Etiology of Cystic Fibrosis-Related Diabetes in a CFTR-knockout Ferret

描述（由申请方提供）：囊性纤维化（CF）是高加索人中最常见的致死性常染色体隐性遗传病，由囊性纤维化传导调节因子（CFTR）氯离子通道缺陷引起。CF中受影响的临床相关组织包括肺、胰腺、肝、肠和胆囊。危及生命的肺部疾病的进展可能会受到其他器官疾病的显著影响，通过代谢和内分泌异常，这些异常仅知之甚少。例如，CF患者中的胰腺疾病导致10-15%的患者患糖尿病，并且这些患者比其他CF患者更早死亡。囊性纤维化相关糖尿病（CFRD）在临床上不同于1型和2型糖尿病，并且可以显著影响CF患者的营养和肺部健康。CFRD很大程度上是由于胰岛素缺乏，但胰岛素敏感性和肝脏葡萄糖产生也可以改变。CFRD中的代谢性疾病可能因肠道吸收缺陷和慢性炎症而加重，导致无法茁壮成长和肺功能迅速下降。由于缺乏面板堆石坝动物模型，阻碍了对该病病理生理学的基础研究。在爱荷华州大学，我们已经在雪貂和猪中产生了两种新的CF模型。CFTR基因敲除雪貂模型的独特之处在于其具有发展CFRD的倾向。猪和雪貂CF模型都保留了在人类CF患者中观察到的胰腺、肝脏、肠道和肺部异常，并且与CFTR缺陷小鼠不同，CFTR缺陷小鼠的主要受影响器官是肠道。拟议的R24种子补助金的目的是建立一个研究人员和跨学科的关系，这将使我们能够表征CF雪貂中观察到的代谢和内分泌缺陷，并确定其与CFRD的关系。CF雪貂模型中疾病过程的解剖需要广泛领域的专业知识，包括：1）比较病理学，2）物种特异性临床测定开发，3）胆汁酸和胆固醇/脂质稳态，4）肠道的脂质吸收，5）葡萄糖和脂质稳态，6）比较细菌学，以及7）CFTR功能和CF相关器官疾病的比较生物学。这笔赠款将为发展爱荷华州大学的五名团队成员和其他机构的四名成员之间的协作互动提供必要的资金。资金要求通过相关分包合同分配给爱荷华州大学的四名主要研究者，并将用于建立工作关系、初步数据和明确的R24研究计划。

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is the most common lethal autosomal recessive disease in Caucasians and is caused by defects in the cystic fibrosis conductance regulator (CFTR) chloride channel. Clinically relevant tissues affected in CF include the lung, pancreas, liver, intestine, and gallbladder. The progression of life-threatening lung disease can be significantly impacted by disease in other organs, through metabolic and endocrine abnormalities that are only poorly understood. For example, pancreatic disease in CF patients leads to diabetes mellitus in 10-15% of patients and these patients die earlier than other CF patients. Cystic fibrosis- related diabetes (CFRD) is clinically distinct from type 1 and type 2 diabetes, and can significantly impact the nutritional and pulmonary health of CF patients. CFRD is largely due to insulin deficiency, but insulin sensitivity and hepatic glucose production can also be altered. Metabolic disease in CFRD can be compounded by defects in intestinal absorption and by chronic inflammation, leading to a failure to thrive and a rapid decline in lung function. A lack of animal models for CFRD has hampered basic research on the pathophysiology of this disease. At the University of Iowa, we have generated two new models of CF in the ferret and pig. Unique to the CFTR-knockout ferret model is a predisposition to developing CFRD. Both the pig and ferret CF models retain the pancreatic, liver, intestinal, and lung abnormalities seen in human CF patients, and differ from CFTR-deficient mice, in which the primary affected organ is the intestine. The purpose of the proposed R24 seeding grant is to build a team of investigators and interdisciplinary relationships that will enable us to characterize the metabolic and endocrine defects observed in CF ferrets and define its relationship to CFRD. Dissection of disease processes in the CF ferret model requires expertise in a wide range of areas including: 1) comparative pathology, 2) species-specific clinical assay development, 3) bile-acid and cholesterol/lipid homeostasis, 4) lipid absorption by the intestine, 5) glucose and lipid homeostasis, 6) comparative bacteriology, and 7) comparative biology of CFTR functions and CF- related organ disease. This grant would provide the funds necessary for developing collaborative interactions between five team members at the University of Iowa and four at other institutions. Funds are requested for distribution through four principal investigators at the University of Iowa, via associated subcontracts, and would be used to establish working relationships, preliminary data, and a well-defined R24 research plan.