Project description:Preterm infants are highly susceptible to sustained lung inflammation, which may be triggered by exposure to multiple environmental cues such as supplemental oxygen (O2) and infections. The underlying mechanisms are still poorly understood. The hypothesis of this study is that dysregulated macrophage activation is a key feature leading to inflammation-mediated development of bronchopulmonary dysplasia (BPD) in preterm infants.
Cord blood samples of preterm infants (n=14) and term infants (n=19) as well as peripheral blood from healthy adults (n=17) were collected. Age-dependent differences in immune responses of monocyte-derived Mä from preterm infants were characterized and compared to term infants and adults after lipopolysaccharide (LPS) exposure.
Project description:This study measured the cytokine, cellular and transcriptomic response to RSV and compared these between preterm and term infants CBMC responses
Project description:Development of the gut microbiota is greatly impacted in preterm infants. Despite increasing knowledge about microbiota composition in preterm infants, knowledge about the functional signatures of the intestinal microbiota remains limited. The aim was to study transitions in microbiota activity during the first six postnatal weeks in ten preterm infants. A total of 64 stool samples were measured by LC-MS/MS.
Project description:Development of the gut microbiota is greatly impacted in preterm infants. Despite increasing knowledge about microbiota composition in preterm infants, knowledge about the functional signatures of the intestinal microbiota remains limited. The aim was to study transitions in microbiota activity during the first six postnatal weeks in ten preterm infants. A total of 64 stool samples were measured by LC-MS/MS.
Project description:We conducted a prospective cohort study with independent Discovery and Validation cohorts, to formulate predictive biomarkers for Bronchopulmonary Dysplasia in extremely preterm infants. Tracheal aspirate samples were collected at birth from extremely preterm infants. Exosomes were extracted from tracheal aspirates and total RNA was extracted from these exosomes from individual samples. miRNA profiling for all ~ 800 miRNAs was conducted on each sample by nanostring platform. This study found that a distinct airway exosomal miRNA sigrature at birth (decreased miR 876-3p) predicts future development of severe Bronchopulmonary Dysplasia in extremely preterm infants.
Project description:Intestinal microbiota colonization is important for intestinal development and health of preterm infants, especially those with extremely low birth weight. Recent studies indicated for a dynamic crosstalk between that gut microbiota and DNA methylome of host intestinal cells. Thereby, we sought to determine the epigenomic and metagenomic consequences of suppression of microbiota colonization in the intestine of preterm neonates to gain insights into biological pathways that shape the interface between the gut microbiota and the preterm intestinal cells. We examined 14 preterm piglets by comparing the conventional preterm neonates with those ones treated with oral antibiotics for genome wide DNA methylation and 16S rDNA microbiome. Our results demonstrated an extensive genome-wide DNA methylation changes in response to the suppression of intestinal microbe colonization, especially genes involved in neonatal immune response signaling and glycol-metabolism pathways were identified. Our study highlights several key genes that might predispose preterm neonates to NEC risk due to their key roles involved in the immune-metabolic networks. Our study not only provided rich omic-data to interpret molecular program in relation with microbiota-associated methylome-proteome network changes, but also confer clinical usage of key gene markers for potential early diagnostics of NEC of preterm neonates.
Project description:DNA methylation (DNAm) plays a determining role in neural cell fate and provides a molecular link between early life stress and life-course neuropsychiatric disease. Preterm birth is a profound environmental stressor that is closely associated with alterations in connectivity of neural systems and long-term neuropsychiatric impairment. The aims of this study were to examine the relationship between preterm birth and DNAm and to investigate factors that contribute to variance in DNAm. DNA was collected from preterm infants (birth < 32 weeks’ gestation) and healthy controls (birth > 37 weeks), and a genome-wide analysis of DNAm was performed; diffusion MRI (dMRI) data were acquired from the preterm group. The major fasciculi were segmented, and fractional anisotropy, mean diffusivity and tract shape were calculated. Principal components analysis was used to investigate the contribution of MRI features and key clinical variables to variance in DNAm. Differentially methylated regions were found within 25 gene bodies and 61 promoters of protein-coding genes in preterm infants compared with controls; 10 of these are associated with neural development or function. Differences detected in the array were validated with pyrosequencing. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 principal components (PC); corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Preterm birth is associated with alterations in the methylome at sites that influence neural development and function. The differentially methylated regions identified provide several promising candidate genes for understanding the genetic/epigenetic basis of preterm brain injury.
Project description:Preterm infants are susceptible to neonatal inflammatory/infective diseases requiring drug therapy. The present study hypothesized that mRNA expression in the blood may be modulated by signaling pathways during treatment. The current study aimed to explore changes in global gene expression in the blood from preterm infants with the objective of identifying patterns or pathways of potential relevance to drug therapy. The infants involved were selected based on maternal criteria indicating increased risk for therapeutic intervention. Global mRNA expression was measured in 107 longitudinal whole blood samples using Affymetrix Human Genome U133 Plus 2.0 arrays; samples were obtained from 20 preterm infants. Unsupervised clustering revealed a distinct homogeneous gene expression pattern in 13 samples derived from seven infants undergoing continuous oxygen therapy. At these sampling times, all but one of the seven infants exhibited severe drops in peripheral capillary saturation levels below 60%. The infants were reoxygenated with 100% inspired oxygen concentration. The other samples (n=94) represented the infants from the cohort at time points when they did not undergo continuous oxygen therapy. Comparing these two sets of samples identified a distinct gene expression pattern of 5,986 significantly differentially expressed genes, of which 5,167 genes exhibited reduced expression levels during transient hypoxia. This expression pattern was reversed when the infants became stable, i.e., when they were not continuously oxygenated and had no events of hypoxia. To identify signaling pathways involved in gene regulation, the Database for Annotation, Visualization and Integrated Discovery online tool was used. Mitogen activated protein kinases, which are normally induced by oxidative stress, exhibited reduced gene expression during hypoxia. In addition, nuclear factor erythroid 2 related factor 2 antioxidant response element target genes involved in oxidative stress protection were also expressed at lower levels, suggesting reduced transcription of this pathway. The findings of the present study suggest that oxidative stress dependent signaling is reduced during hypoxia. Understanding the molecular response in preterm infants during continuous oxygenation may aid in refining therapeutic strategies for oxygen therapy.
Project description:Host immune responses during late-onset sepsis (LOS) in very preterm infants are poorly characterised due to a complex and dynamic pathophysiology and challenges in working with small available blood volumes. We present here an unbiased transcriptomic analysis of whole peripheral blood from very preterm infants at the time of LOS. RNA-Seq was performed on peripheral blood samples (6 – 29 days postnatal age) taken at the time of suspected LOS from very preterm infants <30 weeks gestational age. Infants were classified based on blood culture positivity and elevated C-reactive protein concentrations as having confirmed LOS (n=5), possible LOS (n=4) or no LOS (n=9). Bioinformatics and statistical analyses performed included pathway over-representation and protein-protein interaction network analyses. Plasma cytokine immunoassays were performed to validate differentially expressed cytokine pathways.The blood leukocyte transcriptional responses of infants with confirmed LOS differed significantly from infants without LOS (1,317 differentially expressed genes). However, infants with possible LOS could not be distinguished from infants with no LOS or confirmed LOS. Transcriptional alterations associated with LOS included genes involved in pathogen recognition (mainly TLR pathways), cytokine signalling (both pro-inflammatory and inhibitory responses), immune and haematological regulation (including cell death pathways), and metabolism (altered cholesterol biosynthesis). At the transcriptional-level cytokine responses during LOS were characterised by over-representation of IFN-α/β, IFN-γ, IL-1 and IL-6 signalling pathways and up-regulation of genes for inflammatory responses. Infants with confirmed LOS had significantly higher levels of IL-1α and IL-6 in their plasma. Blood responses in very preterm infants with LOS are characterised by altered host immune responses that appear to reflect unbalanced immuno-metabolic homeostasis.