The Impacts of NR5A2 Pharmacologic Agonism on Pancreas Development and Disease

项目摘要/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 住院的胃肠道原因，胰腺癌仍然是最致命的癌症之一 今天。胰腺疾病一直被认为与肥胖有关，但其机制仍然知之甚少。这个 这项工作的广泛目标是描述与全基因组关联有关的基因 胰腺癌的研究，以阐明发病机制和寻找新的治疗方法 胰腺疾病急需的策略。核受体5A2(NR5A2)就是这样一个基因 与胰腺癌和肥胖症有关，但其致病机制和翻译潜力 都是未知的。我们已经利用斑马鱼模型系统来使用上下文来询问新的路径 胰腺发育和疾病。在K08支持的工作中，使用功能丧失的遗传和 在斑马鱼的药理学方法中，我们之前已经证明NR5A2是正常的 前体内皮细胞分化为成熟的胰腺外分泌腺泡细胞。我们还有 发现NR5A2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，NR5A2不仅是建立的必要的，而且也是 维持腺泡细胞的命运，而NR5A2的缺失可能通过破坏腺泡细胞的身份而促进癌症的形成。 在这些观察的基础上，我们将在这里对斑马鱼进行临床前研究，以调查 假设NR5A2药物激动剂可能对胰腺疾病有有益影响，特别是在 促进胰腺炎后腺泡细胞的恢复，减缓胰腺癌的进展。在目标1中， 我们将研究新近开发的NR5A2的药理激动剂RJW100在 斑马鱼与胰腺炎后腺泡细胞恢复和胰腺癌形成的关系。在目标2中， 我们将探讨肥胖对胰腺外分泌NR5A2活性的影响，并确定 激动剂RJW100可以减轻肥胖导致的胰腺癌风险增加。这些建议 研究将为NR5A2在胰腺中的功能提供关键的新见解，并将提供第一个体内实验 NR5A2作为胰腺治疗和预防策略的药理激动剂的检测 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.