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

项目摘要 急性胰腺炎（AP）在儿童中的发病率越来越高， 成年人。大多数儿童胰腺炎有一个单一的，轻微的，急性发作，解决 没有并发症。然而，一部分患有AP的儿童会反复发作， （定义为急性复发性胰腺炎或阿普）和慢性胰腺炎的一些进展 （CP）。小儿阿普和CP严重影响生活质量，并带来高昂的医疗费用。 很少有研究描述小儿阿普和CP的自然史， 确定其危险因素，并确定疾病进程的预测因素。作为INSPPIRE （国际儿童胰腺炎研究小组：寻找治愈方法），第一个多中心， 在儿科胰腺炎的多学科合作中，我们确定患有阿普的儿童 携带多种遗传风险变异，并迅速转变为CP，外分泌胰腺 免疫功能不全（EPI）和糖尿病（DM）。使儿童易患 早发性胰腺炎、快速进展为CP和外分泌过早丧失， 内分泌功能并不清楚。本申请的目的是描绘 通过对INSPPIRE-2队列进行仔细的前瞻性分析， 定义遗传修饰对疾病进程的影响，并确定其机制 参与胰源性糖尿病（T3 cDM）。总的假设是， 这些因素使儿童易患早发性CP、EPI和DM。我们的具体目标是：1） 表征儿科CP，确定疾病发作和进展的预测因子; 2）确定 遗传变异对疾病发生和进展的影响; 3）确定机制 儿童阿普和CP中潜在的糖调节紊乱。本项目将提供 深入了解小儿胰腺炎的病理生理学，研究遗传因素的影响， 研究糖尿病患者早期胰岛细胞功能障碍的机制。 小儿阿普和CP。我们的长期目标是开发诊断模式和预后因素 和创新的治疗方法。

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.