Early Pathogenesis of Cystic Fibrosis Related Diabetes

描述（由申请人提供）：囊性纤维化（CF）是高加索人群中最常见的致命性遗传疾病，由囊性纤维化电导调节剂（CFTR）氯离子通道缺陷引起。CF是一种多器官疾病，可累及肺、胰腺、肝脏、肠和胆囊。囊性纤维化相关性糖尿病（CFRD）是CF最常见的显著并发症，众所周知，它与发病率和死亡率增加有关。CFRD在病理生理上不同于1型和2型糖尿病，它显著影响CF患者的营养和肺部健康。CFRD的发病率随着年龄的增长而增加，但这种疾病的基础可能发生在生命的早期。血糖异常在CF儿童中并不罕见，13%的6-10岁CF儿童血糖异常在未来几年内发展为糖尿病的风险非常高。因此，早期发现有发展为CFRD风险的CF患者对于改善临床护理至关重要。过去，由于缺乏与人类CF患者临床情况相似的动物模型，对CFRD早期病理生理学的理解受到阻碍。然而，爱荷华大学开发了一种新型的cftr敲除雪貂动物模型，该模型发展了人类CF患者肺部和胰腺疾病的临床病程，包括早期血糖异常和进展为葡萄糖耐受不良。本R24将利用该CF雪貂模型，结合CF婴儿和儿童的人类研究，阐明CF人和雪貂中观察到的内分泌胰腺功能障碍的病理生理机制。本应用程序将定义影响CF中β细胞胰岛素分泌的胰腺内源性和外源性因素，重点关注(i)胰岛内cftr依赖的内在功能，（ii） cftr依赖的胰腺外分泌对胰岛功能障碍的贡献，以及（iii）影响肠岛轴激素的肠道cftr依赖改变。本次R24汇集了胰岛和β细胞离子通道生理学与胰岛素分泌相关（芝加哥大学）、糖尿病和胰腺炎CF动物模型（爱荷华大学）、CFRD患者临床研究（明尼苏达大学）和细菌学（爱荷华州立大学）等领域的专家，以解决CFTR缺陷如何导致糖尿病发展的挑战性问题。尽管该应用侧重于疾病早期病理生理学，但它在识别血液生物标志物以早期诊断有CFRD风险的患者方面也具有很大的潜力。

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is the most common lethal genetic disorder in Caucasian populations and is caused by defects in the cystic fibrosis conductance regulator (CFTR) chloride channel. CF is a multi-organ disease affecting the lung, pancreas, liver, intestine, and gallbladder. Cystic fibrosis related diabetes (CFRD) is the most common significant complication of CF and is well known to be associated with increased morbidity and mortality. CFRD, which is pathophysiologically distinct from type 1 and type 2 diabetes, significantly impacts the nutritional and pulmonary health of CF patients. The incidence of CFRD increases with age, but the underpinnings of the disease likely occur early in life. Glycemic abnormalities are not uncommon in children with CF and the 13% of CF children 6-10 years of age that have abnormal glycemic status are at extraordinarily high risk for development of diabetes within the next few years. Thus, early detection of CF patients at risk for developing CFRD is critical to improved clinical care. Understanding the early pathophysiology of CFRD has been hampered in the past by lack of an animal model with a clinical picture similar to that in humans with CF. However, the University of Iowa has developed a novel CFTR-knockout ferret animal model that develops a clinical course of lung and pancreatic disease as seen in human CF patients, including early glycemic abnormalities and progression to glucose intolerance. This CF ferret model, in conjunction with human studies in CF infants and children, will be used by this R24 to clarify pathophysiologic mechanisms of endocrine pancreas dysfunction observed in both CF humans and ferret. This application will define both pancreatic-intrinsic and -extrinsic factors that influence insulin secretion by the Bet-cell in CF, with a focus on (i) CFTR-dependent intrinsic functions within the islet, (ii) CFTR-dependent exocrine pancreas contributions to islet dysfunction, and (iii) CFTR-dependent alterations in the intestine that influence enteroinsular axis hormones. This R24 has brought together experts in areas of islet and Beta-cell ion channel physiology pertaining to insulin secretion (University of Chicago), diabetes and pancreatitis in CF animal models (University of Iowa), clinical studies in CFRD patients (University of Minnesota), and bacteriology (Iowa State University), to tackle the challenging question of how defects in CFTR lead to the development of diabetes. Although the application focuses on early disease pathophysiology, it also has great potential for identifying blood biomarkers for early diagnosis of patients at risk for CFRD.