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Gene expression profiles of adult peripheral and cord blood mononuclear cells altered by lipopolysaccharide

ABSTRACT: Neonatal gram-negative sepsis is often characterized by a fulminat clinical course compared to adults resulting in higher morbidity and mortality. Genome-wide gene expression analysis can provide insights into the molecular alterations in sepsis. To evaluate in vitro activation of the neonatal and adult immune system, gene expression patterns were compared in mononuclear cells from cord (CBMNC) and adult peripheral blood (APBMNC). To better understand the influence of early molecular signals on the effects of sepsis, Affymetrix gene profiling (8475 genes) was done on RNA isolated from CBMNC and APBMNC without and after incubation with 100 ng/ml lipopolysaccharide (LPS). We demonstrated significant alterations in the expression of 108 CBMNC and APBMNC genes compared with basal levels, 188 significant changes in CBMNC, and 97 in APBMNC, including cytokines, chemokines, and immunoregulatory genes. Furthermore, we found five genes showing a significant interaction effect between cell-type and LPS-stimulation, including tumor necrosis factor receptor superfamily, member 6 (FAS), absent in melanoma 2 (AIM2), malic enzyme 1 (ME1), hemoglobin epsilon 1 (HBE1), and trans-prenyltransferase (TPRT). These results provide further support for a marked difference in the pathogenesis of neonatal and adult sepsis and may stimulate additional studies to investigate some of the altered genes as potential new targets for diagnostic tools and therapeutic strategies. Keywords: LPS response

ORGANISM(S): Homo sapiens

PROVIDER: GSE3140 | GEO | 2005/08/21

SECONDARY ACCESSION(S): PRJNA92967

REPOSITORIES: GEO

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Project description:Neonatal gram-negative sepsis is often characterized by a fulminat clinical course compared to adults resulting in higher morbidity and mortality. Genome-wide gene expression analysis can provide insights into the molecular alterations in sepsis. To evaluate in vitro activation of the neonatal and adult immune system, gene expression patterns were compared in mononuclear cells from cord (CBMNC) and adult peripheral blood (APBMNC). To better understand the influence of early molecular signals on the effects of sepsis, Affymetrix gene profiling (8475 genes) was done on RNA isolated from CBMNC and APBMNC without and after incubation with 100 ng/ml lipopolysaccharide (LPS). We demonstrated significant alterations in the expression of 108 CBMNC and APBMNC genes compared with basal levels, 188 significant changes in CBMNC, and 97 in APBMNC, including cytokines, chemokines, and immunoregulatory genes. Furthermore, we found five genes showing a significant interaction effect between cell-type and LPS-stimulation, including tumor necrosis factor receptor superfamily, member 6 (FAS), absent in melanoma 2 (AIM2), malic enzyme 1 (ME1), hemoglobin epsilon 1 (HBE1), and trans-prenyltransferase (TPRT). These results provide further support for a marked difference in the pathogenesis of neonatal and adult sepsis and may stimulate additional studies to investigate some of the altered genes as potential new targets for diagnostic tools and therapeutic strategies. Experiment Overall Design: The statistical analysis was carried out using the software package R, version 1.9.1, together with libraries gcrma and limma of the Bioconductor Project, version 1.4. The data preprocessing steps, background-adjustment, normalization and computation of GCRMA gene expression measures, were performed according to Wu et al. For the statistical analysis empirical Bayes inference for linear models with factors treatment (basal and LPS stimulated) and cell type (CBMNC and APBMNC) and their interaction was used. From there moderated t-statistics based on shrinkage of the estimated sample variance towards a pooled estimate and corresponding p-values were calculated for comparisons LPS stimulated vs. basal expression for adult and neonatal MNC, and neonatal vs. adult MNC with and without LPS-treatment, respectively, as well as for the interaction effect of the factors treatment and cell type. P-values for each comparison were adjusted according to Benjamini and Hochberg to control the false discovery rate. We used a threshold of 0.01 for the adjusted p-values and selected only those probe sets which showed a fold change => 2

Project description:This a model from the article: Mathematical model of the neonatal mouse ventricular action potential. Wang LJ, Sobie EA. Am J Physiol Heart Circ Physiol. (2008) 294(6) pp H2565-75; 18408122 , Abstract: Therapies for heart disease are based largely on our understanding of the adult myocardium. The dramatic differences in action potential (AP) shape between neonatal and adult cardiac myocytes, however, indicate that a different set of molecular interactions in neonatal myocytes necessitates different treatment for newborns. Computational modeling is useful for synthesizing data to determine how interactions between components lead to systems-level behavior, but this technique has not been used extensively to study neonatal heart cell function. We created a mathematical model of the neonatal (day 1) mouse myocyte by modifying, on the basis of experimental data, the densities and/or formulations of ion transport mechanisms in an adult cell model. The new model reproduces the characteristic AP shape of neonatal cells, with a brief plateau phase and longer duration than the adult (action potential duration at 80% repolarization = 60.1 vs. 12.6 ms). The simulation results are consistent with experimental data, including 1) decreased density and altered inactivation of transient outward K+ currents, 2) increased delayed rectifier K+ currents, 3) Ca2+ entry through T-type as well as L-type Ca2+ channels, 4) increased Ca2+ influx through Na+/Ca2+ exchange, and 5) Ca2+ transients resulting from transmembrane Ca2+ entry rather than release from the sarcoplasmic reticulum (SR). Simulations performed with the model generated novel predictions, including increased SR Ca2+ leak and elevated intracellular Na+ concentration in neonatal compared with adult myocytes. This new model can therefore be used for testing hypotheses and obtaining a better quantitative understanding of differences between neonatal and adult physiology. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Wang_Sobie 2008, version01 The original CellML model was created by: Lloyd, Catherine, May c.lloyd(at)auckland.ac.nz The University of Auckland Auckland Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Gene expression profiles of adult peripheral and cord blood mononuclear cells altered by lipopolysaccharide

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