INSPPIRE: A Longitudinal Cohort Study of Pediatric Chronic Pancreatitis to Predict Clinical Course and Identify Disease Modifiers

项目总结 急性胰腺炎(AP)在儿童中的发病率越来越高。 成年人也是如此。大多数患有胰腺炎的儿童只有一次轻微的急性发作即可治愈 没有并发症。然而，AP儿童中的一部分会出现反复发作 (定义为急性复发性胰腺炎或ARP)和慢性胰腺炎的一些进展 (CP)。儿科ARP和CP显著影响生活质量，并带来高昂的医疗费用。 很少有研究对儿童ARP和CP的自然病程进行表征，以 确定其危险因素，并确定病程的预测因素。作为INSPPIRE (儿童胰腺炎国际研究小组：寻找治疗方法)，第一个多中心， 在儿科胰腺炎的多学科合作中，我们确定患有ARP的儿童 存在多种遗传风险变异，并迅速转变为CP、胰腺外分泌 功能不全(EPI)和糖尿病(DM)。使儿童易患此病的风险因素 早发性胰腺炎，迅速进展为CP和过早丧失外分泌和 内分泌功能还不是很清楚。此应用程序的目标是描述 通过对INSPPIRE-2队列的仔细前瞻性分析，得出儿科CP的自然病史。 确定遗传修饰物对病程的影响并确定其机制 参与胰源性糖尿病(T3cDM)。总体假设是，基因 因素使儿童易患早发性CP、EPI和DM。我们的具体目标是：1) 确定儿童脑瘫的特征，确定疾病发生和进展的预测因素；2)确定 基因变异对疾病发生和发展的影响；3)确定机制 儿童ARP和CP潜在的血糖调节紊乱。该项目将提供 洞察儿童胰腺炎的病理生理，调查遗传因素的影响 胰腺癌早期胰岛细胞功能障碍的机制探讨 儿童ARP和CP。我们的长期目标是开发诊断模式、预后因素 以及儿童ARP和CP的创新治疗方法。

PROJECT SUMMARY Acute pancreatitis (AP) is increasingly recognized in children, with an incidence approaching that of adults. Most children with pancreatitis have a single, mild, acute episode that resolves without complications. However, a subset of children with AP develops recurrent episodes (defined as acute recurrent pancreatitis or ARP) and some progress to chronic pancreatitis (CP). Pediatric ARP and CP significantly impact quality of life and carry high healthcare costs. Few studies have been performed to characterize the natural history pediatric ARP and CP, to identify its risk factors and to determine predictors of disease course. As INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE), the first multicenter, multidisciplinary collaboration in pediatric pancreatitis, we determined that children with ARP harbor multiple genetic risk variants and rapidly transition to CP, exocrine pancreatic insufficiency (EPI) and diabetes mellitus (DM). The risk factors that predispose children to early onset pancreatitis, rapid progression to CP and premature loss of exocrine and endocrine function are not well-known. The objective of this application is to delineate the natural history of pediatric CP through careful prospective analysis of INSPPIRE-2 cohort, to define the impact of genetic modifiers on disease course and to determine the mechanisms involved in pancreatogenic diabetes mellitus (T3cDM). The overall hypothesis is that genetic factors predispose children to early onset CP, EPI, and DM. Our specific aims are: 1) Characterize pediatric CP, determine predictors of disease onset and progression; 2) Determine the impact of genetic variants on disease onset and progression; 3) Identify mechanisms underlying disturbed glucose regulation in pediatric ARP and CP. This project will provide insight into the pathophysiology of pediatric pancreatitis, investigate the impact of genetic variants on disease course and explore the mechanisms of early islet cell dysfunction in pediatric ARP and CP. Our long-term goal is to develop diagnostic modalities, prognostic factors and innovative treatment approaches for pediatric ARP and CP.