Partner: Ilona Kosiuk


Ostatnie publikacje
1.Jaruszewicz-Błońska J., Kosiuk I., Prus W.J., Lipniacki T., A plausible identifiable model of the canonical NF-κB signaling pathway, PLOS ONE, ISSN: 1932-6203, DOI: 10.1371/journal.pone.0286416, Vol.18, No.6, pp.e0286416-1-26, 2023

Streszczenie:

An overwhelming majority of mathematical models of regulatory pathways, including the intensively studied NF-κB pathway, remains non-identifiable, meaning that their parameters may not be determined by existing data. The existing NF-κB models that are capable of reproducing experimental data contain non-identifiable parameters, whereas simplified models with a smaller number of parameters exhibit dynamics that differs from that observed in experiments. Here, we reduced an existing model of the canonical NF-κB pathway by decreasing the number of equations from 15 to 6. The reduced model retains two negative feedback loops mediated by IκBα and A20, and in response to both tonic and pulsatile TNF stimulation exhibits dynamics that closely follow that of the original model. We carried out the sensitivity-based linear analysis and Monte Carlo-based analysis to demonstrate that the resulting model is both structurally and practically identifiable given measurements of 5 model variables from a simple TNF stimulation protocol. The reduced model is capable of reproducing different types of responses that are characteristic to regulatory motifs controlled by negative feedback loops: nearly-perfect adaptation as well as damped and sustained oscillations. It can serve as a building block of more comprehensive models of the immune response and cancer, where NF-κB plays a decisive role. Our approach, although may not be automatically generalized, suggests that models of other regulatory pathways can be transformed to identifiable, while retaining their dynamical features.

Afiliacje autorów:

Jaruszewicz-Błońska J.-IPPT PAN
Kosiuk I.-IPPT PAN
Prus W.J.-IPPT PAN
Lipniacki T.-IPPT PAN
140p.
2.Korwek Z., Czerkies M.K., Jaruszewicz-Błońska J., Prus W.J., Kosiuk I., Kochańczyk M.R., Lipniacki T., Nonself RNA rewires IFN-β signaling: A mathematical model of the innate immune response, Science Signaling, ISSN: 1945-0877, DOI: 10.1126/scisignal.abq1173, Vol.16, No.815, pp.1-16, 2023

Streszczenie:

Type I interferons (IFNs) are key coordinators of the innate immune response to viral infection, which, through activation of the transcriptional regulators STAT1 and STAT2 (STAT1/2) in bystander cells, induce the expression of IFN-stimulated genes (ISGs). Here, we showed that in cells transfected with poly(I:C), an analog of viral RNA, the transcriptional activity of STAT1/2 was terminated because of depletion of the interferon-β (IFN-β) receptor, IFNAR. Activation of RNase L and PKR, products of two ISGs, not only hindered the replenishment of IFNAR but also suppressed negative regulators of IRF3 and NF-κB, consequently promoting IFNB transcription. We incorporated these findings into a mathematical model of innate immunity. By coupling signaling through the IRF3–NF-κB and STAT1/2 pathways with the activities of RNase L and PKR, the model explains how poly(I:C) switches the transcriptional program from being STAT1/2 induced to being IRF3 and NF-κB induced, which converts IFN-β–responding cells to IFN-β–secreting cells.

Afiliacje autorów:

Korwek Z.-IPPT PAN
Czerkies M.K.-IPPT PAN
Jaruszewicz-Błońska J.-IPPT PAN
Prus W.J.-IPPT PAN
Kosiuk I.-IPPT PAN
Kochańczyk M.R.-IPPT PAN
Lipniacki T.-IPPT PAN
140p.