌的进展。在目标1中， 我们将研究最近开发的NR 5A 2药理学激动剂RJW 100在 胰腺炎和胰腺癌形成后腺泡细胞恢复的斑马鱼背景。在目标2中， 我们将探讨肥胖对胰腺外分泌NR 5A 2活性的影响，并确定肥胖是否会影响胰腺外分泌NR 5A 2活性。 激动剂RJW 100可以减轻肥胖引起的胰腺癌风险增加。这些拟议 这些研究将为NR 5A 2在胰腺中的功能提供关键的新见解，并将提供第一个体内研究。 作为胰腺中治疗和预防策略的NR 5A 2药理学激动作用的检查 疾病

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.