Early Pathogenesis of Cystic Fibrosis Related Diabetes

囊性纤维化相关糖尿病的早期发病机制

基本信息

批准号：
9043453
负责人：
JOHN F ENGELHARDT
金额：
$ 1.36万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9043453
关键词：
10 year old 5 year old Adolescent Adult Affect Age Alleles Animal Model Anti-Inflammatory Agents Anti-inflammatory Appearance Arginine Biological Assay Biological Markers Birth Blood Caucasians Cell physiology Cells Child Chloride Channels Clinical Clinical Research Comorbidity Complication Coupled Cyclooxygenase Inhibitors Cystic Fibrosis Data Defect Development Diabetes Mellitus Disease Dose Doxycycline Ductal Epithelial Cell Early Diagnosis Early Intervention Early treatment Endocrine Euglycemic Clamping Event Exocrine pancreas Family suidae Ferrets Functional disorder Gallbladder Glucose Glucose Clamp Glucose Intolerance Goals Health Hepatic Hereditary Disease Hormonal Hormones Human Hyperglycemia Hypoglycemia Ibuprofen Image Impairment In Vitro Incidence Inflammation Inflammation Mediators Inflammatory Insulin Interleukin-6 Intestines Islet Cell Islets of Langerhans Lead Life Liver Lung Mediating Messenger RNA Methods MicroRNAs Modeling Monoclonal Antibody R24 Morbidity - disease rate Neonatal Newborn Infant Nutritional OGTT Organ PET/CT scan Pancreas Pathogenesis Pathology Pathway interactions Peripheral Phase Physiology Play Population Prevention Process Recovery Regulation Research Respiratory physiology Role Salicylic Acids Secondary to Testing Toddler Work age related autocrine cell type children with cystic fibrosis clinical Diagnosis clinical care cohort cystic fibrosis patients defined contribution diabetes risk early cystic fibrosis fluorodeoxyglucose glucose disposal glucose production glucose tolerance high risk hormone regulation impaired glucose tolerance improved in vivo insulin secretion insulin sensitivity islet mortality paracrine prevent single molecule small hairpin RNA stellate cell type I and type II diabetes vector

项目摘要

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 associated with increased morbidity and mortality. CFRD, which is pathophysiologically distinct from type 1 and type 2 diabetes, significantly worsens the nutritional and pulmonary health of CF patients. Glycemic abnormalities are common 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 developing diabetes within the next few years. Our studies in CF ferrets and children 3 months to 5 years of age suggest that the underpinnings of CFRD occur very early in life. Of 12 CF subjects who were 1-5 years of age and have at least one ?F508 allele, 42% demonstrated abnormal glucose tolerance. This high incidence of abnormal glucose tolerance in young CF children as compared to slightly older children (13% at 6-10 years of age) is consistent with our discovery that in CF ferrets glucose intolerance develops in phases (with intervening periods of temporary recovery) that are associated with changes in the regulation of insular axis hormones and fibrotic remodeling of the pancreas. A major goal of this R24 is to identify the early pathophysiologic events involved in CF pancreas remodeling and the development of CFRD. The observed disturbances in insular and entero-insular axis hormones in young CF children are consistent with the hypothesis that both positive and negative adaptive changes influence insulin regulation, and potentially insulin action. Similar age-dependent alterations occur in CF ferrets and will enable us to dissect the mechanisms that underlie these processes. Studies in isolated human, ferret, and pig islets have demonstrated that CFTR impacts glucose-stimulated insulin secretion by islets through its activity in either endocrine cells or islet-associated ductal cells. The propose research will identify pancreas-intrinsic and -extrinsic events that alter insulin secretion and glycemic status in CF, with a focus on defining (i) the islet-intrinsic mechanisms that control CFTR-dependent insulin secretion in vitro and in vivo, (ii) the pancreas-extrinsic mechanisms that lead to abnormal insulin secretion and altered glucose physiology in CF, and (iii) the extent to which endocrine pancreas remodeling contributes to subsequent abnormalities in insulin secretion, and whether amelioration of the primary wave of pancreas inflammation in CF can prevent maladaptive islet remodeling. These studies are expected to identify early blood biomarkers of CFRD risk, as well as methods for early intervention.

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遗传疾病，是由囊性纤维化电导调节剂（CFTR）氯化物通道缺陷引起的。 CF是一种多器官疾病，影响肺，胰腺，肝脏，肠和胆囊。囊性纤维化相关糖尿病（CFRD）是CF的最常见并发症，与发病率和死亡率的增加有关。 CFRD在病理生理上与1型和2型糖尿病不同，它显着恶化了CF患者的营养和肺部健康。血糖异常在CF儿童中很常见，在6-10岁的CF儿童中，具有异常血糖状况的儿童在未来几年内患糖尿病的患者具有异常高的风险。我们在CF雪貂和儿童3个月至5岁的研究中的研究表明，CFRD的基础是生命早期。在1-5岁的12名CF受试者中，至少有1个f508等位基因，有42％的受试者表现出异常的葡萄糖耐受性。与稍大的儿童相比，年轻CF儿童的葡萄糖耐量异常（6-10岁）与我们的发现一致，我们发现，在CF雪貂中，葡萄糖不耐症在阶段（临时恢复的临时恢复）与Insular轴心激素和纤维纤维纤维的变化相关。该R24的主要目标是确定CF胰腺重塑和CFRD发展中涉及的早期病理生理事件。在年轻CF儿童中观察到的岛和肠道轴激素中观察到的干扰与假设阳性和阴性自适应变化都会影响胰岛素调节以及潜在的胰岛素作用的假设一致。在CF雪貂中发生了类似的年龄依赖性改变，将使我们能够剖析这些过程的基础。对分离的人，雪貂和猪胰岛进行的研究表明，CFTR通过胰岛在内分泌细胞或与胰岛相关的导管细胞中的活性影响葡萄糖刺激的胰岛素分泌。提出的研究将确定CF中胰岛素分泌和血糖状态的胰腺内膜和 - 超支事件，重点是定义（i）控制CFTR依赖性胰岛素的体外和体外和体内的胰岛胰岛素分泌的胰岛内部机制，这些机制的体外和胰腺源性机制，（ii）unin sectim in Instormist in Instormistion in Instormist in Instormist in Instormistion in Instormist in Instormistion Instormist in Instormistion in Instormistion in Instormist in Instormistion in Instormistion in Instormistim CF，以及（iii）内分泌胰腺重塑的程度有助于随后的胰岛素分泌异常，以及CF主要胰腺炎症的主要波动是否可以防止疾病疾病的胰岛重塑。预计这些研究将确定CFRD风险的早期血液生物标志物以及早期干预的方法。