Early Pathogenesis of Cystic Fibrosis Related Diabetes

描述(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病，由囊性纤维化传导调节因子(CFTR)氯通道缺陷引起。慢性阻塞性肺疾病是一种影响肺、胰腺、肝、肠、胆的多脏器疾病。囊性纤维化相关糖尿病(CFRD)是CF最常见的重要并发症，众所周知与发病率和死亡率的增加有关。CFRD在病理生理学上有别于1型和2型糖尿病，对CF患者的营养和肺健康有显著影响。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儿童中并不少见，在6-10岁的CF儿童中，13%的儿童具有异常的血糖状态，在未来几年内发展为糖尿病的风险极高。因此，及早发现有发生CFRD风险的CF患者是改善临床护理的关键。过去，由于缺乏临床表现与人类CFRD相似的动物模型，对CFRD早期病理生理学的理解一直受到阻碍。然而，爱荷华大学已经开发出一种新的CFTR基因敲除雪貂动物模型，该模型可以发展出与人类CF患者一样的肺和胰腺疾病的临床过程，包括早期血糖异常和进展为葡萄糖耐量异常。这一CF雪貂模型，结合人类对CF婴儿和儿童的研究，将被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。这项应用将定义影响CF中Bet细胞胰岛素分泌的胰腺内源性和外源性因素，重点是(I)依赖CFTR的胰岛内的内在功能，(Ii)依赖CFTR的外分泌胰腺对胰岛功能障碍的贡献，以及(Iii)依赖CFTR的肠道中影响肠岛轴激素的变化。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(爱荷华大学)、CFRD患者的临床研究(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。虽然这项应用侧重于早期疾病的病理生理学，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巨大的潜力。

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.