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Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers

ABSTRACT: Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers

PROVIDER: PRJNA755978 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15509800.fastq.gz	Fastqsanger.gz
	SRR15509797.fastq.gz	Fastqsanger.gz
	SRR15509798.fastq.gz	Fastqsanger.gz
	SRR15509799.fastq.gz	Fastqsanger.gz

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Similar Datasets

Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers

Project description:In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR)-dependent bicarbonate secretion precipitates the accumulation of viscous mucus in the lumen of respiratory and gastrointestinal epithelial tissues. We investigated whether the combination of elexacaftor (ELX), ivacaftor (IVA) and tezacaftor (TEZ), apart from its well-documented effect on Phe508del-CFTR-mediated chloride transport, also restores bicarbonate transport.

2021-12-14 | GSE182347 | GEO

Exposure of bronchial airway epithelial cells to elexacaftor/tezacaftor/ivacaftor, Pseudomonas aeruginosa strain PA14 and outer membrane vesicles

Project description:Elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta) is highly effective treatment for many cystic fibrosis patients, at least partly because it increases CFTR mediated Cl- and HCO3- secretion by airway epithelial cells leading to improved lung function and less frequent exacerbations and hospitalizations. However, little is known about how ETI affects airway epithelial cells in ways not related to CFTR mediated Cl- and HCO3- secretion, for example how ETI affects the expression of genes other than CFTR or how ETI might affect airway cells’ response to infection. It is established that CF airway cells bearing the delta F 508 mutation the CFTR gene respond characteristically differently from wild type CFTR cells, and we hypothesized that, as a highly effective CFTR modulator, ETI might make airway cells from CF donors respond to pathogen stimulation (Pseudomonas aeruginosa PA14 or outer membrane vesicles isolated from these bacteria) in more the same way that cells from wild type, healthy control cells do. We tested this hypothesis by measuring gene expression responses in polarized primary CF airway cells exposed to ETI alone or ETI in the presence of a pathogen challenge (PA14 or outer membrane vesicles). Responses of CFTR wild type primary CF airway cells to PA14 or outer membrane vesicles was also measured for comparison

2024-06-25 | GSE268718 | GEO

Transcription profiling of undifferentiated human extrahepatic cholangiocyte organoids (ECOs)

Project description:3D cell culture systems (organoids), cultured from extrahepatic bile duct biopsies, resemble biliary epthelium (cholangiocytes) upon culture according to the protocol previously established for culturing intrahepatic cholangiocyte organoids from liver biopsies (Huch et al. Cell 2015). These extrahepatic cholangiocyte organoids (ECOs) in Canonical-Wnt culture conditions maintain their genetic stability, and transcription profile and can be maintained and propagated during long periods of culturing while still maintaining their functional properties. The data presented in this ArrayExpress submission contained micro array results of 3 different ECO lines that were analyzed for their functional cholangiocyte ion-channels, involved in secreting a protective bicarbonate layer. It was shown that these data closely resemble the expression profile of intrahepatic cholangiocyte organoids (ICOs) as described by our group. Results of the ICOs are deposited in the EMBL-EBI ArrayExpress repository under number E-MTAB-9044.

2021-01-01 | E-MTAB-9807 | biostudies-arrayexpress

Transcriptomic responses to Ivacaftor and prediction of Ivacaftor clinical responsiveness

Project description:Rationale: Ivacaftor is a recently FDA-approved drug for the treatment of cystic fibrosis (CF) patients with at least one copy of the G511D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The transcriptomic effect of Ivacaftor in CF patients remains unclear. Objectives: We aim to examine if and how the transcriptome of patients is influenced by Ivacaftor treatment and to determine if these data allow prediction of Ivacaftor responsiveness. Methods: We performed RNA-sequencing (RNA-seq) on PBMCs from CF patients and compared the transcriptomic changes before and after Ivacaftor treatments. Consensus clustering method is employed to stratify patients into sub-groups based on clinical responses post treatment, and determined differences in baseline gene expression. A random forest model is built to predict Ivacaftor responsiveness. Measurement and Main Results: We identified 239 genes that were significantly influenced by Ivacaftor in PBMC. The functions of these genes relate to cell differentiation, microbial infection, inflammation, Toll-like receptor signaling, and metabolism. We classified patients into “good” and “moderate” responders based on clinical response to Ivacraftor. We identified a panel of signature genes and built a statistical model for predicting CFTR modulator responsiveness. Despite a limited sample size, adequate prediction performance was achieved with an accuracy of 0.92. Conclusions: For the first time, the present study demonstrates profound transcriptomic impacts of Ivafactor in CF patients PBMCs and successfully built a statistical model for predicting the clinical responsiveness to Ivacaftor prior to treatment.

2019-08-27 | GSE128723 | GEO

Transcription profiling of undifferentiated human liver-derived intrahepatic cholangiocyte organoids (ICOs)

Project description:3D cell culture systems (organoids), cultured from liver biopsies, resemble biliary epthelium (cholangiocytes) upon culture. These intrahepatic cholangiocyte organoids (ICOs) maintain their gentic stability, transcription profile and can be maintained propagated during long periods of culturing while still maintaining their functional properties. The data presented in this ArrayExpress submission contained micro array results of 6 from 15 different ICO lines that were analyzed for their functional cholangiocyte ion-channels, involved in secreting a protective bicarbonate layer. It was shown that these data closely resemble the expression profiles of extrahepatic cholangiocyte organoids (ECOs), previously described by Sampaziotis et al. and deposited in the EMBL-EBI ArrayExpress repository (E-MTAB-4591)

2020-07-31 | E-MTAB-9044 | biostudies-arrayexpress

Gene expression profile of intestinal organoids from people with cystic fibrosis upon exposure to elexacaftor/tezacaftor/ivacaftor

Project description:Gene expression profile of intestinal organoids from people with cystic fibrosis upon exposure to elexacaftor/tezacaftor/ivacaftor

| PRJNA1095464 | ENA

Exposure of bronchial airway epithelial cells to elexacaftor/tezacaftor/ivacaftor, Pseudomonas aeruginosa strain PA14 and outer membrane vesicles

Project description:Exposure of bronchial airway epithelial cells to elexacaftor/tezacaftor/ivacaftor, Pseudomonas aeruginosa strain PA14 and outer membrane vesicles

| PRJNA1118313 | ENA

Project description:Sputum microbiota in people with cystic fibrosis starting on Elexacaftor/Tezacaftor/Ivacaftor

| PRJNA934375 | ENA

Gene expression profile of intestinal organoids from people with cystic fibrosis upon exposure to elexacaftor/tezacaftor/ivacaftor

Project description:Background: The forskolin-induced swelling assay (FIS) in intestinal organoids (IOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among IOs obtained from people with CF (pwCF) carrying the same genotype. We aimed to characterise the effect of ETI on the transcriptional activity of IOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Methods: Six high- and six low-responding IOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 hours. Gene expression was modelled using negative binomial models adjusted for subjects, having time and incubation with ETI as predictors. Results: Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. IOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. Conclusions: The changes in the IOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of IOs FIS-measured response to ETI. Genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways, seemingly unrelated to the mechanisms of FIS, but possibly related to the effect of ETI itself.

2024-09-01 | GSE263022 | GEO

Longitudinal Effects of Elexacaftor/Tezacaftor/Ivacaftor on Sputum Viscoelastic Properties, Airway Infection and Inflammation in Patients with Cystic Fibrosis

Project description:Rationale: We recently demonstrated that the triple combination CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves lung ventilation and airway mucus plugging determined by multiple-breath washout and magnetic resonance imaging in CF patients with at least one F508del allele. However, effects of ELX/TEZ/IVA on viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. Objectives: To examine the effects of ELX/TEZ/IVA on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged 12 years and older. Methods: In this prospective observational study, we determined sputum rheology, microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ELX/TEZ/IVA. Measurements and Main Results: CF patients with at least one F508del allele and healthy controls were enrolled in this study. ELX/TEZ/IVA improved the elastic and viscous modulus of CF sputum. Further, ELX/TEZ/IVA improved the microbiome α-diversity and decreased the relative abundance of Pseudomonas aeruginosa (P<0.05) in CF sputum. ELX/TEZ/IVA also reduced IL-8 and free NE activity, and shifted the CF sputum proteome towards healthy. Conclusions: Our data demonstrate that ELX/TEZ/IVA improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele, however, without reaching levels close to healthy.

2023-06-22 | PXD041844 | Pride

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