Mechanisms of Hereditary Pancreatitis

摘要： 遗传性胰腺炎（HP）是一种常染色体显性遗传疾病， 胰腺炎（AP）最终发展为慢性胰腺炎（CP）。阳离子胰蛋白酶原基因（或 PRSS1）突变是HP最常见的原因。重要的是，HP患者具有极高的 患胰腺癌的风险高于其他形式的CP。不幸的是，发展有针对性的 由于我们对HP的认识存在差距， 这主要是由于从胰腺获得组织的实际困难 在疾病的早期阶段和缺乏动物模型，重演人类的形式， 这种疾病最近，我们通过表达一种常见的HP突变体， 人PRSS1（PRSS1R122 H）在小鼠中的表达水平与人HP中的表达水平相当。这种新模式 将为我们提供一个强大的工具，以实现我们的长期目标，了解启动事件的 HP和制定其预防和治疗的具体策略。在本提案中，我们将使用 独特的人源化胰腺炎模型，以检验我们的中心假设，即病因因素与 基因改变增加胰蛋白酶活性，通过细胞自主性细胞死亡引起胰腺炎 信号通路和非细胞自主炎症通路。我们将描述这些 HP模型中的信号通路，并通过药理学和遗传学研究它们的作用 接近。我们希望这些研究将大大提高我们的理解的具体作用， 细胞内的人胰蛋白酶原激活在HP的发病机制，并提供新的见解， 预防和治疗干预。重要的是，我们的新的临床相关模型将提供一个 这是开发和测试此类干预措施的有力工具。

Abstract: Hereditary pancreatitis (HP) is an autosomal-dominant disorder with recurrent episodes of acute pancreatitis (AP) that eventually develops into chronic pancreatitis (CP). Cationic trypsinogen gene (or PRSS1) mutations are the most common causes of HP. Importantly, HP patients have an extremely high risk of developing pancreatic cancer than other forms of CP. Unfortunately, the development of targeted preventive or therapeutic interventions for HP has been hampered by gaps in our understanding of its pathophysiology, which is mainly due to the practical difficulties in obtaining tissues from the pancreas during the early stages of the disease and the lack of animal models that recapitulate the human form of the disease. Recently we have developed a novel model of HP by expressing a common mutant of human PRSS1 (PRSS1R122H) in mice at a level equivalent to that found in human HP. This new model will provide us with a powerful tool to fulfill our long-term goal of understanding the initiating events of HP and developing specific strategies for its prevention and therapy. In this proposal, we will use our unique humanized pancreatitis model to test our central hypothesis that etiological factors interact with genetic changes to increase trypsin activity, which causes pancreatitis by cell-autonomous cell death signaling pathways and non-cell-autonomous inflammatory pathways. We will characterize these signaling pathways in the HP model and investigate their roles by both pharmacological and genetic approaches. We expect these studies will significantly improve our understanding of the specific role of intracellular human trypsinogen activation during the pathogenesis of HP and provide new insights for preventive and therapeutic interventions. Importantly, our novel clinically relevant model will provide a powerful tool for developing and testing such interventions.