权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10599931
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/10599931
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 Classification 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 Internal Ribosome Entry Site Intestines Knowledge Life Link Liver Lung Maintenance Maps Mediating Modeling Morbidity - disease rate Mus Natural regeneration Neonatal Nutritional Onset of illness Organ Outcome Pancreas Pancreatic Diseases Pancreatic Injury Pancreatic duct Pancreatitis Pathogenesis Pathway interactions Patients Pattern Phase Phenotype Physiology Population Prevention strategy Preventive treatment Process Property Recovery Reporter Reporting Research Resources Severities Source Specific qualifier value TGFB1 gene Testing Therapeutic Translating VX-770 Withdrawal age related autosome 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 pharmacologic postnatal postnatal period progenitor programs pulmonary function stem cells tool transcriptome sequencing type I and type II diabetes

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项目概述