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：
10397094
负责人：
JOHN F ENGELHARDT
金额：
$ 147.99万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-30 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397094
关键词：
6 year old ATAC-seq Acinar Cell Adolescent Adult Affect Age Animal Model B-Lymphocytes Biology Birth Caucasians Cells Characteristics Child Chloride Channels Chromatin Complication Cystic Fibrosis Data Defect Development Developmental Biology Diabetes Mellitus Disease Dissection Duct (organ) structure Ductal Epithelial Cell Ductal Epithelium Endocrine Environmental Risk Factor Epigenetic Process Event Exocrine pancreas Ferrets Fibrocystic Disease of Pancreas Functional disorder Gallbladder Genetic Engineering Genetic Transcription Glucose Goals Hormones Human Hyperglycemia In Vitro Inflammatory Injury Institution Insulin-Dependent Diabetes Mellitus Internal Ribosome Entry Site Intestines Knowledge Life Link Liver Lung Maintenance Maps Mediating Modeling Morbidity - disease rate Mus Natural regeneration Neonatal Non-Insulin-Dependent Diabetes Mellitus Nutritional Onset of illness Outcome Pancreas Pancreatic Diseases Pancreatic Injury Pancreatic duct Pancreatitis Pathogenesis Pathway interactions Patients Pattern Pharmacology Phase Phenotype Physiology Population Prevention strategy Preventive treatment Process Property Recovery Reporter Reporting Research Resources Severities Source TGFB1 gene Testing Therapeutic Translating VX-770 Withdrawal age related base clinical care comorbidity cystic fibrosis patients cystic fibrosis related diabetes developmental disease endocrine pancreas development fetal genetic manipulation glycemic control in utero in vitro Model in vivo insulin secretion islet islet stem cells lung health mortality novel postnatal postnatal period progenitor programs pulmonary function stem cells tool transcriptome sequencing

项目摘要

1 Project Summary 2 Cystic Fibrosis (CF) is the most common lethal autosomal recessive disorder in Caucasian populations and is 3 caused by defects in the cystic fibrosis conductance regulator (CFTR) chloride channel. CF is a multi-organ 4 disease affecting the lung, pancreas, liver, intestine, and gallbladder. Cystic fibrosis related diabetes (CFRD) is 5 the most common severe complication of CF and is associated with increased morbidity and mortality. CFRD, 6 which is pathophysiologically distinct from type 1 and type 2 diabetes, significantly worsens the nutritional and 7 pulmonary health of CF patients. Our studies in CF ferrets and children 3 months to 6 years of age suggest that 8 the underpinnings of CFRD occur very early in life when acinar cells are lost and inflammatory/fibrotic remodeling 9 occurs. In CF ferrets, this exocrine-driven pancreatic remodeling leads to a glycemic crisis caused by b-cell loss 10 and/or dysfunction. Interestingly, the emergence of newly formed b-cells in CF ferrets coincides with a transient 11 recovery in glycemic control. Nonetheless, those CF ferrets with the greatest early-life glycemic disturbances go 12 on to develop CFRD later in life. We have also reported that a similar pattern of glycemic disturbance and 13 recovery occurs in young CF children. Our central hypothesis proposes that new b-cells in the CF ferret pancreas 14 are derived from exocrine progenitors and/or committed dedifferentiated b-cells. Three lineage tracing ferret 15 models will be used to fate map b-cell progenitors (INS-IRES-CreERT2), ductal-derived endocrine progenitors 16 (KRT7-IRES-CreERT2), and acinar-derived endocrine progenitors (PTF1A-IRES-CreERT2). The use of an additional 17 CFTRG551D ferret model, which affords temporal control of pancreatic disease onset using the CFTR modulator 18 VX-770, will allow for dissection of how the developmental timing of pancreatitis impact progenitor cell states 19 and longer-term progression of CFRD. Our in vivo and in vitro preliminary data also show that CF ferret ductal 20 cells acquire properties consistent with the transcriptional and epigenetic states found in pancreatic progenitors 21 during development. The mechanisms of this alteration will be investigated by using in vitro models and the study 22 of pancreatic progenitor cell specification during in utero development of the CF ferret pancreas. The proposed 23 research has brought together two institutions with expertise in animal modeling of CF pancreatic disease, 24 lineage-tracing of islet endocrine precursors, and integrated physiology of CFRD to delineate the mechanism of 25 islet resurgence in CF using the first ever non-rodent lineage-tracing models. These studies are expected to 26 identify mechanisms not only relevant to CFRD, but also other forms of pancreatogenic diabetes.

1个项目摘要 2囊性纤维化（CF）是高加索人群中最常见的致死常染色体隐性疾病 3由囊性纤维化电导调节剂（CFTR）氯化物通道中的缺陷引起。 CF是多器官 4影响肺，胰腺，肝脏，肠和胆囊的疾病。囊性纤维化相关糖尿病（CFRD）为 5 CF最常见的严重并发症，与发病率和死亡率的增加有关。 CFRD， 6在病理生理上与1型和2型糖尿病不同，显着恶化营养和 7例CF患者的肺部健康。我们在CF雪貂和儿童3个月至6岁的研究中的研究表明 8 CFRD的基础发生在腺泡细胞丢失和炎症/纤维化重塑时的生命早期。 9发生。在CF雪貂中，这种外分泌驱动的胰腺重塑导致由B细胞损失引起的血糖危机 10和/或功能障碍。有趣的是，CF雪貂中新形成的B细胞的出现与瞬态一致 11血糖控制中的恢复。尽管如此，那些具有最大早期血糖障碍的CF雪貂却走了 12开始发展CFRD。我们还报告说，类似的血糖干扰模式和年轻的CF儿童发生13次康复。我们的中心假设提出CF雪貂胰腺中的新B细胞 14源自外分泌祖细胞和/或承诺的去分化B细胞。三个谱系追踪雪貂 15型模型将用于命运B细胞祖细胞（INS-IRES-CREERT2），导管衍生的内分泌祖细胞 16（KRT7-IRES-CREERT2）和腺泡衍生的内分泌祖细胞（PTF1A-IRES-CREERT2）。额外的使用 17 CFTRG551D雪貂模型，可使用CFTR调节剂对胰腺疾病发作的时间控制 18 VX-770，将允许解剖胰腺炎的发育时间如何影响祖细胞状态 CFRD的19和长期进展。我们的体内和体外初步数据还表明CF雪貂导管 20个细胞获得与胰腺祖细胞中发现的转录和表观遗传态相一致的特性 21在开发过程中。这种改变的机制将通过使用体外模型和研究来研究 CF雪貂胰腺的子宫内发育过程中胰腺祖细胞规格的22。提议 23研究汇集了两个机构在CF胰腺疾病的动物建模方面具有专业知识， 24胰岛内分泌前体的谱系追踪以及CFRD的整合生理学来描述机制 25胰岛在CF中使用有史以来的第一个非岩体追踪模型。这些研究有望 26确定机制不仅与CFRD有关，还确定其他形式的胰腺生成糖尿病。