Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Network Balances and Timing Constraints Critical to the Hepatic Stellate Cell Activation Process
Abstract
:1. Introduction
2. Methods
3. Results and Discussion
3.1. microRNAs as Markers of Hepatic Stellate Cell Molecular Phenotypes
3.2. Integrated Model of Signaling and microRNA Regulation
3.2.1. Model of the IL-1/NF-κB Pathway
3.2.2. Model of the IL-6/STAT3 Pathway
3.2.3. Model of the TGF-β/SMAD Pathway
3.3. Crosstalk between Signaling Pathways and Effect on microRNA Levels
3.4. Effects of Timing Differences in NF-κB and STAT3 Activation
3.5. Re-Quiescence from the Activated HSC State
4. Conclusions
Acknowledgments
Author Contributions
Appendix
Reaction | Equation | Parameters |
---|---|---|
IL-1/IL-1R association | k1[IL1][IL1R] | k1 = 0.001 |
IL-1/IL-1R dissociation | | |
IL-1 degradation | k2[IL1] | k2 = 0.001 |
IL-1/IL-1R degradation | k3[IL1/IL1R] | k3 = 0.01 |
PELI1/TRAF6 activation | k4[IL1/IL1R] − k5[miR21] − k6[miR146a] | k4 = 0.5 |
PELI1/TRAF6 degradation | k7[PELI1/TRAF6] | k7 = 0.1 |
NF-κBinactive production | k8 | k8 = 0.3 |
NF-κB activation | | v1 = 0.5 |
NF-κBinactive degradation | k10[NFκBinactive] | k10 = 0.003 |
NF-κBactive inactivation | k11[NFκBactive] | k11 = 0.1 |
NF-κBactive degradation | k12[NFκBactive] | k12 = 0.01 |
IL-6/IL-6R association | k13[IL6][IL6R] | k13 = 0.001 |
IL-6/IL-6R dissociation | | |
IL-6 degradation | k14[IL6] | k14 = 0.001 |
IL-6/IL-6R degradation | k15[IL6/IL6R] | k15 = 0.01 |
STAT3 phosphorylation | | v2 = 0.008 |
STAT3 production | k18 | k18 = 0.08 |
STAT3 degradation | k19[STAT3] | k19 = 0.0008 |
pSTAT3 degradation | | v3 = 0.025 |
SOCS3 production | | v4 = 0.1 |
SOCS3 degradation | k22[SOCS3] | k22 = 0.001 |
TGF-β production | k23[pSTAT3] | k23 = 0.04 |
TGF-β degradation | k24[TGFβ] | k24 = 0.001 |
TGF-β/TβR1 association | k25[TGFβ][TβRI] | k25 = 0.001 |
TGF-β/TβR1 dissociation | | |
TGF-β/TβR1 degradation | k26[TGFβ/TβRI] + k27[SMAD7/SMURF2] | k26 = 0.01 |
SMAD2 production | k28 | k28 = 0.01 |
SMAD2 phosphorylation | | v5 = 10 |
SMAD2 dephosphorylation | | v6 = 0.001 |
pSMAD2 degradation | k33[pSMAD2] | k33 = 0.0005 |
SMAD4 production | k34 − k35[miR146a] | k34 = 0.024 |
SMAD4 degradation | k36[SMAD4] | k36 = 0.0001 |
SMAD7 production | k39 + k40[pSMAD2/SMAD4] − k41[miR21] | k39 = 0.057 |
SMAD7 degradation | k42[SMAD7] | k42 = 0.001 |
SMURF2 production | k43 + k44[pSMAD2/SMAD4] | k43 = 0.05 |
SMURF2 degradation | k45[SMURF2] | k45 = 0.001 |
miR-21 activation | k50 + k51[NFκBactive ] + k52[pSTAT3] + k53[FG] | k50 = 0.75 |
miR-146a activation | k54 + k55[NFκBactive ] − k56[FG] | k54 = 2 |
miR-21 degradation | k57[miR21] | k57 = 0.01 |
Conflicts of Interest
References
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Kuttippurathu, L.; Parrish, A.; Vadigepalli, R. Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Network Balances and Timing Constraints Critical to the Hepatic Stellate Cell Activation Process. Processes 2014, 2, 773-794. https://doi.org/10.3390/pr2040773
Kuttippurathu L, Parrish A, Vadigepalli R. Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Network Balances and Timing Constraints Critical to the Hepatic Stellate Cell Activation Process. Processes. 2014; 2(4):773-794. https://doi.org/10.3390/pr2040773
Chicago/Turabian StyleKuttippurathu, Lakshmi, Austin Parrish, and Rajanikanth Vadigepalli. 2014. "Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Network Balances and Timing Constraints Critical to the Hepatic Stellate Cell Activation Process" Processes 2, no. 4: 773-794. https://doi.org/10.3390/pr2040773
APA StyleKuttippurathu, L., Parrish, A., & Vadigepalli, R. (2014). Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Network Balances and Timing Constraints Critical to the Hepatic Stellate Cell Activation Process. Processes, 2(4), 773-794. https://doi.org/10.3390/pr2040773