Early Pathogenesis of Cystic Fibrosis Related Diabetes

囊性纤维化相关糖尿病的早期发病机制

• 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
• 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

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项目概要 2囊性纤维化（CF）是高加索人群中最常见的致死性常染色体隐性遗传疾病， 3由囊性纤维化传导调节因子（CFTR）氯离子通道缺陷引起。CF是多器官 4.影响肺、胰、肝、肠和胆的疾病。囊性纤维化相关糖尿病（CFRD）是 5是CF最常见的严重并发症，并与发病率和死亡率增加相关。面板堆石坝， 6，其在病理生理学上不同于1型和2型糖尿病，显著增加了营养和 7 CF患者的肺部健康。我们对CF雪貂和3个月至6岁儿童的研究表明， CFRD的基础发生在生命早期，此时腺泡细胞丢失，炎症/纤维化重塑 9发生。在CF雪貂中，这种外分泌驱动的胰腺重塑导致了由b细胞丢失引起的血糖危机 10和/或功能障碍。有趣的是，CF雪貂中新形成的b细胞的出现与一种短暂的 11例血糖控制恢复。尽管如此，那些早期血糖紊乱最严重的CF雪貂 12在以后的生活中发展CFRD。我们还报道了类似的血糖紊乱模式， 13.康复发生在年幼的CF儿童。我们的中心假设是CF雪貂胰腺中的新b细胞 14来源于外分泌祖细胞和/或定向去分化的B细胞。三系追踪雪貂 将使用15个模型对b细胞祖细胞（INS-IRES-CreERT 2）、导管来源的内分泌祖细胞 16（KRT 7-IRES-CreERT 2）和腺泡来源的内分泌祖细胞（PTF 1A-IRES-CreERT 2）。使用附加 17 CFTRG 551 D雪貂模型，其使用CFTR调节剂提供胰腺疾病发作的时间控制 VX-770，将允许解剖胰腺炎的发育时间如何影响祖细胞状态 19和混凝土面板堆石坝的长期发展。我们在体内和体外的初步数据也表明，CF雪貂导管， 20细胞获得与胰腺祖细胞中发现的转录和表观遗传状态一致的特性 21发展中这种改变的机制将通过使用体外模型和本研究进行研究。 图22显示CF雪貂胰腺在子宫内发育期间胰腺祖细胞的特化。拟议 23项研究汇集了两个在CF胰腺疾病动物模型方面具有专业知识的机构， 24胰岛内分泌前体细胞的谱系追踪，以及面板堆石坝的综合生理学， 25胰岛复苏CF使用有史以来第一次非啮齿动物谱系追踪模型。这些研究预计将 26确定不仅与CFRD相关的机制，而且还与其他形式的胰源性糖尿病相关。