Mathematical Modelling of Interleukin-6 induced JAK/STAT Pathway.
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
The signal transduction process in a cell play the main role to transmit in formation from the outside of the cell to the inside of the cell. There are different signal transduction pathways of which three pathways (Akt/PKB signalling pathway, JAK/STAT signalling pathway and MAPK/ERK signalling pathway) are interleukin-6 (IL-6) induced. When keratinocyte HaCaT A5 and fibroblast MSU-1.1 cell lines are induced by IL-6, it is experimentally seen that fibroblast MSU cells have no proliferation, whereas keratinocyte HaCaT cells proliferate. One or more signalling pathways may be involved leading to this observation. When JAK/STAT3 pathway was induced with IL-6 in the two different human cell lines, differences in the dynamics of different species of the pathway were observed. Here, the differences in dynamics of JAK/STAT3 pathway has been explained by data-based modelling using ordinary differential equations. According to the model, differences in SOCS3 gene expression, gp130 and/or STAT3 inhibition by SOCS3 and dephosphorylation of gp130 can explain observed dynamics in keratinocyte HaCaT and fibroblast MSU cells. Although the rate of SOCS3 gene expression in fibroblast MSU cells is more than two times higher than in keratinocyte HaCaT cells, the level of SOCS3 protein concentration in fibroblast MSU is half the SOCS3 protein concentration in keratinocyte HaCaT. This is because of about 20 times stronger negative feedback regulation by SOCS3 in fibroblast MSU than in keratinocyte HaCaT. The identifiability analysis of model parameters show that all of the parameters are structurally identifiable, and most of the parameters are also practically identifiable, making our model very predictive. According to the sensitivity analysis of the model parameters, mean sensitivity of phosphorylated STAT3 import into the nucleus and SOCS3 translation are high in keratinocyte HaCaT in contrast to fibroblast MSU, where SOCS3 gene expression and SOCS3 translation are most sensitive.
Place, publisher, year, edition, pages
Trita-CSC-E, ISSN 1653-5715 ; 2011:145
IdentifiersURN: urn:nbn:se:kth:diva-130794OAI: oai:DiVA.org:kth-130794DiVA: diva2:654241
Master of Science - Computational and Systems Biology