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Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing
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| Zeitschriftentitel: | Gene Regulation and Systems Biology |
|---|---|
| Personen und Körperschaften: | , , , , , |
| In: | Gene Regulation and Systems Biology, 13, 2019, S. 117762501984028 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
SAGE Publications
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| Schlagwörter: |
| author_facet |
Acevedo, Alison Berthel, Ana DuBois, Debra Almon, Richard R Jusko, William J Androulakis, Ioannis P Acevedo, Alison Berthel, Ana DuBois, Debra Almon, Richard R Jusko, William J Androulakis, Ioannis P |
|---|---|
| author |
Acevedo, Alison Berthel, Ana DuBois, Debra Almon, Richard R Jusko, William J Androulakis, Ioannis P |
| spellingShingle |
Acevedo, Alison Berthel, Ana DuBois, Debra Almon, Richard R Jusko, William J Androulakis, Ioannis P Gene Regulation and Systems Biology Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing Computer Science Applications Genetics Molecular Biology Ecology, Evolution, Behavior and Systematics |
| author_sort |
acevedo, alison |
| spelling |
Acevedo, Alison Berthel, Ana DuBois, Debra Almon, Richard R Jusko, William J Androulakis, Ioannis P 1177-6250 1177-6250 SAGE Publications Computer Science Applications Genetics Molecular Biology Ecology, Evolution, Behavior and Systematics http://dx.doi.org/10.1177/1177625019840282 <jats:p> Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway. </jats:p> Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing Gene Regulation and Systems Biology |
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| title |
Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_unstemmed |
Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_full |
Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_fullStr |
Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_full_unstemmed |
Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_short |
Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_sort |
pathway-based analysis of the liver response to intravenous methylprednisolone administration in rats: acute versus chronic dosing |
| topic |
Computer Science Applications Genetics Molecular Biology Ecology, Evolution, Behavior and Systematics |
| url |
http://dx.doi.org/10.1177/1177625019840282 |
| publishDate |
2019 |
| physical |
117762501984028 |
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<jats:p> Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway. </jats:p> |
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| description | <jats:p> Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway. </jats:p> |
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| spelling | Acevedo, Alison Berthel, Ana DuBois, Debra Almon, Richard R Jusko, William J Androulakis, Ioannis P 1177-6250 1177-6250 SAGE Publications Computer Science Applications Genetics Molecular Biology Ecology, Evolution, Behavior and Systematics http://dx.doi.org/10.1177/1177625019840282 <jats:p> Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway. </jats:p> Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing Gene Regulation and Systems Biology |
| spellingShingle | Acevedo, Alison, Berthel, Ana, DuBois, Debra, Almon, Richard R, Jusko, William J, Androulakis, Ioannis P, Gene Regulation and Systems Biology, Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing, Computer Science Applications, Genetics, Molecular Biology, Ecology, Evolution, Behavior and Systematics |
| title | Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_full | Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_fullStr | Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_full_unstemmed | Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_short | Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| title_sort | pathway-based analysis of the liver response to intravenous methylprednisolone administration in rats: acute versus chronic dosing |
| title_unstemmed | Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing |
| topic | Computer Science Applications, Genetics, Molecular Biology, Ecology, Evolution, Behavior and Systematics |
| url | http://dx.doi.org/10.1177/1177625019840282 |