Project description:This study explored how chronic stress influences the activity of signaling pathways that regulate inflammation in the human monocyte transcriptome. The sample consisted of 33 adults caring for a family member with glioblastoma, a terminal brain cancer, and 47 control subjects whose lives were free of major stressors. The subjects were assessed on four occasions across an eight-month period. Relative to controls, caregivers’ monocytes showed increased expression of genes bearing response elements for nuclear-factor kappa B, a key pro-inflammatory transcription factor in monocytes. Simultaneously, caregivers showed reduced expression of genes with response elements for the glucocorticoid receptor, a transcription factor that conveys anti-inflammatory signals to monocytes. These transcriptional disparities were not attributable to demographic or behavioral confounds. They also were not attributable to differences in diurnal cortisol output, or the abundance of glucocorticoid receptor expressed by monocytes. In ex vivo studies of monocytes stimulated with the bacterial product lipopolysaccharide, caregivers showed increased production of the pro-inflammatory cytokine interleukin-6, and were less sensitive to cortisol-mediated inhibition of this response. These findings suggest a scenario wherein chronic stressors engender functional changes that hamper monocytes’ capacity to transduce cortisol’s anti-inflammatory signals. These changes occur in parallel with, and perhaps enable, greater inflammatory signaling via nuclear-factor kappa B. The resulting inflammatory milieu could serve as a pathogenic mechanism through which chronic stressors like caregiving accentuate vulnerability to later health problems. series type: Risk prediction Individual differences in basal leukocyte gene expression profiles as a function of chronic caregiving stress Characteristics included in statistical analyses of gene expression data are provided in each sample records. Please note that educational attainment is scored as following; 0=less than high school, 1=high school diploma or equivalent, 2=associate's degree, 3=bachelor's degree, 4=masters degree, 5=doctoral degree

Project description:The liver x receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARG) nuclear receptor transcription factors (TFs) are master regulators of energy homeostasis that impact tumor cell metabolism and proliferation. To better define the underlying molecular processes governing the genetic control of cellular growth in response to extracellular metabolic signals, we performed a comprehensive, genome-wide characterization of the temporal regulatory cascades mediated by LXR and PPARG signaling in HT29 colorectal cancer cells. For this analysis we applied a multi-tiered approach that incorporated cellular phenotypic assays, gene expression profiles, chromatin state dynamics and nuclear receptor binding patterns. By integrating these orthogonal datasets over time, we uncovered the regulatory architecture of LXR and PPARG activity. Both sets of nuclear receptors inhibited cell proliferation and increased cellular oxidative stress, validating results from independent studies. Despite this metabolic reprogramming, the gene regulatory network programs initiated by these nuclear receptors were widely distinct. PPARG generated a rapid and short-term response while maintaining a gene activator role. By contrast, LXR signaling was prolonged, with initial, predominantly activating functions altering to repressive gene regulatory activities at late time points through RNA polymerase II (RNAP2) promoter pausing. This exhaustive dataset illustrates the complexity of genome function and structure by elucidating how common phenotypic outcomes are genetically encoded through diverse transcriptional programs. Our results further provide a detailed, molecular framework that can be applied to better understanding how extracellular nutrients impact cancer cell physiology and highlight the importance of study designs that incorporate complementary genomic features in a dynamic manner. ChIP-seq and RNA-seq experiments were performed in HT29 cells using vehicle control (DMSO) or after drug treatment (GW3965 and rosiglitazone).

Project description:This a model from the article: Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability. Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. Theor Biol Med Model 2007 Feb 14;4:8 17300722 , Abstract: BACKGROUND: The body's primary stress management system is the hypothalamic pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases. RESULTS: We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high) and one unstable state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS). CONCLUSION: Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. (2007) - version=1.0 The original CellML model was created by: Catherine Lloyd c.lloyd@auckland.ac.nz The University of Auckland This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). 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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	BIOMD0000000576?filename=BIOMD0000000576.m	Other

Dataset Information

Kolodkin2013 - Nuclear receptor-mediated cortisol signalling network

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Optimization of stress response through the nuclear receptor-mediated cortisol signalling network.

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