The neuroendocrine stress response at single-cell resolution reveals adrenal ABCB1 as key regulator of stress adaptation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE161751 | GEO | 2021/01/28
REPOSITORIES: GEO
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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.
2005-01-01 | MODEL1006230036 | BioModels
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.
2005-01-01 | MODEL1006230111 | BioModels
Project description:Inflammation leads the hypothalamus-pituitary-adrenal (HPA) axis activation and increased production of glucocorticoids, which produced by the adrenal cortex, exert potent anti-inflammatory effects. The use of omics, including proteomics revealed metabolic changes in steroidogenic adrenocortical cells, including downregulation of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, decreased ATP production and induction of oxidative stress after lipopolysaccharide (LPS)-induced inflammation.
2023-07-21 | PXD036542 | Pride
Project description:Gene expression profiling of ABCB1 positive and ABCB1 negative OCM1A cells. ABCB1 is an ATP-dependent transporter efflux pump. OCM1A cell line is derived from uveal melanomas. 6 samples (3 ABCB1 positive and 3 ABCB1 negative) from 3 independent ABCB1 shift assays were analysed
2010-09-01 | E-GEOD-21425 | biostudies-arrayexpress
Project description:Background Understanding the genetic basis of phenotypic diversity is a challenge in contemporary biology. Domestication provides a model for unravelling aspects of this, for example with respect to stress sensitivity. Ancestral Red Junglefowl (RJF) show more fearful behaviour and a more pronounced HPA-axis reactivity than its domesticated descendant White Leghorn (WL). By comparing adrenal global gene transcription profiles between WL and RJF as well as their plasma levels of adrenal hormones in response to an acute stress event, we aimed at investigating the molecular basis for the altered physiological stress responsiveness in domesticated chicken.
2015-10-30 | E-MTAB-3622 | biostudies-arrayexpress
Project description:This a model from the article:
A computer simulation of the hypothalamic-pituitary-adrenal axis.
Gonzalez-Heydrich J, Steingard RJ, Kohane I. Proc Annu Symp Comput Appl Med Care
1994;:1010 7949852
,
Abstract:
This paper describes the construction of a computer model that simulates the
hypothalamic-pituitary-adrenal axis (HPA axis) regulation of cortisol
production. It is presented to illustrate the process of physiological modeling
using standard "off the shelf" technologies. The model simulates components of
the HPA axis involved in the continuous secretion and elimination of cortisol,
adrenocorticotropin (ACTH), and corticotropin releasing hormone (CRH). The
physiological relations of these component pieces were modeled based on the
current knowledge of their functioning. Rate constants, half lives, and receptor
affinities were assigned values derived from the experimental literature. At its
current level of development the model is able to accurately simulate the
timing, magnitude and decay of the ACTH and cortisol concentration peaks
resulting from the ovine-CRH stimulation test in normal and hypercortisolemic
patients. The model will be used to predict the effects of lesions in different
components of the HPA axis on the time course of cortisol and ACTH levels. We
plan to use the model to explore the experimental conditions required to
distinguish mechanisms underlying various disorders of the HPA axis,
particularly depression. Efforts are currently underway to validate the model
for a large variety of normal and pathological perturbations of the HPA axis.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Gonzalez-Heydrich J, Steingard RJ, Kohane I. (1994) - version02
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.
2005-01-01 | MODEL0911270004 | BioModels
Project description:Gene expression profiling of ABCB1 positive and ABCB1 negative OCM1A cells. ABCB1 is an ATP-dependent transporter efflux pump. OCM1A cell line is derived from uveal melanomas.
2010-09-01 | GSE21425 | GEO
Project description:Psychological stress is a risk factor for several diseases. In particular, stressor exposure has been linked with various psychiatric disorders. Since the hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the regulation of stress responses, it has been implicated in the etiology of stress related disorders such as PTSD. The HPA axis regulate synthesis and release of glucocorticoids and its dysregulation cause abnormal response to stress. FK506-binding protein 51 (FKBP5) is a co chaperone of HSP90 in the glucocorticoid receptor (GR) molecular complex and a key regulator of the sensitivity of GR. In this study, we profiled the miRNAs in the prefrontal cortex of FKBP5 knock out mice compared to the wild type. Subsequently, we profiled target mRNAs for differentially expressed miRNAs in the FKBP5 deficient mice using several tools for sequence-based miRNA target prediction such as miRDB, DIANA tool, miRmap and TargetScan. Gene ontology analysis suggested that differentially expressed miRNAs in the brain of FKBP5 deficient mice may be involved in neuron development, cell motion, endocytosis, and cell-cell adhesion. These results suggest that Nfasc could be a new target for understanding of the pathophysiology of PTSD.
2020-10-31 | GSE139502 | GEO
Project description:Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing’s syndrome. We define mechanisms of action for the PKAcL205R and W196R variants. Proximity proteomic techniques demonstrate that both Cushing’s mutants are excluded from A kinase anchoring protein (AKAP) signaling islands, whereas live-cell photoactivation microscopy reveals that these kinase mutants indiscriminately diffuse throughout the cell. Only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate PKAc mutants into AKAP complexes abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Analyses of adrenal-specific PKAc-W196R knock-in mice and Cushing’s syndrome patient tissue reveal defective signaling mechanisms of the disease. Surprisingly each Cushing’s mutant engages a different mitogenic signaling pathway, with upregulation of YAP/TAZ by PKAc-L205R and ERK kinase activation by PKAc-W196R. Thus, aberrant spatiotemporal regulation of each Cushing’s variant promotes the transmission of distinct downstream pathogenic signals.
2022-07-12 | PXD030888 | Pride
Project description:Inter-individual differences in cortisol production by the hypothalamus–pituitary–adrenal (HPA) axis are thought to contribute to clinical and pathological heterogeneity of multiple sclerosis (MS). At the same time, accumulating evidence indicates that MS pathogenesis may originate in the normal-appearing white matter (NAWM). Therefore, we performed a genome-wide transcriptional analysis of post-mortem NAWM of 9 control subjects and 18 MS patients to investigate to what extent gene expression reflects disease heterogeneity and HPA-axis activity. Activity of the HPA axis was determined by cortisol levels in cerebrospinal fluid and by numbers of corticotropin-releasing neurons in the hypothalamus, while duration of MS and time to EDSS6 served as indicator of disease severity. Applying weighted gene co-expression network analysis led to the identification of a range of gene modules with highly similar co-expression patterns that strongly correlated with various indicators of HPA-axis activity and/or severity of MS. Interestingly, molecular profiles associated with relatively mild MS and high HPA-axis activity were characterized by increased expression of genes that actively regulate inflammation and by molecules involved in myelination, anti-oxidative mechanism, and neuroprotection. Additionally, group-wise comparisons of gene expression in white matter from control subjects and NAWM from (subpopulations of) MS patients uncovered disease-associated gene expression as well as strongly up- or downregulated genes in patients with relatively benign MS and/or high HPA-axis activity, with many differentially expressed genes being previously undescribed in the context of MS. Overall, the data suggest that HPA-axis activity strongly impacts on molecular mechanisms in NAWM of MS patients, but partly also independently of disease severity.
2019-05-15 | GSE126802 | GEO