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和死亡的主要原因。胰腺炎是一种常见病 住院的胃肠道原因，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 这项工作的广泛目标是表征与全基因组关联相关的基因 胰腺癌研究，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 5A2 (NR5A2) 就是这样的基因之一 与胰腺癌和肥胖相关，但其致病机制和转化潜力 不知道。我们利用斑马鱼模型系统来利用上下文询问新路径 胰腺的发育和疾病。在 K08 支持的工作中，使用功能丧失遗传和 在斑马鱼的药理学方法中，我们之前已经证明 NR5A2 是正常 祖内胚层细胞分化为外分泌胰腺的成熟腺泡细胞。我们还有 发现 NR5A2 的核表达在高脂肪饮食、慢性胰腺炎和 胰腺癌。因此，一个新兴的模型是 NR5A2 不仅对于建立而且对于 维持腺泡细胞的命运，NR5A2 的缺失可能通过破坏腺泡细胞身份的稳定性来促进癌症的形成。 基于这些观察，我们将在斑马鱼中进行临床前研究，以调查 假设 NR5A2 药理激动可能对胰腺疾病有有益作用，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 RJW100（一种最近开发的 NR5A2 药理激动剂）在 斑马鱼胰腺炎后腺泡细胞恢复和胰腺癌形成的背景。在目标 2 中， 我们将探讨肥胖对外分泌胰腺中 NR5A2 活性的影响，并确定是否 激动剂 RJW100 可以减轻肥胖引起的胰腺癌风险增加。这些建议 研究将为 NR5A2 在胰腺中的功能提供重要的新见解，并将提供第一个体内 检查 NR5A2 药理激动作用作为胰腺的治疗和预防策略 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.