The role of CFTR in islet function
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE110935
PROVIDER: PRJNA434833 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6757210_1.fastq.gz | Fastqsanger.gz | |||
| SRR6757210_2.fastq.gz | Fastqsanger.gz | |||
| SRR6757220_1.fastq.gz | Fastqsanger.gz | |||
| SRR6757220_2.fastq.gz | Fastqsanger.gz | |||
| SRR6757211_1.fastq.gz | Fastqsanger.gz |
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Project description:Cystic fibrosis (CF)-related diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting ~35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of b cell CFTR deletion, and normal and CF human pancreas and islets. Specific deletion of CFTR from murine b cells did not affect b cell function. In human islets, CFTR mRNA was minimally expressed, and CFTR protein/electrical activity was not detected. Isolated CF/CFRD islets demonstrated appropriate insulin and glucagon secretion with few changes in key islet-regulatory transcripts. Furthermore, ~65% of b cell area was lost in CF donors, compounded by pancreatic remodeling and immune infiltration of the islet. These results indicate that CFRD is not caused by intrinsic islet dysfunction from CFTR mutation, but rather, by b cell loss and intra-islet inflammation in the setting of a complex pleiotropic disease
2018-04-25 | GSE110935 | GEO
Project description:Inflammation, acinar cell destruction, and ductal cell hyperplasia drive pancreatic remodeling in newborns with cystic fibrosis (CF) lacking a functional CFTR channel. In neonatal CF ferrets, these changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. Little is known about the phenotypic changes in CF ductal epithelium and its potential impact on islet function. Using bulk RNA-seq, scRNA-seq, and ATAC-seq on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3b activation. In the absence of CFTR protein, centroacinar cells (or terminal ductal cells) adopted a bi-potent progenitor-like state associated with enhanced WNT/b-Catenin, TGFb and AKT signaling. Notably, using in vitro and in vivo hypomorphic models of mutant CFTR expression, we show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
2024-09-18 | GSE264021 | GEO
Project description:Loss of CFTR function in the pancreatic duct leads to dysregulated luminal pH causing premature activation of digestive enzymes and tissue necrosis. Drastic alterations in pancreatic tissue architecture and cellular composition changes the microenvironment of the islets. Given that CFTR is expressed in the pancreatic ducts, we hypothesized that loss of functional CFTR impacts islet function by modifying the ductal secretome. To this end, we developed a long-term in vitro pancreatic duct epithelial cell culture system and polarized both WT and CFTR-KO (CF) ferret duct epithelial cells. We profiled the apical and basolateral secretome, and the cellular proteome of both WT and CF duct epithelium using quantitative mass spectrometry. Bioinformatic analysis of differentially secreted proteins mapped to their cognate receptors provided a list of putative paracrine interactions that affect islet function. Signaling pathways and upstream regulators that alter the secretome and cellular proteome profile were computationally mined to characterize disease causing mechanisms. In this study, we provide a proteomic roadmap of perturbed autocrine and paracrine signals from the CF pancreatic duct.
2021-05-27 | PXD025126 | Pride
Project description:Inflammation, acinar cell destruction, and ductal cell hyperplasia drive pancreatic remodeling in newborns with cystic fibrosis (CF) lacking a functional CFTR channel. In neonatal CF ferrets, these changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. Little is known about the phenotypic changes in CF ductal epithelium and its potential impact on islet function. Using bulk RNA-seq, scRNA-seq, and ATAC-seq on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3b activation. In the absence of CFTR protein, centroacinar cells (or terminal ductal cells) adopted a bi-potent progenitor-like state associated with enhanced WNT/b-Catenin, TGFb and AKT signaling. Notably, using in vitro and in vivo hypomorphic models of mutant CFTR expression, we show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
2024-09-18 | GSE264022 | GEO
Project description:Inflammation, acinar cell destruction, and ductal cell hyperplasia drive pancreatic remodeling in newborns with cystic fibrosis (CF) lacking a functional CFTR channel. In neonatal CF ferrets, these changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. Little is known about the phenotypic changes in CF ductal epithelium and its potential impact on islet function. Using bulk RNA-seq, scRNA-seq, and ATAC-seq on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3b activation. In the absence of CFTR protein, centroacinar cells (or terminal ductal cells) adopted a bi-potent progenitor-like state associated with enhanced WNT/b-Catenin, TGFb and AKT signaling. Notably, using in vitro and in vivo hypomorphic models of mutant CFTR expression, we show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
2024-09-18 | GSE264019 | GEO
Project description:Purpose: To identify the cell types that contribute to CFTR expression and function within the proximal-distal axis of the normal human lung. Methods: Single cell RNA-seq (scRNA-seq) was performed on freshly isolated human large and small airway epithelial cells. Single cell-based RNA in situ hybridization (scRNA-ISH) and quantitative RT-PCR (scqRT-PCR) were performed for validation. In vitro culture systems correlated CFTR function to cell types. Lentiviruses were used for cell-type specific transduction of wild-type CFTR in CF cells. Results: scRNA-seq identified secretory cells as dominating CFTR expression in normal human large and particularly small airways, followed by basal cells. Ionocytes expressed the highest CFTR levels but were rare, while expression in ciliated cells was infrequent and low. scRNA-ISH, and scqRT-PCR confirmed the scRNA-seq findings. CF lungs exhibited distributions of CFTR and ionocytes similar to normal controls. CFTR-mediated Cl- secretion tracked secretory cell, not ionocyte, densities. Further, the nucleotide-purinergic regulatory system that controls CFTR-mediated hydration was associated with secretory cells. Lentiviral transduction of wild-type CFTR produced CFTR-mediated Cl- secretion in CF airway secretory cells but not ciliated cells. Conclusions: Secretory cells dominate CFTR expression and function in human airway superficial epithelia. CFTR therapies may need to restore CFTR function to multiple cell types, with a focus on secretory cells.
2020-12-16 | GSE160674 | GEO
Project description:Purpose: To identify the cell types that contribute to CFTR expression and function within the proximal-distal axis of the normal human lung. Methods: Single cell RNA-seq (scRNA-seq) was performed on freshly isolated human large and small airway epithelial cells. Single cell-based RNA in situ hybridization (scRNA-ISH) and quantitative RT-PCR (scqRT-PCR) were performed for validation. In vitro culture systems correlated CFTR function to cell types. Lentiviruses were used for cell-type specific transduction of wild-type CFTR in CF cells. Results: scRNA-seq identified secretory cells as dominating CFTR expression in normal human large and particularly small airways, followed by basal cells. Ionocytes expressed the highest CFTR levels but were rare, while expression in ciliated cells was infrequent and low. scRNA-ISH, and scqRT-PCR confirmed the scRNA-seq findings. CF lungs exhibited distributions of CFTR and ionocytes similar to normal controls. CFTR-mediated Cl- secretion tracked secretory cell, not ionocyte, densities. Further, the nucleotide-purinergic regulatory system that controls CFTR-mediated hydration was associated with secretory cells. Lentiviral transduction of wild-type CFTR produced CFTR-mediated Cl- secretion in CF airway secretory cells but not ciliated cells. Conclusions: Secretory cells dominate CFTR expression and function in human airway superficial epithelia. CFTR therapies may need to restore CFTR function to multiple cell types, with a focus on secretory cells.
2020-12-16 | GSE160673 | GEO
Project description:To unravel CFTR function in endothelial cells (HUVECs), we used two complementary approaches to induce CFTR blockade: (i) the allosteric CFTR inhibitor CFTRinh-(172) which is commonly used in CF research, and (ii) CFTR-specific short hairpin RNAs (shRNA).
2020-10-31 | E-MTAB-8599 | biostudies-arrayexpress
Project description:Production of functional proteins requires multiple steps including gene transcription and post-translational processing. MicroRNAs (miRNA) can regulate individual stages of these processes. Despite the importance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel for epithelial anion transport, how its expression is regulated remains uncertain. We discovered that microRNA-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with a miR-138 mimic increased CFTR mRNA and also enhanced CFTR abundance and transepithelial Cl- permeability independently of elevated mRNA levels. A miR-138 anti-miR had the opposite effects. Importantly, miR-138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis. The most common CFTR mutation, M-NM-^TF508, causes protein misfolding, degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-M-NM-^TF508 and restored Cl- transport to cystic fibrosis airway epithelia. This novel miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process broader than previously recognized. This discovery also provides new therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation. 12 samples of Calu-3 cells representing different interventions.
2012-09-04 | E-GEOD-38956 | biostudies-arrayexpress
Project description:The purpose of this study was to explore baseline expression of miRNome in Cystic Fibrosis Bronchial Epithelial (CFBE41o-) cells stably transfected with wild type (WT) Cystic Fibrosis Transmembrane Conductance regulator (CFTR) and F508del-CFTR. To fulfill this goal miRNA sequencing was done to see miRNA landscape in CFBE41o- Cells with homozygous F508del mutated CFTR and in CFBE41o- Cells with homozygous WT-CFTR, without any treatment condition.
2019-03-28 | GSE128912 | GEO