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

CFTR 敲除雪貂中囊性纤维化相关糖尿病的病因学

• 批准号: 8079159
• 负责人: Michael A. Apicella
• 金额: $ 48.54万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-20 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079159
• 关键词: Affect; Animal Model; Area; Bacteriology; Basic Science; Bile Acids; Caucasians; Caucasoid Race; Chloride Channels; Cholesterol; Chronic; Comparative Biology; Comparative Pathology; Cystic Fibrosis; Data; Defect; Diabetes Mellitus; Disease; Dissection; Endocrine; Etiology; Failure to Thrive; Family suidae; Ferrets; Functional disorder; Funding; Gallbladder; Genes; Glucose; Grant; Health; Hepatic; Homeostasis; Human; Inflammation; Institution; Instruction; Insulin; Intestinal Absorption; Intestines; Iowa; Knock-out; Life; Lipids; Liver; Lung; Lung diseases; Metabolic; Metabolic Diseases; Modeling; Monoclonal Antibody R24; Mus; Nutritional; Organ; Pancreas; Pancreatic Diseases; Patients; Predisposition; Principal Investigator; Process; Research; Research Personnel; Respiratory physiology; Testing; Tissues; Universities; Work; absorption; clinical assay development; clinical care; clinically relevant; comparative; cystic fibrosis patients; disease phenotype; glucose production; insulin sensitivity; member; type I and type II diabetes

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.

描述（由申请人提供）：囊性纤维化（CF）是高加索人中最常见的致死常染色体隐性疾病，是由囊性纤维化电导调节剂（CFTR）氯化物通道的缺陷引起的。在CF中受影响的临床相关组织包括肺，胰腺，肝脏，肠和胆囊。威胁生命的肺部疾病的进展可能会受到其他器官的疾病，新陈代谢和内分泌异常的影响。例如，CF患者的胰腺疾病导致10-15％的患者糖尿病，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）在临床上与1型和2型糖尿病不同，可以显着影响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症，但是胰岛素敏感性和肝葡萄糖产生也可以改变。 CFRD中的代谢疾病可能会因肠道吸收和慢性炎症的缺陷而复杂化，从而导致未能成长和肺功能快速下降。缺乏CFRD动物模型阻碍了该病病理生理学的基础研究。在爱荷华大学，我们在雪貂和猪中生成了两种新的CF型号。 CFTR-KNOCKOUT雪貂模型独有的是开发CFRD的倾向。猪和雪貂模型都保留了人CF患者中胰腺，肝，肠和肺部异常的胰腺，肝脏，肠和肺部异常，并且与CFTR缺陷型小鼠不同，其中主要受影响的器官是肠。拟议的R24种子赠款的目的是建立一个调查人员和跨学科关系的团队，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，并定义其与CFRD的关系。 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-相关器官疾病。这项赠款将为爱荷华大学五个团队成员和其他机构的四名团队成员之间的合作互动提供必要的资金。要求资金通过爱荷华大学的四名主要研究人员通过相关的分包合同分配，并将用于建立工作关系，初步数据和定义明确的R24研究计划。