Effect of treprostinil on rabbit lungs with congenital diaphragmatic hernia
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ABSTRACT:
ORGANISM(S): Oryctolagus cuniculus
PROVIDER: GSE220739 | GEO | 2023/10/31
REPOSITORIES: GEO
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Project description:Analysis of embronic day 30.5 (E30.5) fetal rabbit left lung after creation of diapragmatic hernia (DH) at E25 and tracheal occlusion (TO) at E27. The fetuses of timed pregnant New Zealand rabbits were subjected to creation of a left diaphragmatic hernia at E25 with or without tracheal occlusion at E27. At E30.5, the fetuses were sacrificed with collection of the lateral aspect of the left upper lobe for NextGen mRNA sequencing.
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Project description:Analysis of embronic day 30.5 (E30.5) fetal rabbit left lung after creation of diapragmatic hernia (DH) at E25 and tracheal occlusion (TO) at E27.
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Project description:Investigation into the effects of Congenital Diaphragmatic Hernia (CDH) and subsequent treatment with tracheal occlusion (TO) on the pulmonary transcriptome. A diaphragm defect was created by surgical means in fetal rabbits. The surgical creation of diaphragmatic hernia (DH) allows for direct analysis of changes in pulmonary gene expression due to pulmonary hypoplasia, without the need for gene knockdown (as for KO mice) or use of teratogens (such as nitrofen). The subsequent treatment with tracheal occlusion (TO) was also investigated to determine the changes in gene expression due to forced lung growth in the prenatal phase. RNA-Seq analysis was performed on left lung samples from fetal rabbits. Samples were generated and analysed for DH (n=4), TO (n=6), and control lungs (n=4)
2015-04-15 | E-MTAB-3452 | biostudies-arrayexpress
Project description:Congenital diaphragmatic hernia (CDH) is a severe birth defect frequently associated with pulmonary hypoplasia, pulmonary hypertension, and heart failure. Since amniotic fluid comprises proteins of both fetal and maternal origin, its analysis could provide insights on mechanisms underlying CDH and provide biomarkers for early diagnosis, severity of pulmonary changes and response to treatment. The study objective was to identify proteomic changes in amniotic fluid consistently associated with CDH. Amniotic fluid was obtained at term (37-39 weeks) from women with normal pregnancies (n=5) or carrying fetuses with CDH (n=5). After immuno-depletion of the highest abundance proteins, off-line fractionation and high-resolution tandem mass spectrometry were performed and quantitative differences between the proteomes of the groups were determined. Of 1036 proteins identified, 218 were differentially abundant. Bioinformatics analysis showed significant changes in GP6 signaling, MSP-RON signaling in macrophages pathways and networks associated with cardiovascular system development and function, connective tissue disorders and dermatological conditions. Pulmonary surfactant protein B, osteopontin, kallikrein 5 and galectin 3 were investigated orthogonally using ELISA in larger cohorts to test the observed differences and showed statistically significant differences aiding in the prediction of CDH. The findings provide potential tools for improved clinical detection and management of CDH.
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Project description:Congenital diaphragmatic hernia (CDH) results from incomplete diaphragm development and can be associated with pulmonary hypoplasia, pulmonary hypertension, and heart failure. Currently, few biomarkers are available. Since amniotic fluid comprises proteins of both fetal and maternal origin, its analysis could provide insights on mechanisms underlying CDH and provide biomarkers for early diagnosis, severity of pulmonary changes and response to treatment. The study objective was to identify proteomic changes in amniotic fluid consistently associated with CDH. Amniotic fluid was obtained at term (37-39 weeks) from women with normal pregnancies (n=5) or carrying fetuses with CDH (n=5). After immuno-depletion of the highest abundance proteins, off-line fractionation and high-resolution tandem mass spectrometry were performed and quantitative differences between the proteomes of the groups were determined. Of 1036 proteins identified, 218 were differentially abundant. Bioinformatics analysis showed significant changes in GP6 signaling, MSP-RON signaling in macrophages pathways and networks associated with cardiovascular system development and function, connective tissue disorders and dermatological conditions. Pulmonary surfactant protein B, osteopontin, kallikrein 5 and galectin 3 were investigated orthogonally using ELISA in larger cohorts to test the observed differences and showed statistically significant differences aiding in the prediction of CDH. The findings provide potential tools for improved clinical detection and management of CDH.
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Project description:Gene Mutation and Rescue in Human Congenital Diaphragmatic Hernia (CDH)
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Project description:Congenital diaphragmatic hernia (CDH) is a neonatal anomaly that includes pulmonary hypoplasia and hypertension. We hypothesized that differences in microvascular endothelial cell (EC) heterogeneity may be present during CDH lung development and contribute to nderdevelopment and remodeling of the lungs. Time mated rats were gavaged nitrofen to induce CDH. Left lungs were harvested from healthy control (2HC), nitrofen exposed (NC) and nitrofen-exposed with CDH (CDH) fetuses at E21.5. Transcriptomic analysis was performed using single-cell RNA sequencing, and unbiased clustering revealed 3 distinct microvascular EC clusters. The general microvascular EC cluster (mvEC) had a transcriptomic signature suggestive of increased inflammation in CDH. mvEC differential gene expression (DGE) between NC and CDH revealed downregulation of Ca4, Apln and Ednrb, which define a subpopulation of microvascular ECs important to lung development, gas exchange and repair of alveolar injury (mvCa4+). mvCa4+ ECs were significantly reduced between 2HC (22.6%), NC (13.1%) and CDH (5.3%), demonstrating an impact from lung compression. Gene ontology and Ingenuity Pathway Analysis demonstrated that mvCa4+ ECs are primed for vasculogenesis but have DGE suggestive of impaired cell division. These data suggest that inflammation driven by mvECs and absence of mvCa4+ ECs may contribute to CDH pathogenesis.
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Project description:Kids First Pediatric Research Project on the Genomic Analysis of Congenital Diaphragmatic Hernia
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Project description:Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm and lung hypoplasia. The pathophysiology of lung defects in CDH is poorly understood. To establish a translational model of human airway epithelium in CDH for pathogenic investigation and therapeutic testing, we developed a robust methodology of epithelial progenitor derivation from tracheal aspirates of newborns. Basal stem cells from CDH patients and preterm and term, non-CDH controls were derived and analyzed by bulk RNA-sequencing, ATAC-sequencing, and air-liquid-interface differentiation. Transcriptomic and epigenetic profiling of CDH and non-CDH basal stem cells reveals a disease-specific, proinflammatory signature independent of severity or hernia size. In addition, CDH basal stem cells exhibit defective epithelial differentiation in vitro that recapitulates epithelial phenotypes found in fetal human CDH lung samples and fetal tracheas of the nitrofen rat model of CDH. Furthermore, steroid treatment normalizes epithelial differentiation phenotypes of human CDH basal stem cells in vitro and in nitrofen rat tracheas in vivo. Our findings have identified an interplay between a proinflammatory signature and BSC differentiation as a potential therapeutic target for airway epithelial defects in CDH.
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Project description:Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm and lung hypoplasia. The pathophysiology of lung defects in CDH is poorly understood. To establish a translational model of human airway epithelium in CDH for pathogenic investigation and therapeutic testing, we developed a robust methodology of epithelial progenitor derivation from tracheal aspirates of newborns. Basal stem cells from CDH patients and preterm and term, non-CDH controls were derived and analyzed by bulk RNA-sequencing, ATAC-sequencing, and air-liquid-interface differentiation. Transcriptomic and epigenetic profiling of CDH and non-CDH basal stem cells reveals a disease-specific, proinflammatory signature independent of severity or hernia size. In addition, CDH basal stem cells exhibit defective epithelial differentiation in vitro that recapitulates epithelial phenotypes found in fetal human CDH lung samples and fetal tracheas of the nitrofen rat model of CDH. Furthermore, steroid treatment normalizes epithelial differentiation phenotypes of human CDH basal stem cells in vitro and in nitrofen rat tracheas in vivo. Our findings have identified an interplay between a proinflammatory signature and BSC differentiation as a potential therapeutic target for airway epithelial defects in CDH.
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