Modeling the Interferon Signaling Process of the Immune Response

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Modeling the Interferon Signaling Process of the
Immune Response

• Jeffrey Suhalim
• Dr. Jiayu Liao and Dr. V. G. J. Rodgers
• BRITE

2
Introduction
IFN
Foreign Substance (i.e. Virus)
AV
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Objective

• Develop a mathematical model to describe the
  interferon signaling process
• Use the model to predict the antivirus activity
  response quantitatively
• Significance novel medical treatment for viral
  infection

4
Objective

• Develop a mathematical model to describe the
  interferon signaling process
• Use the model to predict the antivirus activity
  response quantitatively
• Significance novel medical treatment for viral
  infection

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Interferon Signaling Pathway
Antivirus
mRNA
2
Ribosome
1
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Internal Control Mechanisms
2

• JAK Inhibition by SOCS
• reduce the production of STAT dimer

1
2
1 Adapted from Danielle L. Krebs and Douglas J.
Hilton SOCS Proteins Negative Regulators of
Cytokine Signaling (2001)
2 Adapted from David E Levy and J. E. Darnell
Jr. STATs Transcriptional Control and
Biological Impact (2002)
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Internal Control Mechanisms

• SUMOylation by PIAS
• reduce the number of active STAT dimer in the
  nucleus

SUMOylation is modification to a substrate by
conjugating SUMO-protein PIAS (Protein Inhibitor
of Activated STATs) provides specificity to
assist SUMO conjugation to the substrate
2
1
1 Adapted from Ken Shuai and Ben Liu Regulation
of Gene Activation Pathways by PIAS Proteins in
the immune system (2005)
2 Adapted from David E Levy and J. E. Darnell
Jr. STATs Transcriptional Control and
Biological Impact (2002)
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Model

• Lumped Parameter Model
• 3 compartments

Near Surface Region
Ordinary Differential Equation
Cytoplasm
Nucleus
Adapted from David E Levy and J. E. Darnell Jr.
STATs Transcriptional Control and Biological
Impact (2002)
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Mass Transfer

• Constant Flow

C1
F . C1
Cytoplasm
Cytoplasm
Nucleus

• Mass Transfer Coefficient

Nucleus
Figure 1 is adapted from David E Levy and J. E.
Darnell Jr. STATs Transcriptional Control and
Biological Impact (2002)
Cytoplasm
Nucleus
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Model Development
Near Surface Region
1 Adapted from David E Levy and J. E. Darnell
Jr. STATs Transcriptional Control and
Biological Impact (2002)
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Model Development
Near Surface Region
Antivirus
mRNA
1
1 Adapted from David E Levy and J. E. Darnell
Jr. STATs Transcriptional Control and
Biological Impact (2002)
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Model Development
Near Surface Region
Antivirus
PIAS
mRNA
1
1 Adapted from David E Levy and J. E. Darnell
Jr. STATs Transcriptional Control and
Biological Impact (2002)
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Lumped Parameter Model

• Near Surface Region (3 total equations)

1
Near Surface Region
Fig. 1 Adapted from David E Levy and J. E.
Darnell Jr. STATs Transcriptional Control and
Biological Impact (2002)
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Lumped Parameter Model

• Cytoplasm (16 total equations)

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Fig. 1 Adapted from David E Levy and J. E.
Darnell Jr. STATs Transcriptional Control and
Biological Impact (2002)
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Lumped Parameter Model

• Nucleus (8 total equations)

1
Fig. 1 Adapted from David E Levy and J. E.
Darnell Jr. STATs Transcriptional Control and
Biological Impact (2002)
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Current Project

1. Determine values or estimates of unknown
   parameters
2. Experimentally acquire significant unknown
   parameters
3. Develop computational methods for simulation
4. Predict the antivirus activity quantitatively

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Acknowledgement

• Dr. Jiayu Liao and Dr. V. G. J. Rodgers
• Dr. Liaos lab group
• Dr. Rodgers B2K group
• BRITE

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References

• Johnson, Erica S.. 2004. Protein Modification by
  SUMO.. Annu. Rev. Biochem..73, 35582
• Krebs, Danielle L. and Hilton, Douglas J.. 2001.
  SOCS Proteins Negative Regulators of Cytokine
  Signaling. Stem Cells. 19 pp. 378-387
• Levy, David E., and Darnell Jr, J. E.. 2002.
  STATs Transcriptional Control and Biological
  Impact Nature Reviews Molecular Biology. Volume
  III.
• Liao, Jiayu. 1999. Ph.D. thesis, UCLA.
• Rawlings, Jason S., Rosler, Kristin M., and
  Harrison, Douglas A.. 2004. The JAK/STAT
  signaling Pathway. Journal of Cell Science 117
  (8)1281-1283
• Shuai, Ken and Liu, Ben.. 2005. Regulation of
  Gene Activation Pathways by PIAS Proteins in the
  immune system. Nature Reviews Immunology.
• Wormald, Samuel and Hilton, Douglas J.
  Inhibitors of Cytokine Signal Transduction.
  2004. The Journal of Biological Chemistry. Vol.
  279, No. 2, Issue of January 9, pp. 821824

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MATLAB
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Background Information

• Innate immune response
• Cytokine
• Interferon
• JAK-STAT pathway
• STAT dimer ? PKR ? inhibit ribosome ? Apotosis
• Potential application
• Induce the activity of p53
• PCD only when the cell is infected
• ? replace chemotherapy drugs

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JAK-STAT Pathway
1 Adapted from David E Levy and J. E. Darnell
Jr. STATs Transcriptional Control and
Biological Impact (2002)
2 Adapted from Virtual Cell lthttp//vcell.ndsu.n
odak.edu/christjo/vcell/animationSite/translation
/elongation.htmlgt
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SUMOylation by PIAS
The activation and conjugation process will be
assumed to react spontaneously and and thus,
SUMO-UBC9 complex is always available in the
system. The only reaction described in the model
is the ligation The only reaction described in
the model is the ligation Small Ubiquitin
related Modifier (SUMO) Ubiquitin mark protein
for destruction
activation
Isopeptide Bond
conjugation
Ligation
Adapted from Ken Shuai and Ben Liu Regulation of
Gene Activation Pathways by PIAS Proteins in the
immune system (2005)
Sumoylation Post Translational Modification to
a protein (STAT dimers)
PIAS
STAT
STATsumo
peptide bond
SENP
http//en.wikipedia.org/wiki/Peptide_bond