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死性遗传疾病，由囊性纤维化传导调节因子（CFTR）氯离子通道缺陷引起。CF是一种影响肺、胰腺、肝、肠和胆囊的多器官疾病。囊性纤维化相关糖尿病（CFRD）是CF最常见的重要并发症，并且众所周知与发病率和死亡率增加相关。CFRD在病理生理学上与1型和2型糖尿病不同，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，但疾病的基础可能发生在生命的早期。糖基化异常在患有CF的儿童中并不少见，并且具有异常血糖状态的13%的6-10岁CF儿童在未来几年内发展为糖尿病的风险非常高。因此，早期发现CF患者发生CFRD的风险是改善临床护理的关键。由于缺乏与人类CF相似的临床表现的动物模型，过去对CFRD早期病理生理学的理解一直受到阻碍。然而，爱荷华州大学已经开发了一种新的CFTR敲除雪貂动物模型，其发展了如在人类CF患者中所见的肺和胰腺疾病的临床过程，包括早期血糖异常和葡萄糖耐受不良的进展。该CF雪貂模型与CF婴儿和儿童的人类研究相结合，将由该R24用于阐明在CF人类和雪貂中观察到的内分泌胰腺功能障碍的病理生理机制。本申请将定义影响CF中Bet-cell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依赖性内在功能，（ii）CFTR依赖性外分泌胰腺对胰岛功能障碍的贡献，以及（iii）影响肠胰岛轴激素的肠中CFTR依赖性改变。该R24汇集了与胰岛素分泌相关的胰岛和β细胞离子通道生理学（芝加哥大学）、CF动物模型中的糖尿病和胰腺炎（爱荷华州大学）、CFRD患者的临床研究（明尼苏达大学）和细菌学（爱荷华州州立大学）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。虽然该应用程序的重点是早期疾病的病理生理学，它也有很大的潜力，确定血液生物标志物的早期诊断患者的风险CFRD。

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.